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Clinical Trial Results:
An open-label, multi-center, sINGlE arm clinical study to evaluate treatment efficacy and quality of life in women with hormone-receptor-positive, HER2-negative loco-regionally recurrent or metastatic breast cancer receiving palbociclib (PD 0332991) in combination with an aromatase inhibitor, or fulvestrant after prior endocrine therapy (INGE-B)

Summary
EudraCT number	2015-001603-32
Trial protocol	DE
Global end of trial date	15 Feb 2023

Results information
Results version number	v1(current)
This version publication date	06 Jan 2024
First version publication date	06 Jan 2024
Other versions
Summary report(s)	INGE-B_CSR_Synopsis

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

iOM-04318

ISRCTN number

US NCT number

NCT02894398

WHO universal trial number (UTN)

Sponsor organisation name

iOMEDICO AG

Sponsor organisation address

Ellen-Gottlieb-Str. 19, Freiburg, Germany, 79106

Public contact

Clinical Trial Information Desk, iOMEDICO AG, +49 761152420, info@iomedico.com

Scientific contact

Clinical Trial Information Desk, iOMEDICO AG, +49 761152420, info@iomedico.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Sep 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 Dec 2022

Global end of trial reached?

Yes

Global end of trial date

15 Feb 2023

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of palbociclib in addition to an aromatase inhibitor or fulvestrant after prior endocrine therapy in pre-/perimenopausal and postmenopausal women with HR+/HER2- advanced breast cancer (locally advanced, inoperable or metastatic) as first or later-line of treatment.

Protection of trial subjects

This study was planned, conducted, and analyzed according to the protocol and in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP)-guidelines “Note for Good Clinical Practice” (CPMP/ICH/135/95) based on the principles laid down in the Declaration of Helsinki (1964) and its amendments (latest amendment Fortaleza, Brazil, 2013). The study was duly conducted in compliance with the Arzneimittelgesetz (AMG; Medicinal Products Act/German Drug Law), and the corresponding Directive 2001/20/EC. Essential documents will be retained in accordance with the ICH-GCP. Informed consent (signed ICF) was obtained from each patient by the investigator prior to inclusion of the patient into the study in accordance with § 40 I 3 No. 3 Lit. b), II 1 AMG and § 40 I 3 No. 3 Lit. c), IIa 1&2 AMG. The nature, objective and importance of the study, the possible benefits and disadvantages or risks, and the study procedures were explained to each patient orally and in writing. The patients were informed that their participation was voluntary, that they were free to withdraw from the study at any time, and that choosing not to participate would not impact on the patient’s care or future treatment.

Background therapy

Initially, the phase II study assessed palbociclib and letrozole in two patient groups (as first-line treatment and as later-line treatment). Following the marketing approval of the combination of Palbociclib and an aromatase inhibitor, or palbociclib and fulvestrant after prior endocrine therapy in the European Union (November 2016), all study drugs were available on prescription by the treating physician. The investigators were advised to refer to the current applicable version of the German SmPC of respective study drug. The starting dose of respective drug and mode of administration were as follows: AI: given orally on a continuous daily schedule (on days 1 to 28 of a 28-day cycle): o Letrozole: 2.5 mg once daily. o Anastrozole: 1 mg once daily. o Exemestane: 25 mg once daily. Fulvestrant: 500 mg given on days 1, 15 and 29 (cycle 1 only), thereafter once per 28-day cycle (intramuscular injection) In pre- or perimenopausal women, ET had to be combined with a luteinizing hormone-releasing (LHRH) agonist.

Evidence for comparator

Not applicable (no comparators). The treatment groups were not compared to each other but analyzed separately.

Actual start date of recruitment

06 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 388

Worldwide total number of subjects

388

EEA total number of subjects

388

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

188

From 65 to 84 years

197

85 years and over

Subject disposition

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Recruitment details

Eligible patients were scheduled for the combination treatment of palbociclib with the respective endocrine partner by the treating physician and were treated until progressive disease (PD), intolerable toxicity, withdrawal of informed consent, or death. As soon as 60 eligible patients were enrolled into a respective group, it was was closed.

Screening details

Patients were screened for eligibility within one month prior to first administration of study treatment. Specific assessments had to be performed within one week prior to first administration of study treatment.

Number of subjects started

388

Number of subjects completed

350

Reason: Number of subjects

Screening failure: 27

Reason: Number of subjects

Consent withdrawn by subject: 7

Reason: Number of subjects

Lost to follow-up: 1

Reason: Number of subjects

Protocol deviation: 1

Reason: Number of subjects

other: 2

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Not applicable. This was an non-randomized, multi-center open label clinical trial.

Are arms mutually exclusive

Yes

TG1 (LET1)

Arm description

Palbociclib and letrozole as first-line therapy

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD-0332991

Other name

IBRANCE®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

According to SmPC: Palbociclib was orally administered once a day at 125 mg for 21 days followed by 7 days off treatment for each 28-day cycle (schedule 3/1). Oral study drugs were self-administered by the patient. The site personnel ensured that patients clearly understand the directions for self-medication.

Investigational medicinal product name

Letrozole

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

According to SmPC: The dose of letrozole according was 2.5 mg taken orally once daily continuously throughout the 28-day cycle. Oral study drugs were self-administered by the patient. The site personnel ensured that patients clearly understand the directions for self-medication. In pre- or perimenopausal women, the endocrine therapy had to be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

TG2 (LET2+)

Arm description

Palbociclib and letrozole as second- or later-line therapy

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD-0332991

Other name

IBRANCE®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Letrozole

Investigational medicinal product code

ATC-Code: L02BG04

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

TG3 (FUL1)

Arm description

Palbociclib and fulvestrant as first-line therapy after prior endocrine therapy (adjuvant).

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD-0332991

Other name

IBRANCE®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

ATC-Code: L02BA03

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

According to SmPC: The dose of fulvestrant was 500 mg administered intramuscularly on Days 1, 15 of the first cycle, and once monthly (Day 1) thereafter. In pre- or perimenopausal women, the endocrine therapy had to be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

TG4 (FUL2+)

Arm description

Palbociclib and fulvestrant as second- or later-line therapy after prior endocrine therapy (adjuvant and/or palliative).

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD-0332991

Other name

IBRANCE®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

ATC-Code: L02BA03

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

TG5 (ANA1)

Arm description

Palbociclib and anastrozole as first-line therapy

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD-0332991

Other name

IBRANCE®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Anastrozole

Investigational medicinal product code

ATC-Code: L02BG03

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

According to SmPC: Anastrozole was administered orally at 1 mg once daily as continuous daily dosing schedule according to the SmPC. Oral study drugs were self-administered by the patient. The site personnel ensured that patients clearly understand the directions for self-medication. In pre- or perimenopausal women, the endocrine therapy had to be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

TG6 (EXE1)

Arm description

Palbociclib and exemestane as first-line therapy

Arm type

Experimental

Investigational medicinal product name

Palbociclib

Investigational medicinal product code

PD-0332991

Other name

IBRANCE®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Exemestane

Investigational medicinal product code

ATC Code L02BG0

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

According to SmPC: Exemestane was administered orally at 25 mg once daily as continuous daily dosing schedule Oral study drugs were self-administered by the patient. The site personnel ensured that patients clearly understand the directions for self-medication. In pre- or perimenopausal women, the endocrine therapy has to be combined with a luteinizing hormone releasing hormone (LHRH) agonist.

Number of subjects in period 1 ^[1]	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)
Started	62	60	50	61	60	57
Completed	43	47	35	47	52	50
Not completed	19	13	15	14	8	7
Consent withdrawn by subject	9	3	5	1	1	3
other	2	1	1	1	-	1
Lost to follow-up	6	6	7	6	7	3
Administrative reason	2	3	2	6	-	-

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: 388 patients were enrolled/screened; 351 patients were treated (= SAF, Safety analysis population); 350 patients were analysed (FAS, Full analysis set).

Baseline characteristics

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Reporting group title

TG1 (LET1)

Reporting group description

Palbociclib and letrozole as first-line therapy

Reporting group title

TG2 (LET2+)

Reporting group description

Palbociclib and letrozole as second- or later-line therapy

Reporting group title

TG3 (FUL1)

Reporting group description

Palbociclib and fulvestrant as first-line therapy after prior endocrine therapy (adjuvant).

Reporting group title

TG4 (FUL2+)

Reporting group description

Palbociclib and fulvestrant as second- or later-line therapy after prior endocrine therapy (adjuvant and/or palliative).

Reporting group title

TG5 (ANA1)

Reporting group description

Palbociclib and anastrozole as first-line therapy

Reporting group title

TG6 (EXE1)

Reporting group description

Palbociclib and exemestane as first-line therapy

Reporting group values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Total
Number of subjects	62	60	50	61	60	57	350
Age categorical
Units: Subjects
Adults (18-64 years)	25	41	16	26	35	30	173
From 65-84 years	36	19	33	35	25	26	174
85 years and over	1	0	1	0	0	1	3
Age continuous
Units: years
median (full range (min-max))	67.3 (31.7 to 87.4)	60.9 (33.2 to 80.4)	69.8 (45.8 to 87.0)	68.4 (38.0 to 82.3)	63.4 (38.6 to 82.4)	64.8 (38.2 to 86.2)	-
Gender categorical
Units: Subjects
Female	62	60	50	61	60	57	350
ECOG Performance Status
Units: Subjects
Grade 0	37	39	25	29	43	28	201
Grade 1	22	20	23	27	17	26	135
Grade 2	3	1	2	5	0	2	13
Grade 3	0	0	0	0	0	0	0
Grade 4	0	0	0	0	0	0	0
Missing	0	0	0	0	0	1	1
Primary Tumor localization at Primary Diagnosis
Units: Subjects
Left	29	30	23	29	26	30	167
Right	29	26	22	27	31	24	159
Bilateral	4	4	5	5	3	2	23
Unknown	0	0	0	0	0	1	1
TNM (Tumor sizes) at Primary Diagnosis
Units: Subjects
Tis	1	1	1	0	0	0	3
T1	15	18	15	17	19	12	96
T2	24	29	27	19	24	24	147
T3	8	3	4	6	5	8	34
T4	12	2	3	11	7	8	43
Tx	2	7	0	8	5	5	27
TNM (Lymph nodes) at Primary Diagnosis
Units: Subjects
N0	16	21	20	14	12	15	98
N1	19	18	14	22	25	18	116
N2	16	8	9	7	9	11	60
N3	7	5	5	7	5	6	35
NX	4	8	2	11	9	7	41
TNM (Metastases) at Primary Diagnosis
Units: Subjects
M0	40	44	44	33	31	38	230
M1	20	15	4	27	26	17	109
MX	2	1	2	1	3	2	11
Tumor Stage (AJCC) at Primary Diagnosis
Units: Subjects
Stage 0	1	1	1	0	0	0	3
Stage I	9	8	6	8	5	5	41
Stage IIA	5	14	16	6	6	8	55
Stage IIB	7	5	9	8	9	7	45
Stage IIIA	12	8	7	5	5	10	47
Stage IIIB	2	0	0	1	1	3	7
Stage IIIC	2	3	4	3	0	3	15
Stage IV	22	16	6	28	29	19	120
Missing	2	5	1	2	5	2	17
Presence of Distant Metastases at Primary Diagnosis
Units: Subjects
Yes	20	15	4	27	26	16	108
No	40	44	44	33	31	38	230
Missing	2	1	2	1	3	3	12
Presence of Inoperable Tumor at Primary Diagnosis
Units: Subjects
Yes	10	10	2	17	20	15	74
No	52	50	48	44	40	42	276
Resection of Primary Tumor
Units: Subjects
Yes	48	53	45	44	33	39	262
No	14	7	5	17	27	18	88
Resection Outcome
Units: Subjects
R0	43	45	36	36	26	34	220
R1	1	4	4	1	4	2	16
R2	0	0	0	0	0	0	0
RX	4	4	5	7	3	3	26
Not applicable	14	7	5	17	27	18	88
Histology of Primary Tumor
Units: Subjects
Invasive ductal	43	38	38	31	37	43	230
Invasive lobular	8	11	6	18	14	9	66
Inflammatory	0	1	0	0	0	0	1
Other	11	10	6	12	9	5	53
Tumor Grading at Primary Diagnosis
Units: Subjects
G1	3	7	2	4	2	3	21
G2	45	42	35	37	40	39	238
G3	11	6	11	14	12	11	65
G4	0	1	0	0	0	0	1
GX	3	4	2	6	6	4	25
HER2 Status at Inclusion
Units: Subjects
Negative	61	60	50	61	60	57	349
Unknown	1	0	0	0	0	0	1
HR Status at Inclusion
Units: Subjects
Positive	62	60	50	61	60	57	350
Measurability and Bone-only Metastatic Status at Inclusion
Units: Subjects
Measurable disease - bone-only	3	2	2	6	4	2	19
Measurable disease - non-bone-only	46	49	32	38	33	41	239
Non-Measurable disease - bone-only	12	8	16	16	20	11	83
Non-Measurable disease - non-bone-only	1	1	0	1	3	3	9
Prior Endocrine Therapy
Units: Subjects
Yes	37	57	47	61	24	38	264
No	25	3	3	0	36	19	86
Prior Targeted Therapy
Units: Subjects
Yes	1	16	1	9	2	1	30
No	61	44	49	52	58	56	320
Prior Chemotherapy
Units: Subjects
Yes	29	45	33	38	23	27	195
No	33	15	17	23	37	30	155
Prior Radiotherapy
Units: Subjects
Yes	42	48	40	51	29	35	245
No	20	12	10	10	31	22	105
BMI
Units: kg/m2
median (full range (min-max))	25.7 (16.0 to 39.2)	25.7 (17.0 to 46.6)	25.8 (16.7 to 39.9)	26.0 (17.7 to 44.1)	26.0 (17.6 to 44.0)	26.5 (14.1 to 42.9)	-
Treatment Free Interval (TFI) - FAS
TFI was defined as interval between end of last (neo)adjuvant therapy (or, if unavailable, date of last tumor resection) to first date of diagnosis of relapse after, or, if unavailable, to last date of diagnosis prior to end of last (neo)adjuvant therapy. 121 pts without distant metastasis or locally advanced/inoperable/not complete resectable tumor at primary diagnosis were evaluable. TFI (FAS) ≤12 m: TG1 (n=19): 45.2%; TG3 (n=22): 48.9%; TG5 (n=14): 41,2%; TG6 (n=16): 40.0% TFI (FAS) >12 m: TG1 (n=14): 33.3%; TG3 (n=13): 28.9%; TG5 (n=11): 32.4%; TG6 (n=12): 30.0% 000 = Not applicable
Units: months
arithmetic mean (standard deviation)	38.1 ± 66.016	000 ± 000	20.3 ± 32.903	000 ± 000	32.59 ± 52.648	24.77 ± 38.926	-
Treatment Free Interval (TFI) - mPP
TFI was defined as interval between end of last (neo)adjuvant therapy (or, if unavailable, date of last tumor resection) to first date of diagnosis of relapse after, or, if unavailable, to last date of diagnosis prior to end of last (neo)adjuvant therapy. 47 pts without distant metastasis or locally advanced/inoperable/not complete resectable tumor at primary diagnosis were evaluable. TFI (FAS) ≤12 m: TG5 (n=13): 44.8%; TG6 (n=15): 39.5% TFI (FAS) >12 m: TG5 (n=8): 27.6%; TG6 (n=11): 28.9% 000 = Not applicable
Units: months
arithmetic mean (standard deviation)	000 ± 000	000 ± 000	000 ± 000	000 ± 000	28.9 ± 39.012	25.1 ± 40.002	-

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS comprised all patients who received at least one dose of palbociclib and the respective endocrine partner and was the relevant population for all analyses but safety analyses.

Subject analysis set title

Modified per-protocol set (mPP)

Subject analysis set type

Per protocol

Subject analysis set description

The mPP comprised all patients who received palbociclib plus anastrozole or palbociclib plus exemestane as first-line treatment in the palliative setting. The rationale for this set was the inclusion of patients into recruitment group 2 and 3 [i.e., treatment groups TG5 (ANA1) and TG6 (EXE1)] who received palbociclib plus AI in later-line treatment instead of first-line treatment according to study protocol. No other protocol deviations were considered as relevant for the mPP. Selected analyses of the FAS were performed additionally with the mPP set.

Subject analysis sets values	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects	350	107
Age categorical
Units: Subjects
Adults (18-64 years)	173	60
From 65-84 years	174	47
85 years and over	3	0
Age continuous
Units: years
median (full range (min-max))	65.4 (31.7 to 87.4)	63.5 (38.2 to 82.4)
Gender categorical
Units: Subjects
Female	350	107
ECOG Performance Status
Units: Subjects
Grade 0	201	68
Grade 1	135	36
Grade 2	13	2
Grade 3	0	0
Grade 4	0	0
Missing	1	1
Primary Tumor localization at Primary Diagnosis
Units: Subjects
Left	167	48
Right	159	52
Bilateral	23	5
Unknown	1	1
TNM (Tumor sizes) at Primary Diagnosis
Units: Subjects
Tis	3	0
T1	96	27
T2	147	44
T3	34	13
T4	43	14
Tx	27	9
TNM (Lymph nodes) at Primary Diagnosis
Units: Subjects
N0	98	26
N1	116	38
N2	60	18
N3	35	10
NX	41	15
TNM (Metastases) at Primary Diagnosis
Units: Subjects
M0	230	62
M1	109	40
MX	11	5
Tumor Stage (AJCC) at Primary Diagnosis
Units: Subjects
Stage 0	3	0
Stage I	41	9
Stage IIA	55	12
Stage IIB	45	15
Stage IIIA	47	14
Stage IIIB	7	4
Stage IIIC	15	2
Stage IV	120	45
Missing	17	6
Presence of Distant Metastases at Primary Diagnosis
Units: Subjects
Yes	108	39
No	230	62
Missing	12	6
Presence of Inoperable Tumor at Primary Diagnosis
Units: Subjects
Yes	74	33
No	276	74
Resection of Primary Tumor
Units: Subjects
Yes	262	66
No	88	41
Resection Outcome
Units: Subjects
R0	220	55
R1	16	6
R2	0	0
RX	26	5
Not applicable	88	41
Histology of Primary Tumor
Units: Subjects
Invasive ductal	230	72
Invasive lobular	66	23
Inflammatory	1	0
Other	53	12
Tumor Grading at Primary Diagnosis
Units: Subjects
G1	21	5
G2	238	71
G3	65	21
G4	1	0
GX	25	10
HER2 Status at Inclusion
Units: Subjects
Negative	249	107
Unknown	1	0
HR Status at Inclusion
Units: Subjects
Positive	350	107
Measurability and Bone-only Metastatic Status at Inclusion
Units: Subjects
Measurable disease - bone-only	19	6
Measurable disease - non-bone-only	239	68
Non-Measurable disease - bone-only	83	28
Non-Measurable disease - non-bone-only	9	5
Prior Endocrine Therapy
Units: Subjects
Yes	264	55
No	86	52
Prior Targeted Therapy
Units: Subjects
Yes	30	1
No	320	106
Prior Chemotherapy
Units: Subjects
Yes	195	43
No	155	64
Prior Radiotherapy
Units: Subjects
Yes	245	57
No	105	50
BMI
Units: kg/m2
median (full range (min-max))	26.04 (14.1 to 46.6)	26.2 (14.1 to 44.0)
Treatment Free Interval (TFI) - FAS
TFI was defined as interval between end of last (neo)adjuvant therapy (or, if unavailable, date of last tumor resection) to first date of diagnosis of relapse after, or, if unavailable, to last date of diagnosis prior to end of last (neo)adjuvant therapy. 121 pts without distant metastasis or locally advanced/inoperable/not complete resectable tumor at primary diagnosis were evaluable. TFI (FAS) ≤12 m: TG1 (n=19): 45.2%; TG3 (n=22): 48.9%; TG5 (n=14): 41,2%; TG6 (n=16): 40.0% TFI (FAS) >12 m: TG1 (n=14): 33.3%; TG3 (n=13): 28.9%; TG5 (n=11): 32.4%; TG6 (n=12): 30.0% 000 = Not applicable
Units: months
arithmetic mean (standard deviation)	000 ± 000	000 ± 000
Treatment Free Interval (TFI) - mPP
TFI was defined as interval between end of last (neo)adjuvant therapy (or, if unavailable, date of last tumor resection) to first date of diagnosis of relapse after, or, if unavailable, to last date of diagnosis prior to end of last (neo)adjuvant therapy. 47 pts without distant metastasis or locally advanced/inoperable/not complete resectable tumor at primary diagnosis were evaluable. TFI (FAS) ≤12 m: TG5 (n=13): 44.8%; TG6 (n=15): 39.5% TFI (FAS) >12 m: TG5 (n=8): 27.6%; TG6 (n=11): 28.9% 000 = Not applicable
Units: months
arithmetic mean (standard deviation)	000 ± 000	000 ± 000

End points

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Reporting group title

TG1 (LET1)

Reporting group description

Palbociclib and letrozole as first-line therapy

Reporting group title

TG2 (LET2+)

Reporting group description

Palbociclib and letrozole as second- or later-line therapy

Reporting group title

TG3 (FUL1)

Reporting group description

Palbociclib and fulvestrant as first-line therapy after prior endocrine therapy (adjuvant).

Reporting group title

TG4 (FUL2+)

Reporting group description

Palbociclib and fulvestrant as second- or later-line therapy after prior endocrine therapy (adjuvant and/or palliative).

Reporting group title

TG5 (ANA1)

Reporting group description

Palbociclib and anastrozole as first-line therapy

Reporting group title

TG6 (EXE1)

Reporting group description

Palbociclib and exemestane as first-line therapy

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS comprised all patients who received at least one dose of palbociclib and the respective endocrine partner and was the relevant population for all analyses but safety analyses.

Subject analysis set title

Modified per-protocol set (mPP)

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Clinical Benefit Rate (CBR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

Clinical Benefit Rate (CBR) - Patients with measurable disease (calculated acc. to RECIST 1.1) ^[1]

End point description

For the analysis of the primary endpoint, only the Best Overall Response (BOR) calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was evaluated. The analysis was performed for each treatment subgroup separately. No formal comparison was performed. ****************************** Clinical Benefit Rate (CBR % [95% CI]): FAS (N=258): TG1 (LET1): 71.4% [56.7, 83.4] TG2 (LET2+): 45.1% [31.1, 59.7] TG3 (FUL1): 58.8% [40.7, 75.4] TG4 (FUL2+): 40.9 % [26.3, 56.8] TG5 (ANA1): 56.8% [39.5, 72.9] TG6 (EXE1): 65.1% [49.1, 79.0] ****************************** mPP (N=74): TG5 (ANA1): 56.2% [37.7, 73.6] TG6 (EXE1): 64.3% [48.0, 78.4] ****************************** Total (FAS): 56.2% [49.9, 62.3] Total (mPP: 60.8% [48.8, 72.0] ******************************

End point type

Primary

End point timeframe

CBR was defined as proportion of pts with BOR (CR, PR or stable disease (SD) for ≥ 24 weeks from first day of study drug administration) relative to all pts with measurable disease at baseline for ≥ 24 weeks from day of first study drug administration.

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the exploratory nature of the study, no formal hypotheses for the primary objective was given (the analysis was done descriptively).

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49	51	34	44	37	43	258	74
Units: Patients
number (not applicable)	35	23	20	18	37	28	145	45

No statistical analyses for this end point

Primary: Best Overall Response Rate (BOR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

Best Overall Response Rate (BOR) - Patients with measurable disease (calculated acc. to RECIST 1.1) ^[2]

End point description

BOR was defined as the proportion of patients with best overall response (CR or PR or stable disease (SD) for ≥ 24 weeks. For the analysis of the primary endpoint (CBR), only the Best Overall Response (BOR) calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was evaluated.

End point type

Primary

End point timeframe

Tumor response (BOR) was evaluated after 24 weeks from day of first study drug administration.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[3]	51 ^[4]	34 ^[5]	44 ^[6]	37 ^[7]	43 ^[8]	258 ^[9]	74 ^[10]
Units: Patients
CR	2	0	1	1	0	3	7	3
PR	28	8	14	12	16	17	95	31
SD >=24 wks	5	15	5	5	5	8	43	11
SD < 24 wks	6	3	4	11	6	9	39	15
PD	6	21	8	8	8	6	57	12
NE	0	1	0	0	0	0	1	0
Missing	2	3	2	7	2	0	16	2

Notes
[3] - CR: 4.1%; PR: 57.1%; SD≥24: 10.2%; SD<24: 12.2%; PD: 12.3%; NE: 0.0%; Missing: 4.1%
[4] - CR: 0.0%; PR: 15.7%; SD≥24: 29.4%; SD<24: 5.9%; PD: 41.2%; NE: 2.0%; Missing: 5.9%
[5] - CR: 2.9%; PR: 41.2%; SD≥24: 14.7%; SD<24: 11.8%; PD: 23.5%; NE: 0.0%; Missing: 5.9%
[6] - CR: 2.3%; PR: 27.3%; SD≥24: 11.4%; SD<24: 25.0%; PD: 18.2%; NE: 0.0%; Missing: 15.9%
[7] - CR: 0.0%; PR: 43.2%; SD≥24: 13.5%; SD<24: 16.2%; PD: 21.6%; NE: 0.0%; Missing: 5.4%
[8] - CR: 7.0%; PR: 39.5%; SD≥24: 18.6%; SD<24: 20.9%; PD: 14.0%; NE: 0.0%; Missing: 0.0%
[9] - CR: 2.7%; PR: 36.8%; SD≥24: 16.7%; SD<24: 15.1%; PD: 22.1%; NE: 0.4%; Missing: 6.2%
[10] - CR: 4.1%; PR: 41.9%; SD≥24: 14.9%; SD<24: 20.3%; PD: 16.3%; NE: 0.0%; Missing: 2.7%

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CBR) - Patients with measurable disease (IA)

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End point title

Clinical Benefit Rate (CBR) - Patients with measurable disease (IA)

End point description

For the analysis of the secondary endpoint, the Best Overall Response (BOR) in patients with measurable disease according to investigator assessment (IA) was evaluated. The analysis was performed for each treatment subgroup separately. No formal comparison was performed. ****************************** Clinical Benefit Rate (CBR % [95% CI]): FAS (N=258): TG1 (LET1): 75.5% [61.1, 86.7] TG2 (LET2+): 45.1% [31.1, 59.7] TG3 (FUL1): 61.8% [43.6, 77.8] TG4 (FUL2+): 45.5% [30.4, 61.2] TG5 (ANA1): 70.3% [53.0, 84.1] TG6 (EXE1): 74.4% [58.8, 86.5] ****************************** mPP (N=74): TG5 (ANA1): 71.9% [53.3, 86.3] TG6 (EXE1): 73.8% [58.0, 86.1] ****************************** Total (FAS): 61.6% [55.4, 67.6] Total (mPP): 73.0% [61.4, 82.6] ******************************

End point type

Secondary

End point timeframe

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49	51	34	44	37	43	258	74
Units: Patients	37	23	21	20	26	32	159	54

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

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End point title

Clinical Benefit Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

End point description

For the analysis of the secondary endpoint, the Best Overall Response (BOR) in all patients (with measurable and non-measurable disease) according to investigator assessment (IA) was evaluated. The analysis was performed for each treatment subgroup separately. No formal comparison was performed. ****************************** Clinical Benefit Rate (CBR % [95% CI]): FAS (N=350): TG1 (LET1): 71.0% [58.1, 81.8] TG2 (LET2+): 48.3% [35.2, 61.6] TG3 (FUL1): 64.0% [49.2, 77.1] TG4 (FUL2+): 50.8% [37.7, 63.9] TG5 (ANA1): 76.7% [64.0, 86.6] TG6 (EXE1): 73.7% [60.3, 84.5] ****************************** mPP (N=107): TG5 (ANA1): 79.2% [65.9, 89.2] TG6 (EXE1): 74.1%) [60.3, 85.0] ****************************** Total (FAS): 64.0% [58.7, 69.0] Total (mPP): 76.6% [67.5, 84.3] ******************************

End point type

Secondary

End point timeframe

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62	60	50	61	60	57	350	107
Units: Patients	44	29	32	31	46	42	224	82

No statistical analyses for this end point

Secondary: Clinical Benefit Rate by change in FACT-B Total Score - All patients [(measurable and non-measurable disease (IA)]

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End point title

Clinical Benefit Rate by change in FACT-B Total Score - All patients [(measurable and non-measurable disease (IA)]

End point description

For the analysis of the secondary endpoint, all patients (with measurable and non-measurable disease) and Clinical Benefit according to investigator assessment (IA) were evaluated and stratified by change in FACT-B total score (TS). Minimum clinically important difference in FACT-B total score was defined as 7 points. Analysis was conducted in patients with FACT-B total score available at baseline as well as at 12 weeks. (Abbreviation: TS = FACT-B total score) Patients with an improvement in FACT-B total score had a higher clinical benefit (80.3%) compared to patients with deterioration in FACT-B (68.1%) or patients with no clinically important change in FACT-B (70.7%).

End point type

Secondary

End point timeframe

Assessment of the CBR (in all patients by investigator assessment), stratified by change in FACT-B total score at 12 weeks compared to baseline.

End point values	Full Analysis Set (FAS)
Number of subjects analysed
Units: Patients
Pts (N=72) - with deterioration in TS	49
Pts (N=99) - no clinically important diff. in TS	70
Pts (N=61) - with improvement in TS	49
Pts (N=46) - with TS not determinable at wk 12	36

No statistical analyses for this end point

Secondary: Physicians Assessment of Global Health Status

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End point title

Physicians Assessment of Global Health Status

End point description

Investigator assessment of the global health status (GHS) was performed at baseline (BL) and up to 10 treatment cycles, day 1 (FAS). GHS at BL (n, %): Very good: 61 (17.4); Rather good: 144 (41.1); Fair: 86 (24.6); Rather poor: 17 (4.9);Very poor: 1 (0.3); Not assessed: 41 (11.7); Missing: 0 (0.0). The patient`s global health status assessed by the physician at the current time and the change from last visit was analyzed for all patients.

End point type

Secondary

End point timeframe

From baseline up to treatment cycle 10. CSR Tab 11-34 Kategorien noch eintrage und Changes GHS eintragen.

End point values	Full Analysis Set (FAS)
Number of subjects analysed	350 ^[11]
Units: Patients
Baseline (N=350) - Much improved	0
Baseline (N=350) - Minimally improved	0
Baseline (N=350) - No change	0
Baseline (N=350) - Minimally worse	0
Baseline (N=350) - Much worse	0
Baseline (N=350) - Not assessed	0
Baseline (N=350) - Missing	0
Cycle 1 (N=350) - Much improved	3
Cycle 1 (N=350) - Minimally improved	14
Cycle 1 (N=350) - No change	253
Cycle 1 (N=350) - Minimally worse	10
Cycle 1 (N=350) - Much worse	3
Cycle 1 (N=350) - Not assessed	62
Cycle 1 (N=350) - Missing	5
Cycle 2 (N=340) - Much improved	5
Cycle 2 (N=340) - Minimally improved	45
Cycle 2 (N=340) - No change	228
Cycle 2 (N=340) - Minimally worse	23
Cycle 2 (N=340) - Much worse	3
Cycle 2 (N=340) - Not assessed	36
Cycle 2 (N=340) - Missing	0
Cycle 3 (N=324) - Much improved	8
Cycle 3 (N=324) - Minimally improved	50
Cycle 3 (N=324) - No change	208
Cycle 3 (N=324) - Minimally worse	29
Cycle 3 (N=324) - Much worse	2
Cycle 3 (N=324) - Not assessed	35
Cycle 3 (N=324) - Missing	1
Cycle 4 (N=288) - Much improved	7
Cycle 4 (N=288) - Minimally improved	46
Cycle 4 (N=288) - No change	193
Cycle 4 (N=288) - Minimally worse	13
Cycle 4 (N=288) - Much worse	2
Cycle 4 (N=288) - Not assessed	25
Cycle 4 (N=288) - Missing	2
Cycle 5 (N=265) - Much improved	4
Cycle 5 (N=265) - Minimally improved	40
Cycle 5 (N=265) - No change	174
Cycle 5 (N=265) - Minimally worse	12
Cycle 5 (N=265) - Much worse	1
Cycle 5 (N=265) - Not assessed	32
Cycle 5 (N=265) - Missing	2
Cycle 6 (N=249) - Much improved	6
Cycle 6 (N=249) - Minimally improved	39
Cycle 6 (N=249) - No change	166
Cycle 6 (N=249) - Minimally worse	10
Cycle 6 (N=249) - Much worse	3
Cycle 6 (N=249) - Not assessed	23
Cycle 6 (N=249) - Missing	2
Cycle 7 (N=233) - Much improved	4
Cycle 7 (N=233) - Minimally improved	42
Cycle 7 (N=233) - No change	151
Cycle 7 (N=233) - Minimally worse	9
Cycle 7 (N=233) - Much worse	0
Cycle 7 (N=233) - Not assessed	26
Cycle 7 (N=233) - Missing	1
Cycle 8 (N=225) - Much improved	5
Cycle 8 (N=225) - Minimally improved	23
Cycle 8 (N=225) - No change	152
Cycle 8 (N=225) - Minimally worse	17
Cycle 8 (N=225) - Much worse	0
Cycle 8 (N=225) - Not assessed	26
Cycle 8 (N=225) - Missing	2
Cycle 9 (N=212) - Much improved	5
Cycle 9 (N=212) - Minimally improved	24
Cycle 9 (N=212) - No change	147
Cycle 9 (N=212) - Minimally worse	10
Cycle 9 (N=212) - Much worse	1
Cycle 9 (N=212) - Not assessed	25
Cycle 9 (N=212) - Missing	0
Cycle 10 (N=191) - Much improved	3
Cycle 10 (N=191) - Minimally improved	25
Cycle 10 (N=191) - No change	134
Cycle 10 (N=191) - Minimally worse	11
Cycle 10 (N=191) - Much worse	0
Cycle 10 (N=191) - Not assessed	18
Cycle 10 (N=191) - Missing	0

Notes
[11] - 000 = not applicable

No statistical analyses for this end point

Secondary: Best Overall Response Rate (BOR) - Patients with measurable disease (IA)

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End point title

Best Overall Response Rate (BOR) - Patients with measurable disease (IA)

End point description

BOR was defined as the proportion of patients with best overall response (CR or PR or stable disease (SD) for ≥ 24 weeks). For the analysis of the secondary endpoint, the BOR according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

Tumor response (BOR) was evaluated after 24 weeks from day of first study drug administration.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[12]	51 ^[13]	34 ^[14]	44 ^[15]	37 ^[16]	43 ^[17]	258 ^[18]	74 ^[19]
Units: Patients
CR	2	0	2	1	0	2	7	2
PR	25	10	12	10	17	23	97	38
SD ≥ 24	10	13	7	9	9	7	55	14
SD < 24	2	3	3	8	5	5	26	9
PD	8	21	8	9	4	6	56	9
NE	0	1	0	0	0	0	1	0
Missing	2	3	2	7	2	0	16	2

Notes
[12] - CR: 4.1%; PR: 51.0%; SD≥24: 20.4%; SD<24: 4.1%; PD: 16.3%; NE: 0.0%; Missing: 4.1%
[13] - CR: 0.0%; PR: 19.6%; SD≥24: 25.5%; SD<24: 5.9%; PD: 41.3%; NE: 2.0%; Missing: 5.9%
[14] - CR: 5.9%; PR: 35.3%; SD≥24: 20.6%; SD<24: 8.8%; PD: 23.5%; NE: 0.0%; Missing: 5.9%
[15] - CR: 2.3%; PR: 22.7%; SD≥24: 20.5%; SD<24: 18.2%; PD: 20.5%; NE: 0.0%; Missing: 15.9%
[16] - CR: 0.0%; PR: 45.9%; SD≥24: 24.3%; SD<24: 13.5%; PD: 10.8%; NE: 0.0%; Missing: 5.4%
[17] - CR: 4.7%; PR: 53.5%; SD≥24: 16.3%; SD<24: 11.6%; PD: 14.0%; NE: 0.0%; Missing: 0.0%
[18] - CR: 2.7%; PR: 37.6%; SD≥24: 21.3%; SD<24: 10.1%; PD: 21.7%; NE: 0.4%; Missing: 6.2%
[19] - CR: 2.7%; PR: 51.4%; SD≥24: 18.9%; SD<24: 12.2%; PD: 12.2%; NE: 0.0%; Missing: 2.7%

No statistical analyses for this end point

Secondary: Best Overall Response Rate (BOR) - All patients [(measurable and non-measurable disease (IA)]

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End point title

Best Overall Response Rate (BOR) - All patients [(measurable and non-measurable disease (IA)]

End point description

BOR was defined as the proportion of patients with best overall response (CR or PR or stable disease (SD) for ≥ 24 weeks). For the analysis of the secondary endpoint in all patients (with measurable and non-measurable disease) , the Best Overall Response (BOR) according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

Tumor response (BOR) was evaluated after 24 weeks from day of first study drug administration.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[20]	60 ^[21]	50 ^[22]	61 ^[23]	60 ^[24]	57 ^[25]	350 ^[26]	107 ^[27]
Units: Patients
CR	2	0	3	2	1	2	10	3
PR	25	10	12	13	21	24	105	43
SD ≥ 24	17	19	17	16	24	16	109	36
SD < 24	6	6	4	11	6	5	38	9
PD	9	21	10	11	4	6	61	9
NE	0	1	0	0	0	0	1	0
Missing	3	3	4	8	4	4	26	7

Notes
[20] - CR: 3.2%; PR: 40.3%; SD≥24: 27.4%; SD<24: 9.7%; PD: 14.5%; NE: 0.0%; Missing: 4.8%
[21] - CR: 0.0%; PR: 16.7%; SD≥24: 31.7%; SD<24: 10.0%; PD: 35.0%; NE: 1.7%; Missing: 5.0%
[22] - CR: 6.0%; PR: 24.0%; SD≥24: 34.0%; SD<24: 8.0%; PD: 20.0%; NE: 0.0%; Missing: 8.0%
[23] - CR: 3.3%; PR: 21.3%; SD≥24: 26.2%; SD<24: 18.0%; PD: 18.0%; NE: 0.0%; Missing: 13.1%
[24] - CR: 1.7%; PR: 35.0%; SD≥24: 40.0%; SD<24: 10.0%; PD: 6.7%; NE: 0.0%; Missing: 6.7%
[25] - CR: 3.5%; PR: 42.1%; SD≥24: 28.1%; SD<24: 8.8%; PD: 10.5%; NE: 0.0%; Missing: 7.0%
[26] - CR: 2.9%; PR: 30.0%; SD≥24: 31.1%; SD<24: 10.9%; PD: 17.4%; NE: 0.3%; Missing: 7.4%
[27] - CR: 2.8%; PR: 40.2%; SD≥24: 33.6%; SD<24: 8.5%; PD: 8.4%; NE: 0.0%; Missing: 6.5%

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

Overall Response Rate (ORR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

End point description

ORR was defined as proportion of patients in whom any response (CR/PR) could be achieved. For the analysis of the secondary endpoint in patients with measurable disease, the Overall Response Rate (ORR) calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was evaluated.

End point type

Secondary

End point timeframe

From day of first study drug administration until documented tumor response.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[28]	51 ^[29]	34 ^[30]	44 ^[31]	37 ^[32]	43 ^[33]	258 ^[34]	74 ^[35]
Units: Patients	30	8	15	13	16	20	102	34

Notes
[28] - ORR (%) [95% CI]: 61.2% [46.2, 74.8]
[29] - ORR (%) [95% CI]: 15.7% [7.0, 28.6]
[30] - ORR (%) [95% CI]: 44.1% [27.2, 62.1]
[31] - ORR (%) [95% CI]: 29.5% [16.8, 45.2]
[32] - ORR (%) [95% CI]: 43.2% [27.1, 60.5]
[33] - ORR (%) [95% CI]: 46.5% [31.2, 62.3]
[34] - ORR (%) [95% CI]: 39.5% [33.5, 45.8]
[35] - ORR (%) [95% CI]: 45.9% [34.3, 57.9]

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) - Patients with measurable disease (IA)

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End point title

Overall Response Rate (ORR) - Patients with measurable disease (IA)

End point description

For the analysis of the secondary endpoint in patients with measurable disease, the Overall Response Rate (ORR) according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

ORR was defined as proportion of patients in whom any response (CR/PR) could be achieved.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[36]	51 ^[37]	34 ^[38]	44 ^[39]	37 ^[40]	43 ^[41]	258 ^[42]	74 ^[43]
Units: Patients	27	10	14	11	17	25	104	40

Notes
[36] - ORR (%) [95% CI]: 55.1% [40.2, 69.3]
[37] - ORR (%) [95% CI]: 19.6% [9.8, 33.1]
[38] - ORR (%) [95% CI]: 41.2% [24.6, 59.3]
[39] - ORR (%) [95% CI]: 25.0% [13.2, 40.3]
[40] - ORR (%) [95% CI]: 45.9% [29.5, 63.1]
[41] - ORR (%) [95% CI]: 58.1% [42.1, 73.0]
[42] - ORR (%) [95% CI]: 40.3% [34.3, 46.6]
[43] - ORR (%) [95% CI]: 54.1% [42.1, 65.7]

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR) - All patients [measurable and non-measurable disease (IA)]

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End point title

Overall Response Rate (ORR) - All patients [measurable and non-measurable disease (IA)]

End point description

ORR was defined as proportion of patients in whom any response (CR/PR) could be achieved. For the analysis of the secondary endpoint in all patients (with measurable and non-measurable disease), the Overall Response Rate (ORR) according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

From day of first study drug administration until documented tumor response.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[44]	60 ^[45]	50 ^[46]	61 ^[47]	60 ^[48]	57 ^[49]	350 ^[50]	107 ^[51]
Units: Patients	27	10	15	15	22	26	115	46

Notes
[44] - ORR (%) [95% CI]: 43.5% [31.0, 56.7]
[45] - ORR (%) [95% CI]: 16.7% [8.3, 28.5]
[46] - ORR (%) [95% CI]: 30.0% [17.9, 44.6]
[47] - ORR (%) [95% CI]: 24.6% [14.5, 37.3]
[48] - ORR (%) [95% CI]: 36.7% [24.6, 50.1]
[49] - ORR (%) [95% CI]: 45.6% [32.4, 59.3]
[50] - ORR (%) [95% CI]: 32.9% [28.0, 38.1]
[51] - ORR (%) [95% CI]: 43.0% [33.5, 52.9]

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

Disease Control Rate (DCR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

End point description

DCR was defined as as the proportion of patients with CR, PR, or stable disease (SD) relative to all patients in the respective population. For the analysis of the secondary endpoint, tumor response calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was evaluated.

End point type

Secondary

End point timeframe

From day of first study drug administration until documented tumor response.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[52]	51 ^[53]	34 ^[54]	44 ^[55]	37 ^[56]	43 ^[57]	258 ^[58]	74 ^[59]
Units: Patients	41	26	24	29	27	37	184	60

Notes
[52] - DCR (%) [95% CI]: 83.7% [70.3, 92.7]
[53] - DCR (%) [95% CI]: 51.0% [36.6, 65.2]
[54] - DCR (%) [95% CI]: 70.6% [52.5, 84.9]
[55] - DCR (%) [95% CI]: 65.9% [50.1, 79.5]
[56] - DCR (%) [95% CI]: 73.0% [55.9, 86.2]
[57] - DCR (%) [95% CI]: 86.0% [72.1, 94.7]
[58] - DCR (%) [95% CI]: 71.3% [65.4, 76.8]
[59] - DCR (%) [95% CI]: 81.1% [70.3, 89.3]

No statistical analyses for this end point

Secondary: Disease Control Rate (CBR) - Patients with measurable disease (IA)

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End point title

Disease Control Rate (CBR) - Patients with measurable disease (IA)

End point description

DCR was defined as as the proportion of patients with CR, PR, or stable disease (SD) relative to all patients in the respective population. For the analysis of the secondary endpoint in patients with measurable disease, the Disease Control Rate (DCR) according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

From day of first study drug administration until documented tumor response.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[60]	51 ^[61]	34 ^[62]	44 ^[63]	37 ^[64]	43 ^[65]	258 ^[66]	74 ^[67]
Units: Patients	39	26	24	28	31	37	185	63

Notes
[60] - DCR (%) [95% CI]: 79.6% [65.7, 89.8]
[61] - DCR (%) [95% CI]: 51.0% [36.6, 65.2]
[62] - DCR (%) [95% CI]: 70.6% [52.5, 84.9]
[63] - DCR (%) [95% CI]: 63.6% [47.8, 77.6]
[64] - DCR (%) [95% CI]: 83.8% [68.0, 93.8]
[65] - DCR (%) [95% CI]: 86.0% [72.1, 94.7]
[66] - DCR (%) [95% CI]: 71.7% [65.8, 77.1]
[67] - DCR (%) [95% CI]: 85.1% [75.0, 92.3]

No statistical analyses for this end point

Secondary: Disease Control Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

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End point title

Disease Control Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

End point description

DCR was defined as as the proportion of patients with CR, PR, or stable disease (SD) relative to all patients in the respective population. For the analysis of the secondary endpoint in all patients (with measurable and non-measurable disease), the Disease Control Rate (DCR) according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

From day of first study drug administration until documented tumor response.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[68]	60 ^[69]	50 ^[70]	61 ^[71]	60 ^[72]	57 ^[73]	350 ^[74]	107 ^[75]
Units: Patients	50	35	36	42	52	47	262	91

Notes
[68] - DCR (%) [95% CI]: 80.6% [68.6, 89.6]
[69] - DCR (%) [95% CI]: 58.3% [44.9, 70.9]
[70] - DCR (%) [95% CI]: 72.0% [57.5, 83.8]
[71] - DCR (%) [95% CI]: 68.9% [55.7, 80.1]
[72] - DCR (%) [95% CI]: 86.7% [75.4, 94.1]
[73] - DCR (%) [95% CI]: 82.5% [70.1, 91.3]
[74] - DCR (%) [95% CI]: 74.9% [70.0, 79.3]
[75] - DCR (%) [95% CI]: 85.0% [76.9, 91.2]

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

Progression Free Survival (PFS) - Patients with measurable disease (calculated acc. to RECIST 1.1)

End point description

PFS defined as the time interval measured from the day of first study drug administration to first progression or death, whichever came first. Patients without documented tumour progression (tumour assessment or documentation at final examination) or death at the time of analysis were censored at their last date of tumour evaluation or at the start date of a subsequent antineoplastic therapy, whichever came first. PFS was estimated by using the Kaplan-Meier method. For the analysis of the secondary endpoint in patients with measurable disease, tumor response calculated according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was evaluated.

End point type

Secondary

End point timeframe

From the day of first study drug administration to first progression or death, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49	51	34	44	37	43	258	74 ^[76]
Units: Months
median (confidence interval 95%)	11.8 (8.3 to 19.7)	5.3 (3.0 to 8.7)	8.1 (5.2 to 9.3)	5.7 (4.6 to 10.6)	12.3 (5.4 to 16.6)	15.0 (9.2 to 22.5)	8.7 (8.1 to 11.0)	13.7 (9.2 to 17.7)

Notes
[76] - TG5 (ANA1): Median [95% CI]: 11.7 [5.4, 16.6] TG6 (EXE1): Median [95% CI]: 15.0 [8.7, 23.1]

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Patients with measurable disease (IA)

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End point title

Progression Free Survival (PFS) - Patients with measurable disease (IA)

End point description

PFS was defined as the time interval measured from the day of first study drug administration to first progression or death, whichever came first. Patients without documented tumour progression (tumour assessment or documentation at final examination) or death at the time of analysis were censored at their last date of tumour evaluation or at the start date of a subsequent antineoplastic therapy, whichever came first. PFS was estimated by using the Kaplan-Meier method. For the analysis of the secondary endpoint in patients with measurable disease, tumor response according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

From the day of first study drug administration to first progression or death, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49	51	34	44	37	43	258	74 ^[77]
Units: Months
median (confidence interval 95%)	14.5 (8.8 to 21.3)	5.5 (3.0 to 11.6)	8.4 (4.7 to 13.7)	7.4 (3.3 to 10.6)	16.3 (10.3 to 32.1)	22.5 (11.5 to 29.7)	11.5 (9.2 to 14.3)	22.0 (12.9 to 26.9)

Notes
[77] - TG5 (ANA1): Median [95% CI]: 18.9 [19.3, 35.1] TG6 (EXE1): Median [95% CI]: 23.1 [11.3, 30.3]

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - All patients [measurable and non-measurable disease (IA)]

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End point title

Progression Free Survival (PFS) - All patients [measurable and non-measurable disease (IA)]

End point description

PFS was defined as the time interval measured from the day of first study drug administration to first progression or death, whichever came first. Patients without documented tumour progression (tumour assessment or documentation at final examination) or death at the time of analysis were censored at their last date of tumour evaluation or at the start date of a subsequent antineoplastic therapy, whichever came first. PFS was estimated by using the Kaplan-Meier method. For the analysis of the secondary endpoint in all patients (with measurable and non-measurable disease) , the tumor response according to investigator assessment (IA) was evaluated.

End point type

Secondary

End point timeframe

From the day of first study drug administration to first progression or death, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62	60	50	61	60	57	350	107 ^[78]
Units: Months
median (confidence interval 95%)	18.0 (11.2 to 24.3)	8.7 (4.1 to 19.4)	13.7 (8.0 to 30.4)	8.2 (5.6 to 10.9)	23.3 (13.2 to 32.1)	22.5 (15.8 to 26.9)	14.6 (11.5 to 26.9)	22.6 (17.0 to 25.5)

Notes
[78] - TG5 (ANA1): Median [95% CI]: 23.3 [13.7, 38.7] TG6 (EXE1): Median [95% CI]: 22.6 [16.0, 26.9]

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Patients with measurable disease

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End point title

Overall Survival (OS) - Patients with measurable disease

End point description

OS was defined as the time interval measured from the day of first study drug administration to time of death from any cause. Survival status was assessed regardless of treatment discontinuation reason until EOS, death, lost to follow-up, or withdrawal of informed consent, whatever came first. Last date the patient was known to be alive was used if a patient had no documented date of death and OS for the patient was considered censored. OS was estimated by using the Kaplan-Meier method. (95% CI: 999 = not applicable)

End point type

Secondary

End point timeframe

OS was defined as the time interval measured from the day of first study drug administration to time of death from any cause.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49	51	34	44	37	43	258	74 ^[79]
Units: Months
median (confidence interval 95%)	35.1 (29.2 to 46.6)	30.9 (16.0 to 39.9)	33.9 (12.5 to 49.2)	19.1 (14.4 to 36.4)	52.6 (24.3 to 999)	34.0 (23.1 to 44.8)	33.4 (28.8 to 36.4)	39.2 (26.9 to 53.8)

Notes
[79] - TG5 (ANA1): Median [95% CI]: 52.6 [21.7, NA] TG6 (EXE1): Median [95% CI]: 34.8 [25.0, 47.3]

No statistical analyses for this end point

Secondary: Overall Survival (OS) - All patients (measurable and non-measurable disease)

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End point title

Overall Survival (OS) - All patients (measurable and non-measurable disease)

End point description

End point type

Secondary

End point timeframe

OS was defined as the time interval measured from the day of first study drug administration to time of death from any cause.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62	60	50	61	60	57	350	107 ^[80]
Units: Months
median (confidence interval 95%)	40.0 (32.9 to 58.8)	34.7 (20.7 to 41.7)	49.2 (31.5 to 999)	26.9 (15.6 to 37.2)	53.8 (32.1 to 999)	34.0 (26.9 to 41.0)	37.2 (33.4 to 41.7)	40.9 (32.2 to 52.6)

Notes
[80] - TG5 (ANA1): Median [95% CI]: 54.6 [40.3, NA] TG6 (EXE1): Median [95% CI]: 34.0 [27.1, 41.0]

No statistical analyses for this end point

Secondary: 1-Year PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

1-Year PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

End point description

The 1-year PFS rate was be calculated using the Kaplan-Meier method. PFS was defined as the time interval measured from the day of first study drug administration to first progression or death, whichever came first. Patients without documented tumour progression (tumour assessment or documentation at final examination) or death within 1 year were censored. No imputation for missing assessments was be performed. (N = number of events (PD/ Death) within 1 year)

End point type

Secondary

End point timeframe

From the day of first study drug administration to progression or death within 1 year, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[81]	51 ^[82]	34 ^[83]	44 ^[84]	37 ^[85]	43 ^[86]	258 ^[87]	74 ^[88]
Units: Patients	23	32	23	30	18	19	145	34

Notes
[81] - 1-y PFS Rate: 48.8% [33.6, 62.4]
[82] - 1-y PFS Rate: 30.6% [17.8, 44.3]
[83] - 1-y PFS Rate: 30.3% [15.9, 46.1]
[84] - 1-y PFS Rate: 25.6% [13.4, 39.8]
[85] - 1-y PFS Rate: 50.0% [32.9, 64.9]
[86] - 1-y PFS Rate: 55.0% [38.9, 68.5]
[87] - 1-y PFS Rate: 40.2% [34.0, 46.3]
[88] - 1-y PFS Rate: 52.9% [40.8, 63.7] TG5(ANA1): 48.4% [30.2, 64.4] TG6(EXE1): 56.3% [39.9, 63.7]

No statistical analyses for this end point

Secondary: 1-Year PFS Rate - Patients with measurable disease (IA)

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End point title

1-Year PFS Rate - Patients with measurable disease (IA)

End point description

End point type

Secondary

End point timeframe

From the day of first study drug administration to progression or death within 1 year, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[89]	51 ^[90]	34 ^[91]	44 ^[92]	37 ^[93]	43 ^[94]	258 ^[95]	74 ^[96]
Units: Patients	20	31	20	28	13	16	128	27

Notes
[89] - 1-y PFS Rate: 56.3% [40.8, 69.3]
[90] - 1-y PFS Rate: 32.5% [19.3, 46.3]
[91] - 1-y PFS Rate: 39.4% [23.1, 55.4]
[92] - 1-y PFS Rate: 32.1% [18.6, 46.5]
[93] - 1-y PFS Rate: 63.5% [45.5, 76.9]
[94] - 1-y PFS Rate: 62.1% [45.8, 74.8]
[95] - 1-y PFS Rate: 47.5% [41.1, 53.6
[96] - 1-y PFS Rate: 62.4% [50.1, 72.4] TG5(ANA1): 64.0% [44.4, 78.2] TG6(EXE1): 61.2% [44.7, 74.2]

No statistical analyses for this end point

Secondary: 1-Year PFS Rate - All patients [measurable and non-measurable disease (IA)]

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End point title

1-Year PFS Rate - All patients [measurable and non-measurable disease (IA)]

End point description

End point type

Secondary

End point timeframe

From the day of first study drug administration to progression or death within 1 year, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[97]	60 ^[98]	50 ^[99]	61 ^[100]	60 ^[101]	57 ^[102]	350 ^[103]	107 ^[104]
Units: Patients	23	32	23	37	18	18	151	32

Notes
[97] - 1-y PFS Rate: 60.0% [46.1, 71.4]
[98] - 1-y PFS Rate: 42.0% [28.7, 54.6]
[99] - 1-y PFS Rate: 52.2% [37.3, 65.1]
[100] - 1-y PFS Rate: 35.6% [23.5, 47.9]
[101] - 1-y PFS Rate: 67.3% [53.2, 78.0]
[102] - 1-y PFS Rate: 66.9% [52.7, 77.7]
[103] - 1-y PFS Rate: 54.0% [48.4, 59.2]
[104] - 1-y PFS Rate: 67.8% [57.6, 76.0] TG5(ANA1): 68.7% [53.5, 79.8] TG6(EXE1): 66.9% [52.2, 78.0]

No statistical analyses for this end point

Secondary: 2-y PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

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End point title

2-y PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

End point description

The 2-year PFS rate was be calculated using the Kaplan-Meier method. PFS was defined as the time interval measured from the day of first study drug administration to first progression or death, whichever came first. Patients without documented tumour progression (tumour assessment or documentation at final examination) or death within 2 year were censored. No imputation for missing assessments was be performed. (N = number of events (PD/Death) within 2 years)

End point type

Secondary

End point timeframe

From the day of first study drug administration to progression or death within 2 years, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[105]	51 ^[106]	34 ^[107]	44 ^[108]	37 ^[109]	43 ^[110]	258 ^[111]	74 ^[112]
Units: Patients	31	39	27	33	27	28	185	51

Notes
[105] - 2-y PFS Rate: 29.9% [17.1, 43.8]
[106] - 2-y PFS Rate: 11.1% [3.7, 23.2]
[107] - 2-y PFS Rate: 17.3% [6.6, 32.2]
[108] - 2-y PFS Rate: 18.0% [7.9, 31.2]
[109] - 2-y PFS Rate: 24.2% [11.7, 39.2]
[110] - 2-y PFS Rate: 32.9% [19.3, 47.2]
[111] - 2-y PFS Rate: 22.5% [17.3, 28.1]
[112] - 2-y PFS Rate: 28.5% [18.5, 39.3] TG5(ANA1): 21.5% [9.0, 37.5] TG6(EXE1): 33.7% [19.8, 48.2]

No statistical analyses for this end point

Secondary: 2-y PFS Rate - Patients with measurable disease (IA)

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End point title

2-y PFS Rate - Patients with measurable disease (IA)

End point description

End point type

Secondary

End point timeframe

From the day of first study drug administration to progression or death within 2 year, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[113]	51 ^[114]	34 ^[115]	44 ^[116]	37 ^[117]	43 ^[118]	258 ^[119]	74 ^[120]
Units: Patients	30	37	23	33	22	22	167	40

Notes
[113] - 2-y PFS Rate: 32.7% [19.4, 46.6]
[114] - 2-y PFS Rate: 17.5% [7.8, 30.3]
[115] - 2-y PFS Rate: 30.3% [15.9, 46.1]
[116] - 2-y PFS Rate: 18.9% [8.5, 32.3]
[117] - 2-y PFS Rate: 36.8% [21.2, 52.5]
[118] - 2-y PFS Rate: 47.4% [31.7, 61.5]
[119] - 2-y PFS Rate: 30.2% [24.4, 36.1]
[120] - 2-y PFS Rate: 43.4% [31.6, 54.5] TG5(ANA1): 36.1% [19,4, 53.0] TG6(EXE1): 48.6% [32.6, 62.8]

No statistical analyses for this end point

Secondary: 2-y PFS Rate - All patients [measurable and non-measurable disease (IA)]

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End point title

2-y PFS Rate - All patients [measurable and non-measurable disease (IA)]

End point description

End point type

Secondary

End point timeframe

From the day of first study drug administration to progression or death within 1 year, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[121]	60 ^[122]	50 ^[123]	61 ^[124]	60 ^[125]	57 ^[126]	350 ^[127]	107 ^[128]
Units: Patients	34	40	26	44	30	29	203	42

Notes
[121] - 2-y PFS Rate: 39.1% [26.2, 51.7]
[122] - 2-y PFS Rate: 25.3% [14.4, 37.8]
[123] - 2-y PFS Rate: 45.9% [31.5, 59.2]
[124] - 2-y PFS Rate: 22.6% [12.7, 34.3]
[125] - 2-y PFS Rate: 44.5% [31.0, 57.2]
[126] - 2-y PFS Rate: 45.4% [31.6, 58.2]
[127] - 2-y PFS Rate: 36.8% [31.5, 42.1]
[128] - 2-y PFS Rate: 45.4% [35.2, 55.0] TG5(ANA1): 44.6% [30.1, 58.1] TG6(EXE1): 46.1% [31.8, 59.2]

No statistical analyses for this end point

Secondary: 1-y Overall Survival Rate - Patients with measurable disease

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End point title

1-y Overall Survival Rate - Patients with measurable disease

End point description

The 1-year OS rate was calculated using the Kaplan-Meier method. 1-Year OS Rate (Kaplan-Meier) was defined as the proportion of patients without event death measured 1 year after the day of first study drug administration. (N = number of events (Death) within 1 year)

End point type

Secondary

End point timeframe

From the day of first study drug administration to death within 1 year.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[129]	51 ^[130]	34 ^[131]	44 ^[132]	37 ^[133]	43 ^[134]	258 ^[135]	74 ^[136]
Units: Patients	5	13	9	11	4	5	47	8

Notes
[129] - 1-y OS Rate: 88.5% [74.4, 95.1]
[130] - 1-y OS Rate: 71.1% [55.4, 82.1]
[131] - 1-y OS Rate: 71.1% [51.8, 83.8]
[132] - 1-y OS Rate: 73.5% [57.2, 84.4]
[133] - 1-y OS Rate: 89.0% [73.4, 95.7]
[134] - 1-y OS Rate: 87.8% [73.2, 94.7]
[135] - 1-y OS Rate: 80.3% [74.6, 84.8]
[136] - 1-y OS Rate: 88.9% [78.9, 94.3] TG5(ANA1): 90.5% [73.4, 96.8] TG6(EXE1): 87.5% [72.5, 94.6]

No statistical analyses for this end point

Secondary: 1-y Overall Survival Rate - All patients [measurable and non-measurable disease (IA)]

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End point title

1-y Overall Survival Rate - All patients [measurable and non-measurable disease (IA)]

End point description

End point type

Secondary

End point timeframe

From the day of first study drug administration to death within 1 year.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[137]	60 ^[138]	34 ^[139]	44 ^[140]	37 ^[141]	37 ^[142]	350 ^[143]	107 ^[144]
Units: Patients	5	13	9	12	5	7	51	10

Notes
[137] - 1-y OS Rate: 91.0% [79.6, 96.2]
[138] - 1-y OS Rate: 76.0% [62.2, 85.3]
[139] - 1-y OS Rate: 80.1% [65.2, 89.1]
[140] - 1-y OS Rate: 79.3% [66.4, 87.7]
[141] - 1-y OS Rate: 91.3% [80.4, 96.3]
[142] - 1-y OS Rate: 87.2% [75.0, 93.7]
[143] - 1-y OS Rate: 84.3% [79.9, 87.8]
[144] - 1-y OS Rate: 90.2% [82.5, 94.6] TG5(ANA1): 92.1% [80.4, 97.0] TG6(EXE1): 88.3% [75.8, 94.6]

No statistical analyses for this end point

Secondary: 2-y Overall Survival Rate - Patients with measurable disease

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End point title

2-y Overall Survival Rate - Patients with measurable disease

End point description

The 2-year OS rate was calculated using the Kaplan-Meier method. 2-Year OS Rate (Kaplan-Meier) was defined as the proportion of patients without event death measured 2 years after the day of first study drug administration. (N = number of events (Death) within 2 years)

End point type

Secondary

End point timeframe

From the day of first study drug administration to death within 2 years.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	49 ^[145]	51 ^[146]	34 ^[147]	44 ^[148]	37 ^[149]	43 ^[150]	258 ^[151]	74 ^[152]
Units: Patients	5	13	9	11	4	5	47	8

Notes
[145] - 2-y OS Rate: 74.8% [57.9, 85.6]
[146] - 2-y OS Rate: 55.3% [39.0, 68.9]
[147] - 2-y OS Rate: 60.1% [40.3, 75.2]
[148] - 2-y OS Rate: 44.4% [28.5, 59.1]
[149] - 2-y OS Rate: 70.5% [51.9, 83.0]
[150] - 2-y OS Rate: 65.4% [48.7, 77.9]
[151] - 2-y OS Rate: 61.4% [54.6, 67.4]
[152] - 2-y OS Rate: 67.8% [55.3, 77.5] TG5(ANA1): 68.6% [48.0, 82.4] TG6(EXE1): 67.1% [50.1, 79.4]

No statistical analyses for this end point

Secondary: 2-y OS Rate - All patients [measurable and non-measurable disease (IA)]

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End point title

2-y OS Rate - All patients [measurable and non-measurable disease (IA)]

End point description

End point type

Secondary

End point timeframe

From the day of first study drug administration to death within 2 years.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62 ^[153]	60 ^[154]	50 ^[155]	61 ^[156]	60 ^[157]	57 ^[158]	350 ^[159]	107 ^[160]
Units: Patients	5	13	9	12	5	7	51	10

Notes
[153] - 2-y OS Rate: 80.2% [66.2, 88.9]
[154] - 2-y OS Rate: 61.2% [46.4, 73.1]
[155] - 2-y OS Rate: 72.7% [56.9, 83.6]
[156] - 2-y OS Rate: 52.6% [38.5, 64.9]
[157] - 2-y OS Rate: 72.1% [58.0, 82.2]
[158] - 2-y OS Rate: 69.9% [55.6, 80.4]
[159] - 2-y OS Rate: 67.8% [62.2, 72.7]
[160] - 2-y OS Rate: 72.2% [62.0, 80.0] TG5(ANA1): 72.2% [56.9, 82.9] TG6(EXE1): 72.0% [57.3, 82.4]

No statistical analyses for this end point

Secondary: Treatment details - Treatment duration (All patients, FAS)

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End point title

Treatment details - Treatment duration (All patients, FAS)

End point description

Time on treatment was defined as difference of date of last administration and date of first administration of palbociclib plus a proportional factor for the 7 days without treatment at the end of a cycle. It was calculated as follows: Time on treatment = 1 + date of last administration-date of first administration + p (with p = ⌊1/3*(1+ date of last administration-date of first administration in last cycle)⌋. Palbociclib treatment beyond study specific EOT was not considered as study treatment and was not considered for calculation of time on treatment.

End point type

Secondary

End point timeframe

From date of first administration to last administration of palbociclib plus a proportional factor for the 7 days without treatment at the end of a cycle.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62	60	50	61	60	57	350	107 ^[161]
Units: Months
median (full range (min-max))	50.0 (4.0 to 312.0)	27.6 (8.3 to 308.0)	45.6 (1.3 to 285.0)	33.0 (0.7 to 273.0)	67.1 (4.0 to 279.0)	71.6 (2.7 to 268.0)	45.1 (0.7 to 312.0)	71.57 (2.7 to 279.0)

Notes
[161] - TG5(ANA1): 67.1 [4.0 - 279.0] TG6(EXE1): 73.7 [2.7 - 268.0]

No statistical analyses for this end point

Secondary: Treatment details - Treatment modifications (All patients, FAS / mPP)

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End point title

Treatment details - Treatment modifications (All patients, FAS / mPP)

End point description

Number of patients with at least one documented treatment modification (palbociclib or the combination partner letrozole, fulvestrant, anastrozole, exemestane). (N = 999 indicates "not applicable")

End point type

Secondary

End point timeframe

Treatment modifications (palbociclib or the combination partner letrozole, fulvestrant, anastrozole, exemestane) were documented from first day of study medication application until end of treatment (EOT).

End point values	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	350	107
Units: Patients
Palbociclib - Interrupt.	231	74
Palbociclib - Dose modif.	130	44
Letrozole (LET1) - Interrupt.	24	999
Letrozole (LET1) - Dose modif.	0	999
Letrozole (LET2+) - Interrupt.	13	999
Letrozole (LET2+) -Dose modif.	0	999
Fulvestrant (FUL1) - Interrupt.	8	999
Fulvestrant (FUL1) - Dose modif.	0	999
Fulvestrant (FUL2+) - Interrupt.	12	999
Fulvestrant (FUL2+) - Dose modif.	2	999
Anastrozole (ANA1): Interrupt.	18	15
Anastrozole (ANA1): Dose modif.	0	0
Exemestane (EXE1) - Interrupt.	17	16
Exemestane (EXE1) - Dose modif.	0	0

No statistical analyses for this end point

Secondary: Treatment details - Reason for treatment modification [Palbociclib - All patients, FAS / mPP)]

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End point title

Treatment details - Reason for treatment modification [Palbociclib - All patients, FAS / mPP)]

End point description

Number of patients with at least one documented treatment modification and underlying reasons for treatment modification (palbociclib).

End point type

Secondary

End point timeframe

Reasons for treatment modifications (palbociclib) were documented from first day of study medication application until end of treatment (EOT).

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)	Modified per-protocol set (mPP)
Number of subjects analysed	62	60	50	61	60	57	350	107
Units: Patients
(S)AE	41	27	24	30	39	29	190	62
Inacceptable toxicity	13	10	6	9	19	13	70	29
Non-compliance	13	9	5	3	10	10	50	20
Administrative reason	15	10	10	16	18	21	90	35
Concomitant medication	0	0	1	0	0	0	1	0

No statistical analyses for this end point

Secondary: Treatment details - Relative dose intensity overall (SAF)

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End point title

Treatment details - Relative dose intensity overall (SAF)

End point description

Relative dose intensity (overall) was defined as proportion of received dose regarding the standard dose of 125 mg on a daily basis for 21 days (palbociclib). Relative dose intensity overall [%] = 100 x (total dose received/time on treatment [weeks] / (21 x 125mg/4 weeks)

End point type

Secondary

End point timeframe

Relative dose intensity (overall) was calculated from first day of study medication application until end of treatment (EOT).

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)
Number of subjects analysed	62	60	50	61	60	57
Units: Relative dose intensity [%]
median (full range (min-max))
Palbociclib	93.0 (49.8 to 102.7)	96.4 (62.8 to 100.5)	99.1 (55.6 to 106.3)	96.2 (48.1 to 106.7)	95.5 (43.2 to 100.4)	95.5 (47.6 to 103.7)
Endocrine partner	100.0 (88.6 to 101.4)	100.0 (94.6 to 101.5)	82.0 (47.6 to 97.1)	80.6 (4.5 to 95.5)	92.0 (82.1 to 92.0)	92.0 (74.7 to 92.0)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - FACT-B Trial Outcome Index

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End point title

Patient Reported Outcome (FAS) - FACT-B Trial Outcome Index

End point description

HRQoL will be assessed with the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first). The questionnaire was analysed according to the manual [FACIT: FACT-B]. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire is subdivided into four QoL domains (i.e., physical well-being (PWB), functional well-being (FWB), emotional well-being (EWB), social/family well-being (SWB)) and a disease specific domain (breast cancer specific concerns (BCS)), with the total FACT-B score being calculated by summing the individual subscale scores. Higher scores indicate better quality of life. FACT-B Trial Outcome Index: Score range: 0 - 96 N = number of evaluable questionnaires / time point PRO results were displayed for TG1 – TG 4 in the FAS.

End point type

Secondary

End point timeframe

Before first application of study medication (baseline) and every 12 weeks until end of treatment (EOT).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	313 ^[162]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=313)	61.2 ± 25.3
week 12 (N=268)	61.2 ± 15.0
week 24 (N=217)	62.0 ± 14.6
week 36 (N=183)	61.8 ± 15.1
week 48 (N=157)	63.3 ± 15.7
week 60 (N=137)	62.0 ± 15.4
week 72 (N=123)	63.6 ± 14.8
week 84 (N=107)	63.0 ± 15.3
week 96 (N=98)	62.0 ± 16.7
week 108 (N=79)	63.2 ± 15.9
week 120 (N=72)	63.4 ± 15.9
EOT (N=111)	58.8 ± 15.4

Notes
[162] - N = number of evaluable questionnaires (at baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - FACT-G Total Score

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End point title

Patient Reported Outcome (FAS) - FACT-G Total Score

End point description

HRQoL will be assessed with the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first). The questionnaire was analysed according to the manual [FACIT: FACT-B]. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire is subdivided into four QoL domains (i.e., physical well-being (PWB), functional well-being (FWB), emotional well-being (EWB), social/family well-being (SWB)) and a disease specific domain (breast cancer specific concerns (BCS)), with the total FACT-B score being calculated by summing the individual subscale scores. Higher scores indicate better quality of life. FACT-G Total Score: Score range 0 - 108 N = number of evaluable questionnaires / time point PRO results were displayed for TG1 – TG 4 in the FAS.

End point type

Secondary

End point timeframe

Before first application of study medication (baseline) and every 12 weeks until end of treatment (EOT).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	304 ^[163]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=304)	73.3 ± 15.7
week 12 (N=263)	73.8 ± 16.4
week 24 (N=212)	73.6 ± 15.6
week 36 (N=180)	73.4 ± 17.4
week 48 (N=154)	75.7 ± 17.6
week 60 (N=138)	74.0 ± 17.6
week 72 (N=122)	76.0 ± 17.3
week 84 (N=105)	75.4 ± 16.5
week 96 (N=97)	74.2 ± 19.5
week 108 (N=75)	75.1 ± 18.0
week 120 (N=71)	74.5 ± 17.7
EOT (N=110)	71.0 ± 16.4

Notes
[163] - N = number of evaluable questionnaires (at baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - FACT-B Total Score

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End point title

Patient Reported Outcome (FAS) - FACT-B Total Score

End point description

HRQoL will be assessed with the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first). The questionnaire was analysed according to the manual [FACIT: FACT-B]. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire is subdivided into four QoL domains (i.e., physical well-being (PWB), functional well-being (FWB), emotional well-being (EWB), social/family well-being (SWB)) and a disease specific domain (breast cancer specific concerns (BCS)), with the total FACT-B score being calculated by summing the individual subscale scores. Higher scores indicate better quality of life. FACT-B Trial Total score: Score range 0 - 148 N = number of evaluable questionnaires / time point PRO results were displayed for TG1 – TG 4 in the FAS.

End point type

Secondary

End point timeframe

Before first application of study medication (baseline) and every 12 weeks until end of treatment (EOT).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	326 ^[164]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=303)	98.5 ± 19.7
week 12 (N=262)	98.2 ± 20.2
week 24 (N=212)	98.2 ± 20.2
week 36 (N=179)	97.8 ± 21.4
week 48 (N=155)	100.0 ± 21.9
week 60 (N=136)	97.9 ± 22.0
week 72 (N=122)	100.5 ± 21.4
week 84 (N=104)	99.3 ± 21.5
week 96 (N=96)	98.3 ± 24.5
week 108 (N=75)	99.4 ± 22.6
week 120 (N=71)	98.8 ± 21.9
EOT (N=108)	95.0 ± 20.3

Notes
[164] - Number of returned questionnaires (baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - FACT-B Trial Outcome Index

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End point title

Patient Reported Outcome (mPP) - FACT-B Trial Outcome Index

End point description

End point type

Secondary

End point timeframe

Before first application of study medication (baseline) and every 12 weeks until end of treatment (EOT).

End point values	Modified per-protocol set (mPP)
Number of subjects analysed
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=95)	58.6 ± 15.4
week 12 (N=88)	60.6 ± 15.1
week 24 (N=78)	60.6 ± 14.8
week 36 (N=68)	62.7 ± 15.0
week 48 (N=59)	61.3 ± 16.6
week 60 (N=52)	61.4 ± 15.9
week 72 (N=47)	62.6 ± 14.7
week 84 (N=43)	61.7 ± 16.1
week 96 (N=42)	61.6 ± 16.5
week 108 (N=34)	61.1 ± 17.5
week 120 (N=29)	60.3 ± 17.9
EOT (N=26)	59.8 ± 15.1

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - FACT-G Total Score

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End point title

Patient Reported Outcome (mPP) - FACT-G Total Score

End point description

HRQoL will be assessed with the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first). The questionnaire was analysed according to the manual [FACIT: FACT-B]. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire is subdivided into four QoL domains (i.e., physical well-being (PWB), functional well-being (FWB), emotional well-being (EWB), social/family well-being (SWB)) and a disease specific domain (breast cancer specific concerns (BCS)), with the total FACT-B score being calculated by summing the individual subscale scores. Higher scores indicate better quality of life. FACT-B Trial Total score: Score range 0 - 148 N = number of evaluable questionnaires / time point PRO results were displayed for TG5 and TG6 in the mPP.

End point type

Secondary

End point timeframe

Before first application of study medication (baseline) and every 12 weeks until end of treatment (EOT).

End point values	Modified per-protocol set (mPP)
Number of subjects analysed	92 ^[165]
Units: Unit on a scale
arithmetic mean (standard deviation)
Baseline (N=92)	71.1 ± 16.3
week 12 (N=86)	72.6 ± 16.4
week 24 (N=75)	71.8 ± 16.5
week 36 (N=67)	72.9 ± 18.6
week 48 (N=57)	73.4 ± 17.4
week 60 (N=52)	72.5 ± 17.6
week 72 (N=48)	74.3 ± 17.5
week 84 (N=41)	73.4 ± 17.6
week 96 (N=41)	73.4 ± 19.2
week 108 (N=33)	71.2 ± 19.4
week 120 (N=29)	70.5 ± 19.4
EOT (N=27)	72.7 ± 16.1

Notes
[165] - N = number of evaluable questionnaires (at baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - FACT-B Total Score

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End point title

Patient Reported Outcome (mPP) - FACT-B Total Score

End point description

HRQoL will be assessed with the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first). The questionnaire was analysed according to the manual [FACIT: FACT-B]. The Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire is subdivided into four QoL domains (i.e., physical well-being (PWB), functional well-being (FWB), emotional well-being (EWB), social/family well-being (SWB)) and a disease specific domain (breast cancer specific concerns (BCS)), with the total FACT-B score being calculated by summing the individual subscale scores. Higher scores indicate better quality of life. FACT-B Trial Total score: Score range 0 - 148 N = number of evaluable questionnaires / time point PRO results were displayed for TG5 and TG6 in the mPP.

End point type

Secondary

End point timeframe

Before first application of study medication (baseline) and every 12 weeks until end of treatment (EOT).

End point values	Modified per-protocol set (mPP)
Number of subjects analysed	92 ^[166]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=92)	95.4 ± 20.1
week 12 (N=86)	96.8 ± 21.0
week 24 (N=75)	96.0 ± 20.8
week 36 (N=67)	97.3 ± 22.3
week 48 (N=57)	97.6 ± 22.3
week 60 (N=51)	96.5 ± 22.5
week 72 (N=48)	98.3 ± 21.9
week 84 (N=41)	97.6 ± 22.9
week 96 (N=41)	97.2 ± 24.0
week 108 (N=33)	95.5 ± 24.8
week 120 (N=29)	93.5 ± 24.0
EOT (N=26)	96.0 ± 20.3

Notes
[166] - N = number of evaluable questionnaires (at baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - FACT-B Time to deterioration

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End point title

Patient Reported Outcome (FAS) - FACT-B Time to deterioration ^[167]

End point description

For FACT-B total score a decrease of ≥ 7 points (MID for FACT-B total score) compared to baseline was considered as relevant change. TTD was estimated by using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[167] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	233 ^[168]
Units: Months
median (confidence interval 95%)	8.8 (5.7 to 24.9)	5.7 (3.7 to 22.2)	11.9 (5.4 to 23.9)	8.5 (5.0 to 15.3)	8.5 (5.8 to 12.1)

Notes
[168] - N = number of patients in the (FAS TG1 - TG4).

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - FACT-G Time to deterioration

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End point title

Patient Reported Outcome (FAS) - FACT-G Time to deterioration ^[169]

End point description

For FACT-G total score a decrease of ≥ 5 points (MID for FACT-G total score) compared to baseline will be considered as relevant change. TTD was estimated by using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[169] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	233 ^[170]
Units: Months
median (confidence interval 95%)	6.7 (3.2 to 14.6)	5.7 (3.6 to 25.8)	11.9 (5.2 to 23.9)	8.6 (4.4 to 15.6)	8.1 (5.7 to 12.1)

Notes
[170] - N = number of patients in FAS (TG1 - TG4).

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - FACT-B Time to deterioration

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End point title

Patient Reported Outcome (mPP) - FACT-B Time to deterioration ^[171]

End point description

For FACT-B total score a decrease of ≥ 7 points (MID for FACT-B total score) compared to baseline was considered as relevant change. TTD was estimated by using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[171] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG5 (ANA1)	TG6 (EXE1)	Modified per-protocol set (mPP)
Number of subjects analysed	53	54	107
Units: Months
median (confidence interval 95%)	19.7 (5.9 to 24.7)	9.1 (5.5 to 16.4)	12.2 (6.2 to 20.9)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - FACT-G Time to deterioration

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End point title

Patient Reported Outcome (mPP) - FACT-G Time to deterioration ^[172]

End point description

For FACT-G total score a decrease of ≥ 5 points (MID for FACT-G total score) compared to baseline will be considered as relevant change. TTD was estimated by using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[172] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG5 (ANA1)	TG6 (EXE1)	Modified per-protocol set (mPP)
Number of subjects analysed	53	54	107
Units: Months
median (confidence interval 95%)	19.7 (5.9 to 27.9)	8.6 (6.0 to 16.4)	11.1 (6.3 to 21.6)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - Brief Fatique Inventory (BFI)

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End point title

Patient Reported Outcome (FAS) - Brief Fatique Inventory (BFI)

End point description

Cancer-related fatigue was assessed using the Brief Fatigue Inventory (BFI) questionnaire comprising questions on severity of fatigue and its interference in daily functioning. Included were six questions on the impairment of general activity, mood, walking ability, normal work, relations with others and enjoyment of life considering physical, emotional/affective and cognitive issues that may be associated with fatigue. Items on severity and impairment are rated on an eleven-point numerical rating scale (zero = no fatigue and 10 = worst fatigue imaginable). A global fatigue score can be obtained by averaging all the items, with higher scores signifying higher intensity and impairment. N = number of evaluable questionnaires / time point. PRO results were displayed for TG1 – TG6 in the FAS.

End point type

Secondary

End point timeframe

Fatigue was assessed with the BFI (Brief Fatigue Inventory) questionnaire abt baseline and every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	321 ^[173]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=321)	3.54 ± 2.14
week 12 (N=273)	3.77 ± 2.19
week 24 (N=217)	3.92 ± 2.20
week 36 (N=187)	3.89 ± 2.20
week 48 (N=158)	3.69 ± 2.26
week 60 (N=140)	3.91 ± 2.38
week 72 (N=125)	3.75 ± 2.24
week 84 (N=110)	3.76 ± 2.23
week 96 (N=99)	3.97 ± 2.43
week 108 (N=79)	3.73 ± 2.48
week 120 (N=73)	3.69 ± 2.26
EOT (N=118)	4.15 ± 2.25

Notes
[173] - N = number of eveluable questionnaires (baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - Brief Fatique Inventory (BFI)

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End point title

Patient Reported Outcome (mPP) - Brief Fatique Inventory (BFI)

End point description

End point type

Secondary

End point timeframe

Fatigue was assessed with the BFI (Brief Fatigue Inventory) questionnaire abt baseline and every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first).

End point values	Modified per-protocol set (mPP)
Number of subjects analysed	100 ^[174]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=100)	3.64 ± 2.22
week 12 (N=87)	3.92 ± 2.28
week 24 (N=76)	4.10 ± 2.28
week 36 (N=97)	3.80 ± 2.36
week 48 (N=59)	3.94 ± 2.29
week 60 (N=54)	4.17 ± 2.43
week 72 (N=48)	3.88 ± 2.20
week 84 (N=43)	3.94 ± 2.46
week 96 (N=41)	4.09 ± 2.46
week 108 (N=34)	4.00 ± 2.71
week 120 (N=29)	3.75 ± 2.47
EOT (N=31)	4.20 ± 2.41

Notes
[174] - N = number of evaluable questionnaires (baseline).

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - Brief fatique inventory (BFI) Time to deterioration

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End point title

Patient Reported Outcome (FAS) - Brief fatique inventory (BFI) Time to deterioration ^[175]

End point description

An increase of the BFI Global Score by at least 2 points compared to baseline is considered as a relevant change at the respective time point. TTD was estimated by using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[175] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	350 ^[176]
Units: Months
median (confidence interval 95%)	22.1 (7.9 to 32.4)	19.7 (10.6 to 25.8)	19.2 (8.1 to 49.2)	14.9 (14.6 to 22.1)	17.4 (14.6 to 22.1)

Notes
[176] - N = patients of TG1 - TG6

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - Brief fatique Inventory (BFI) Time to deterioration

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End point title

Patient Reported Outcome (mPP) - Brief fatique Inventory (BFI) Time to deterioration ^[177]

End point description

An increase of the BFI Global Score by at least 2 points compared to baseline is considered as a relevant change at the respective time point. TTD was estimated by using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[177] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG5 (ANA1)	TG6 (EXE1)	Modified per-protocol set (mPP)
Number of subjects analysed	53	54	107
Units: Months
median (confidence interval 95%)	20.9 (8.5 to 30.0)	15.8 (7.2 to 32.3)	17.4 (11.1 to 24.4)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Anxiety

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End point title

Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Anxiety

End point description

The HADS-S is a self-assessment questionnaire consisting of 14 items, of which seven each are covering anxiety and depression subscales, respectively. The questionnaire was analysed according to the manual.

End point type

Secondary

End point timeframe

From baseline and over time every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	325 ^[178]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=325)	6.79 ± 4.08
week 12 (N=276)	6.55 ± 3.94
week 24 (N=221)	6.42 ± 4.00
week 36 (N=189)	6.39 ± 3.83
week 48 (N=159)	6.37 ± 3.88
week 60 (N=140)	6.50 ± 4.11
week 72 (N=127)	6.58 ± 3.90
week 84 (N=112)	6.52 ± 3.72
week 96 (N=100)	6.47 ± 4.08
week 108 (N=80)	6.18 ± 3.58
week 120 (N=73)	6.07 ± 4.22
EOT (N=122)	7.30 ± 4.05

Notes
[178] - N = number of evaluable questionnaires (baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Anxiety

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End point title

Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Anxiety

End point description

End point type

Secondary

End point timeframe

From baseline and over time every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first).

End point values	Modified per-protocol set (mPP)
Number of subjects analysed	101 ^[179]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=100)	7.84 ± 4.06
week 12 (N=90)	6.73 ± 3.85
week 24 (N=78)	6.94 ± 3.91
week 36 (N=69)	6.70 ± 3.52
week 48 (N=60)	6.90 ± 4.02
week 60 (N=54)	6.71 ± 4.01
week 72 (N=49)	6.78 ± 3.85
week 84 (N=44)	7.09 ± 3.99
week 96 (N=42)	6.95 ± 3.86
week 108 (N=34)	6.41 ± 3.96
week 120 (N=29)	7.55 ± 4.38
EOT (N=31)	7.71 ± 4.37

Notes
[179] - N = number of evaluable questionnaires (baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Anxiety Time to deterioration

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End point title

Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Anxiety Time to deterioration ^[180]

End point description

For anxiety subscore an increase of 3.15 points (MID for anxiety subscore) or more from baseline will be considered as relevant change.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[180] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	350
Units: Months
median (confidence interval 95%)	32.4 (11.2 to 40.0)	22.3 (10.9 to 33.0)	33.9 (11.1 to 55.0)	15.3 (10.6 to 24.8)	23.2 (17.4 to 32.3)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Anxiety Time to deterioration

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End point title

Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Anxiety Time to deterioration ^[181]

End point description

For anxiety subscore an increase of 3.15 points (MID for anxiety subscore) or more from baseline will be considered as relevant change.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[181] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG5 (ANA1)	TG6 (EXE1)	Modified per-protocol set (mPP)
Number of subjects analysed	53	54	107
Units: Months
median (confidence interval 95%)	43.5 (20.9 to 999)	20.0 (11.2 to 32.2)	24.4 (20.0 to 44.8)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Depression

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End point title

Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Depression

End point description

End point type

Secondary

End point timeframe

From baseline and over time every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	326 ^[182]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=326)	5.51 ± 4.19
week 12 (N=276)	5.61 ± 4.00
week 24 (N=220)	5.50 ± 3.90
week 36 (N=189)	5.43 ± 3.40
week 48 (N=159)	5.21 ± 3.83
week 60 (N=140)	5.46 ± 4.23
week 72 (N=127)	5.02 ± 3.60
week 84 (N=112)	5.29 ± 3.40
week 96 (N=100)	5.57 ± 4.32
week 108 (N=80)	5.44 ± 4.19
week 120 (N=73)	5.89 ± 5.14
EOT (N=122)	6.28 ± 4.27

Notes
[182] - N =number of evaluable questionnaires (baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Depression

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End point title

Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Depression

End point description

End point type

Secondary

End point timeframe

From baseline and over time every 12 weeks until PD (or start of next anti-cancer therapy, whatever comes first).

End point values	Modified per-protocol set (mPP)
Number of subjects analysed	101 ^[183]
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (N=101)	6.27 ± 4.51
week 12 (N=90)	5.84 ± 4.20
week 24 (N=77)	5.97 ± 4.03
week 36 (N=69)	5.56 ± 4.19
week 48 (N=60)	5.42 ± 3.95
week 60 (N=54)	5.63 ± 4.51
week 72 (N=49)	5.08 ± 3.63
week 84 (N=44)	5.70 ± 4.34
week 96 (N=42)	5.76 ± 4.20
week 108 (N=34)	5.82 ± 4.67
week 120 (N=29)	6.97 ± 5.61
EOT (N=31)	6.13 ± 4.25

Notes
[183] - N = number of evaluable questionnaires (baseline)

No statistical analyses for this end point

Secondary: Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Depression Time to deterioration

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End point title

Patient Reported Outcome (FAS) - Hospital Anxiety and Depression Scale (HADS) - Depression Time to deterioration ^[184]

End point description

For depression subscore an increase of 3.15 points (MID for depression subscore) or more from baseline will be considered as relevant change.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[184] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	350 ^[185]
Units: Months
median (confidence interval 95%)	23.9 (11.5 to 34.6)	20.5 (10.6 to 26.9)	33.8 (16.5 to 55.0)	14.9 (9.6 to 22.9)	22.3 (16.8 to 27.1)

Notes
[185] - N = TG1 - TG6

No statistical analyses for this end point

Secondary: Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Depression Time to deterioration

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End point title

Patient Reported Outcome (mPP) - Hospital Anxiety and Depression Scale (HADS) - Depression Time to deterioration ^[186]

End point description

For depression subscore an increase of 3.15 points (MID for depression subscore) or more from baseline will be considered as relevant change. The questionnaire was analysed according to the manual.

End point type

Secondary

End point timeframe

Time to deterioration (TTD) was the time between date of baseline questionnaire and date of the questionnaire with first relevant change to baseline, or death, whichever came first.

Notes
[186] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Due to the exploratory nature of the study, the analysis was done descriptively.

End point values	TG5 (ANA1)	TG6 (EXE1)	Modified per-protocol set (mPP)
Number of subjects analysed	53	54	107 ^[187]
Units: Units on a scale
median (confidence interval 95%)	20.9 (6.3 to 27.9)	32.3 (16.4 to 36.4)	24.4 (16.7 to 32.3)

Notes
[187] - N = TG5 - TG6

No statistical analyses for this end point

Secondary: Physician's Assessment of Patient's Global Health Status (FAS, all patients) Physical well-being according to Physician

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End point title

Physician's Assessment of Patient's Global Health Status (FAS, all patients) Physical well-being according to Physician

End point description

The physician’s global health status assessment reflected the physician’s opinion of the patient’s overall clinical condition. The questionnaire ascertained the patient’s overall physical health status. The questionnaire was completed by the physician after every patient examination (data shown for baseline and over time up to 10 cycles).

End point type

Secondary

End point timeframe

At baseline and over time (every cycle at day 1).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	350
Units: Patients
Baseline (N=350) – Very good	61
Baseline (N=350) – Rather good	144
Baseline (N=350) – Fair	86
Baseline (N=350) – Rather poor	17
Baseline (N=350) – Very poor	1
Baseline (N=350) – not assessed	41
Baseline (N=350) – missing	0
Cycle 1 Day 1 (N=350) – Very good	54
Cycle 1 Day 1 (N=350) – Rather good	133
Cycle 1 Day 1 (N=350) – Fair	81
Cycle 1 Day 1 (N=350) – Rather poor	18
Cycle 1 Day 1 (N=350) – Very poor	2
Cycle 1 Day 1 (N=350) – not assessed	62
Cycle 1 Day 1 (N=350) – missing	0
Cycle 2 Day 1 (N=340) – Very good	59
Cycle 2 Day 1 (N=340) – Rather good	145
Cycle 2 Day 1 (N=340) – Fair	81
Cycle 2 Day 1 (N=340) – Rather poor	18
Cycle 2 Day 1 (N=340) – Very poor	1
Cycle 2 Day 1 (N=340) – not assessed	36
Cycle 2 Day 1 (N=340) – missing	0
Cycle 3 Day 1 (N=324) – Very good	60
Cycle 3 Day 1 (N=324) – Rather good	136
Cycle 3 Day 1 (N=324) – Fair	77
Cycle 3 Day 1 (N=324) – Rather poor	14
Cycle 3 Day 1 (N=324) – Very poor	1
Cycle 3 Day 1 (N=324) – not assessed	35
Cycle 3 Day 1 (N=324) – missing	1
Cycle 4 Day 1 (N=288) – Very good	52
Cycle 4 Day 1 (N=288) – Rather good	133
Cycle 4 Day 1 (N=288) – Fair	62
Cycle 4 Day 1 (N=288) – Rather poor	13
Cycle 4 Day 1 (N=288 – Very poor	1
Cycle 4 Day 1 (N=288) – not assessed	25
Cycle 4 Day 1 (N=288) – missing	2
Cycle 5 Day 1 (N=265) – Very good	54
Cycle 5 Day 1 (N=265) – Rather good	110
Cycle 5 Day 1 (N=265) – Fair	56
Cycle 5 Day 1 (N=265) – Rather poor	11
Cycle 5 Day 1 (N=265 – Very poor	0
Cycle 5 Day 1 (N=265) – not assessed	32
Cycle 5 Day 1 (N=265) – missing	2
Cycle 6 Day 1 (N=249) – Very good	51
Cycle 6 Day 1 (N=249) – Rather good	122
Cycle 6 Day 1 (N=249) – Fair	41
Cycle 6 Day 1 (N=249) – Rather poor	9
Cycle 6 Day 1 (N=249 – Very poor	1
Cycle 6 Day 1 (N=249) – not assessed	23
Cycle 6 Day 1 (N=249) – missing	2
Cycle 7 Day 1 (N=233) – Very good	54
Cycle 7 Day 1 (N=233) – Rather good	105
Cycle 7 Day 1 (N=233) – Fair	37
Cycle 7 Day 1 (N=233) – Rather poor	10
Cycle 7 Day 1 (N=233 – Very poor	0
Cycle 7 Day 1 (N=233) – not assessed	26
Cycle 7 Day 1 (N=233) – missing	1
Cycle 8 Day 1 (N=225) – Very good	41
Cycle 8 Day 1 (N=225) – Rather good	112
Cycle 8 Day 1 (N=225) – Fair	33
Cycle 8 Day 1 (N=225) – Rather poor	9
Cycle 8 Day 1 (N=225 – Very poor	2
Cycle 8 Day 1 (N=225) – not assessed	26
Cycle 8 Day 1 (N=225) – missing	2
Cycle 9 Day 1 (N=212) – Very good	47
Cycle 9 Day 1 (N=212) – Rather good	97
Cycle 9 Day 1 (N=212) – Fair	29
Cycle 9 Day 1 (N=212) – Rather poor	13
Cycle 9 Day 1 (N=212) – Very poor	1
Cycle 9 Day 1 (N=212) – not assessed	25
Cycle 9 Day 1 (N=212) – missing	0
Cycle 10 Day 1 (N=191) – Very good	47
Cycle 10 Day 1 (N=191) – Rather good	91
Cycle 10 Day 1 (N=191) – Fair	25
Cycle 10 Day 1 (N=191) – Rather poor	10
Cycle 10 Day 1 (N=191) – Very poor	0
Cycle 10 Day 1 (N=191) – not assessed	18
Cycle 10 Day 1 (N=191) – missing	0

No statistical analyses for this end point

Secondary: Hospitalizations - Frequency and reason for hospitalization

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End point title

Hospitalizations - Frequency and reason for hospitalization

End point description

Hospitalisation was defined as any initial admission (even less than 24 hours) in a hospital or equivalent healthcare facility or any prolongation to an existing admission. Admission also included transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a tuberculosis unit). An emergency room visit did not necessarily constitute a hospitalisation; the event leading to the emergency room visit was assessed for medical importance. Hospitalizations were documented and analysed on the basis of reported SAEs.

End point type

Secondary

End point timeframe

From treatment start until PD or start of next antineoplastic therapy, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	60	57	350 ^[188]
Units: Patients
Patients with Hospitalization - yes	17	11	11	20	12	14	85
Patients with Hospitalization - no	45	49	39	41	48	44	266
Patients with Hospitalization - missing	0	0	0	0	0	0	0
Reason for Hospitalization - (S)AE	15	7	10	19	8	11	70
Reason for Hospitalization - Pre-pl. treatm./surg.	1	2	0	4	3	1	11
Reason for Hospitalization - other	0	2	1	0	2	1	6

Notes
[188] - N = 351 patients [corresponds to Safety analysis population (SAF)]

No statistical analyses for this end point

Secondary: Hospitalizations - Duration of hospitalization

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End point title

Hospitalizations - Duration of hospitalization

End point description

End point type

Secondary

End point timeframe

From treatment start until PD or start of next antineoplastic therapy, whichever came first.

End point values	TG1 (LET1)	TG2 (LET2+)	TG3 (FUL1)	TG4 (FUL2+)	TG5 (ANA1)	TG6 (EXE1)	Full Analysis Set (FAS)
Number of subjects analysed	62	60	50	61	60	57	350
Units: days
median (full range (min-max))	8.0 (1.0 to 85.0)	2.5 (2.0 to 17.0)	9.0 (2.0 to 23.0)	7.0 (1.0 to 14.0)	7.5 (3.0 to 14.0)	6.5 (1.0 to 17.0)	7.0 (1.0 to 85.0)

No statistical analyses for this end point

Secondary: Adverse events as pot. Indicators for Progressive disease

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End point title

Adverse events as pot. Indicators for Progressive disease

End point description

To investigate whether organ-specific symptoms may serve as indicators for PD, cough and dyspnea (lung), bone pain (bones) and fatigue were analyzed (multiple PTs). The following events (TEAE) were considered (TEAE occurred at least at least once): “cough” or “dyspnea”, “bone pain” grade 3/4, or “fatigue” grade 3/4 and any of these symptoms. Categories: PD yes: PD (progressive disease - including death due to tumour disease) within 6 weeks after onset of symptome. PD no: No PD within 6 weeks after onset of symptome.

End point type

Secondary

End point timeframe

From treatment start and over time up to end of treatment (including 30 days safety follow-up).

End point values	Full Analysis Set (FAS)
Number of subjects analysed	351 ^[189]
Units: Patients
Cough or dyspnoe (CTCAE grade 3/4; n=7) – PD yes	0
Cough or dyspnoe (CTCAE grade 3/4; n=7) – PD no	7
Cough or dyspnoe (CTCAE grade1/2; n=90) – PD yes	13
Cough or dyspnoe (CTCAE grade1/2; n=90) – PD no	77
Bone pain (CTCAE grade 3/4; n=2) – PD yes	0
Bone pain (CTCAE grade 3/4; n=2) – PD no	2
Bone pain (CTCAE grade 1/2; n=42) – PD yes	1
Bone pain (CTCAE grade 1/2; n=42) – PD no	41
Fatigue (CTCAE grade 3/4 (n=8) – PD yes	2
Fatigue (CTCAE grade 3/4 (n=8) – PD no	6
Fatigue (CTCAE grade 1/2 (n=144) – PD yes	7
Fatigue (CTCAE grade 1/2 (n=144) – PD no	137

Notes
[189] - N = 351 [Safety analysis population (SAF)]

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From date of patient's signed informed consent until disease progression or start of next anti-cancer therapy, whatever came first.

Adverse event reporting additional description

An AE was classified as a treatment-emergent AE (TEAE) if it had emerged or worsened in the on-treatment period. On-treatment period: from day of first dose of study medication to 30 days after last dose of study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

TG 1

Reporting group description

Text Safety Set

Reporting group title

TG 2

Reporting group description

Safety Set

Reporting group title

TG 3

Reporting group description

Reporting group title

TG 4

Reporting group description

Safety Set

Reporting group title

TG 5

Reporting group description

Safety Set

Reporting group title

TG 6

Reporting group description

Safety Set

Serious adverse events	TG 1	TG 2	TG 3	TG 4	TG 5	TG 6
Total subjects affected by serious adverse events
subjects affected / exposed	24 / 62 (38.71%)	13 / 60 (21.67%)	16 / 50 (32.00%)	25 / 61 (40.98%)	14 / 60 (23.33%)	20 / 58 (34.48%)
number of deaths (all causes)	31	42	23	38	26	36
number of deaths resulting from adverse events	5	4	1	6	2	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	1 / 62 (1.61%)	2 / 60 (3.33%)	1 / 50 (2.00%)	3 / 61 (4.92%)	1 / 60 (1.67%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 3	0 / 1	0 / 2
Metastases to liver
subjects affected / exposed	1 / 62 (1.61%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to stomach
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arterial occlusive disease
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dry gangrene
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Iliac artery stenosis
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Fatigue
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrosis
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular stent occlusion
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Emphysema
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	4 / 62 (6.45%)	0 / 60 (0.00%)	1 / 50 (2.00%)	2 / 61 (3.28%)	1 / 60 (1.67%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 62 (3.23%)	2 / 60 (3.33%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Panic attack
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device breakage
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood glucose increased
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural diarrhoea
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic neck syndrome
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Restless legs syndrome
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VIth nerve paralysis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Epiretinal membrane
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal fissure
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 62 (1.61%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 62 (1.61%)	1 / 60 (1.67%)	0 / 50 (0.00%)	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Acute hepatitis B
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin necrosis
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exposed bone in jaw
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fistula inflammation
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteolysis
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	3 / 62 (4.84%)	2 / 60 (3.33%)	1 / 50 (2.00%)	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	2 / 62 (3.23%)	0 / 60 (0.00%)	2 / 50 (4.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess jaw
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis clostridial
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	2 / 50 (4.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	2 / 58 (3.45%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Influenca
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 62 (0.00%)	1 / 60 (1.67%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	1 / 58 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	0 / 50 (0.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	TG 1	TG 2	TG 3	TG 4	TG 5	TG 6
Total subjects affected by non serious adverse events
subjects affected / exposed	58 / 62 (93.55%)	58 / 60 (96.67%)	49 / 50 (98.00%)	55 / 61 (90.16%)	58 / 60 (96.67%)	56 / 58 (96.55%)
Vascular disorders
Hot flush
subjects affected / exposed	5 / 62 (8.06%)	7 / 60 (11.67%)	7 / 50 (14.00%)	4 / 61 (6.56%)	12 / 60 (20.00%)	3 / 58 (5.17%)
occurrences all number	5	7	9	4	12	3
Hypertension
subjects affected / exposed	2 / 62 (3.23%)	3 / 60 (5.00%)	1 / 50 (2.00%)	3 / 61 (4.92%)	1 / 60 (1.67%)	3 / 58 (5.17%)
occurrences all number	2	3	1	8	1	12
Lymphoedema
subjects affected / exposed	2 / 62 (3.23%)	0 / 60 (0.00%)	3 / 50 (6.00%)	2 / 61 (3.28%)	1 / 60 (1.67%)	1 / 58 (1.72%)
occurrences all number	2	0	3	2	1	1
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	0 / 62 (0.00%)	2 / 60 (3.33%)	3 / 50 (6.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	2 / 58 (3.45%)
occurrences all number	0	2	3	1	0	2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 62 (1.61%)	2 / 60 (3.33%)	0 / 50 (0.00%)	1 / 61 (1.64%)	3 / 60 (5.00%)	2 / 58 (3.45%)
occurrences all number	1	3	0	1	3	4
Fatigue
subjects affected / exposed	25 / 62 (40.32%)	24 / 60 (40.00%)	19 / 50 (38.00%)	12 / 61 (19.67%)	24 / 60 (40.00%)	17 / 58 (29.31%)
occurrences all number	34	30	25	13	27	21
Influenza like illness
subjects affected / exposed	5 / 62 (8.06%)	2 / 60 (3.33%)	1 / 50 (2.00%)	2 / 61 (3.28%)	0 / 60 (0.00%)	5 / 58 (8.62%)
occurrences all number	7	6	1	2	0	8
Mucosal dryness
subjects affected / exposed	2 / 62 (3.23%)	3 / 60 (5.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	1 / 58 (1.72%)
occurrences all number	2	3	1	0	1	1
Mucosal inflammation
subjects affected / exposed	1 / 62 (1.61%)	3 / 60 (5.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	3 / 60 (5.00%)	2 / 58 (3.45%)
occurrences all number	1	3	0	0	3	1
Oedema peripheral
subjects affected / exposed	3 / 62 (4.84%)	3 / 60 (5.00%)	1 / 50 (2.00%)	3 / 61 (4.92%)	3 / 60 (5.00%)	2 / 58 (3.45%)
occurrences all number	4	3	1	3	3	2
Peripheral swelling
subjects affected / exposed	1 / 62 (1.61%)	1 / 60 (1.67%)	3 / 50 (6.00%)	1 / 61 (1.64%)	2 / 60 (3.33%)	2 / 58 (3.45%)
occurrences all number	1	1	3	1	2	2
Pyrexia
subjects affected / exposed	4 / 62 (6.45%)	2 / 60 (3.33%)	3 / 50 (6.00%)	2 / 61 (3.28%)	4 / 60 (6.67%)	5 / 58 (8.62%)
occurrences all number	5	2	3	3	6	8
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 62 (11.29%)	3 / 60 (5.00%)	4 / 50 (8.00%)	3 / 61 (4.92%)	9 / 60 (15.00%)	7 / 58 (12.07%)
occurrences all number	8	4	4	3	9	7
Dyspnoea
subjects affected / exposed	5 / 62 (8.06%)	4 / 60 (6.67%)	5 / 50 (10.00%)	8 / 61 (13.11%)	9 / 60 (15.00%)	9 / 58 (15.52%)
occurrences all number	7	4	5	10	12	12
Epistaxis
subjects affected / exposed	8 / 62 (12.90%)	5 / 60 (8.33%)	4 / 50 (8.00%)	4 / 61 (6.56%)	3 / 60 (5.00%)	5 / 58 (8.62%)
occurrences all number	9	5	4	4	4	6
Pleural effusion
subjects affected / exposed	3 / 62 (4.84%)	1 / 60 (1.67%)	3 / 50 (6.00%)	0 / 61 (0.00%)	2 / 60 (3.33%)	5 / 58 (8.62%)
occurrences all number	5	1	3	0	3	6
Psychiatric disorders
Depression
subjects affected / exposed	5 / 62 (8.06%)	3 / 60 (5.00%)	1 / 50 (2.00%)	1 / 61 (1.64%)	3 / 60 (5.00%)	1 / 58 (1.72%)
occurrences all number	5	3	2	1	3	1
Insomnia
subjects affected / exposed	4 / 62 (6.45%)	4 / 60 (6.67%)	1 / 50 (2.00%)	1 / 61 (1.64%)	2 / 60 (3.33%)	0 / 58 (0.00%)
occurrences all number	4	4	1	1	2	0
Sleep disorder
subjects affected / exposed	4 / 62 (6.45%)	5 / 60 (8.33%)	1 / 50 (2.00%)	0 / 61 (0.00%)	2 / 60 (3.33%)	3 / 58 (5.17%)
occurrences all number	4	5	1	0	2	3
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 62 (1.61%)	4 / 60 (6.67%)	1 / 50 (2.00%)	3 / 61 (4.92%)	4 / 60 (6.67%)	5 / 58 (8.62%)
occurrences all number	1	4	1	4	5	5
Aspartate aminotransferase increased
subjects affected / exposed	3 / 62 (4.84%)	8 / 60 (13.33%)	1 / 50 (2.00%)	5 / 61 (8.20%)	4 / 60 (6.67%)	6 / 58 (10.34%)
occurrences all number	4	12	1	7	4	8
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 62 (0.00%)	5 / 60 (8.33%)	1 / 50 (2.00%)	1 / 61 (1.64%)	1 / 60 (1.67%)	3 / 58 (5.17%)
occurrences all number	0	5	3	1	1	3
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 62 (0.00%)	3 / 60 (5.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	2 / 58 (3.45%)
occurrences all number	0	4	0	0	0	2
Gamma-glutamyltransferase increased
subjects affected / exposed	2 / 62 (3.23%)	2 / 60 (3.33%)	0 / 50 (0.00%)	2 / 61 (3.28%)	1 / 60 (1.67%)	4 / 58 (6.90%)
occurrences all number	2	2	0	2	3	4
Neutrophil count decreased
subjects affected / exposed	12 / 62 (19.35%)	8 / 60 (13.33%)	8 / 50 (16.00%)	8 / 61 (13.11%)	6 / 60 (10.00%)	9 / 58 (15.52%)
occurrences all number	39	16	16	16	34	21
Platelet count decreased
subjects affected / exposed	3 / 62 (4.84%)	1 / 60 (1.67%)	4 / 50 (8.00%)	0 / 61 (0.00%)	3 / 60 (5.00%)	2 / 58 (3.45%)
occurrences all number	3	1	5	0	30	7
White blood cell count decreased
subjects affected / exposed	5 / 62 (8.06%)	4 / 60 (6.67%)	6 / 50 (12.00%)	4 / 61 (6.56%)	5 / 60 (8.33%)	5 / 58 (8.62%)
occurrences all number	6	6	10	16	62	12
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 62 (6.45%)	6 / 60 (10.00%)	4 / 50 (8.00%)	4 / 61 (6.56%)	8 / 60 (13.33%)	8 / 58 (13.79%)
occurrences all number	6	6	10	6	8	9
Dysgeusia
subjects affected / exposed	3 / 62 (4.84%)	0 / 60 (0.00%)	2 / 50 (4.00%)	4 / 61 (6.56%)	0 / 60 (0.00%)	3 / 58 (5.17%)
occurrences all number	4	0	2	4	0	3
Headache
subjects affected / exposed	8 / 62 (12.90%)	7 / 60 (11.67%)	5 / 50 (10.00%)	3 / 61 (4.92%)	12 / 60 (20.00%)	8 / 58 (13.79%)
occurrences all number	12	7	5	4	15	9
Paraesthesia
subjects affected / exposed	2 / 62 (3.23%)	3 / 60 (5.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	2 / 60 (3.33%)	4 / 58 (6.90%)
occurrences all number	2	3	0	0	2	4
Polyneuropathy
subjects affected / exposed	4 / 62 (6.45%)	4 / 60 (6.67%)	1 / 50 (2.00%)	1 / 61 (1.64%)	1 / 60 (1.67%)	2 / 58 (3.45%)
occurrences all number	5	4	1	1	1	2
Sciatica
subjects affected / exposed	0 / 62 (0.00%)	0 / 60 (0.00%)	3 / 50 (6.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	1 / 58 (1.72%)
occurrences all number	0	0	3	0	1	1
Taste disorder
subjects affected / exposed	4 / 62 (6.45%)	2 / 60 (3.33%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences all number	6	2	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 62 (16.13%)	2 / 60 (3.33%)	11 / 50 (22.00%)	8 / 61 (13.11%)	3 / 60 (5.00%)	8 / 58 (13.79%)
occurrences all number	10	4	11	16	10	16
Leukopenia
subjects affected / exposed	18 / 62 (29.03%)	8 / 60 (13.33%)	11 / 50 (22.00%)	14 / 61 (22.95%)	17 / 60 (28.33%)	10 / 58 (17.24%)
occurrences all number	27	24	22	31	30	17
Neutropenia
subjects affected / exposed	29 / 62 (46.77%)	24 / 60 (40.00%)	18 / 50 (36.00%)	26 / 61 (42.62%)	30 / 60 (50.00%)	27 / 58 (46.55%)
occurrences all number	103	56	59	86	144	88
Thrombocytopenia
subjects affected / exposed	5 / 62 (8.06%)	4 / 60 (6.67%)	5 / 50 (10.00%)	3 / 61 (4.92%)	6 / 60 (10.00%)	6 / 58 (10.34%)
occurrences all number	9	4	6	3	7	10
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 62 (1.61%)	4 / 60 (6.67%)	2 / 50 (4.00%)	1 / 61 (1.64%)	5 / 60 (8.33%)	6 / 58 (10.34%)
occurrences all number	1	4	2	1	7	7
Eye disorders
Lacrimation increased
subjects affected / exposed	4 / 62 (6.45%)	3 / 60 (5.00%)	2 / 50 (4.00%)	4 / 61 (6.56%)	2 / 60 (3.33%)	3 / 58 (5.17%)
occurrences all number	4	3	3	4	2	5
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 62 (3.23%)	3 / 60 (5.00%)	2 / 50 (4.00%)	2 / 61 (3.28%)	5 / 60 (8.33%)	4 / 58 (6.90%)
occurrences all number	2	3	2	2	5	4
Abdominal pain upper
subjects affected / exposed	2 / 62 (3.23%)	5 / 60 (8.33%)	4 / 50 (8.00%)	5 / 61 (8.20%)	3 / 60 (5.00%)	3 / 58 (5.17%)
occurrences all number	7	5	5	5	4	3
Aphthous ulcer
subjects affected / exposed	3 / 62 (4.84%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	3 / 60 (5.00%)	1 / 58 (1.72%)
occurrences all number	4	0	0	0	5	1
Constipation
subjects affected / exposed	6 / 62 (9.68%)	3 / 60 (5.00%)	10 / 50 (20.00%)	6 / 61 (9.84%)	3 / 60 (5.00%)	1 / 58 (1.72%)
occurrences all number	6	3	18	6	3	1
Diarrhoea
subjects affected / exposed	12 / 62 (19.35%)	9 / 60 (15.00%)	11 / 50 (22.00%)	14 / 61 (22.95%)	11 / 60 (18.33%)	14 / 58 (24.14%)
occurrences all number	15	16	20	24	16	19
Dyspepsia
subjects affected / exposed	5 / 62 (8.06%)	0 / 60 (0.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	3 / 60 (5.00%)	2 / 58 (3.45%)
occurrences all number	6	0	1	0	3	2
Nausea
subjects affected / exposed	16 / 62 (25.81%)	15 / 60 (25.00%)	12 / 50 (24.00%)	15 / 61 (24.59%)	16 / 60 (26.67%)	15 / 58 (25.86%)
occurrences all number	21	25	24	17	26	20
Stomatitis
subjects affected / exposed	9 / 62 (14.52%)	8 / 60 (13.33%)	4 / 50 (8.00%)	3 / 61 (4.92%)	5 / 60 (8.33%)	5 / 58 (8.62%)
occurrences all number	15	9	5	3	5	6
Vomiting
subjects affected / exposed	5 / 62 (8.06%)	7 / 60 (11.67%)	7 / 50 (14.00%)	10 / 61 (16.39%)	10 / 60 (16.67%)	11 / 58 (18.97%)
occurrences all number	6	8	10	10	14	19
Skin and subcutaneous tissue disorders
Back pain
subjects affected / exposed	10 / 62 (16.13%)	5 / 60 (8.33%)	6 / 50 (12.00%)	5 / 61 (8.20%)	8 / 60 (13.33%)	9 / 58 (15.52%)
occurrences all number	13	5	7	5	9	10
Alopecia
subjects affected / exposed	23 / 62 (37.10%)	12 / 60 (20.00%)	13 / 50 (26.00%)	7 / 61 (11.48%)	15 / 60 (25.00%)	8 / 58 (13.79%)
occurrences all number	26	13	14	7	17	9
Dermatitis acneiform
subjects affected / exposed	4 / 62 (6.45%)	0 / 60 (0.00%)	0 / 50 (0.00%)	0 / 61 (0.00%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences all number	6	0	0	0	0	0
Dry skin
subjects affected / exposed	7 / 62 (11.29%)	5 / 60 (8.33%)	2 / 50 (4.00%)	4 / 61 (6.56%)	5 / 60 (8.33%)	4 / 58 (6.90%)
occurrences all number	8	5	2	5	5	4
Erythema
subjects affected / exposed	4 / 62 (6.45%)	1 / 60 (1.67%)	1 / 50 (2.00%)	1 / 61 (1.64%)	0 / 60 (0.00%)	0 / 58 (0.00%)
occurrences all number	5	1	1	1	0	0
Pruritus
subjects affected / exposed	8 / 62 (12.90%)	1 / 60 (1.67%)	1 / 50 (2.00%)	1 / 61 (1.64%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences all number	8	1	1	1	1	0
Rash
subjects affected / exposed	5 / 62 (8.06%)	5 / 60 (8.33%)	2 / 50 (4.00%)	2 / 61 (3.28%)	4 / 60 (6.67%)	8 / 58 (13.79%)
occurrences all number	9	5	3	2	4	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	8 / 62 (12.90%)	10 / 60 (16.67%)	8 / 50 (16.00%)	6 / 61 (9.84%)	16 / 60 (26.67%)	8 / 58 (13.79%)
occurrences all number	10	13	9	8	17	9
Bone pain
subjects affected / exposed	8 / 62 (12.90%)	3 / 60 (5.00%)	4 / 50 (8.00%)	2 / 61 (3.28%)	9 / 60 (15.00%)	6 / 58 (10.34%)
occurrences all number	9	3	4	2	18	7
Muscle spasms
subjects affected / exposed	4 / 62 (6.45%)	8 / 60 (13.33%)	2 / 50 (4.00%)	3 / 61 (4.92%)	1 / 60 (1.67%)	2 / 58 (3.45%)
occurrences all number	10	12	2	6	1	2
Myalgia
subjects affected / exposed	1 / 62 (1.61%)	1 / 60 (1.67%)	1 / 50 (2.00%)	1 / 61 (1.64%)	4 / 60 (6.67%)	1 / 58 (1.72%)
occurrences all number	1	1	1	1	4	1
Pain in extremity
subjects affected / exposed	7 / 62 (11.29%)	1 / 60 (1.67%)	7 / 50 (14.00%)	7 / 61 (11.48%)	5 / 60 (8.33%)	3 / 58 (5.17%)
occurrences all number	9	1	7	10	5	4
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 62 (4.84%)	7 / 60 (11.67%)	5 / 50 (10.00%)	2 / 61 (3.28%)	2 / 60 (3.33%)	4 / 58 (6.90%)
occurrences all number	3	11	5	2	2	4
COVID-19
subjects affected / exposed	1 / 62 (1.61%)	0 / 60 (0.00%)	4 / 50 (8.00%)	2 / 61 (3.28%)	1 / 60 (1.67%)	0 / 58 (0.00%)
occurrences all number	1	0	4	2	1	0
Cystitis
subjects affected / exposed	1 / 62 (1.61%)	3 / 60 (5.00%)	1 / 50 (2.00%)	0 / 61 (0.00%)	1 / 60 (1.67%)	3 / 58 (5.17%)
occurrences all number	1	9	3	0	1	3
Infection
subjects affected / exposed	1 / 62 (1.61%)	1 / 60 (1.67%)	0 / 50 (0.00%)	1 / 61 (1.64%)	6 / 60 (10.00%)	1 / 58 (1.72%)
occurrences all number	1	1	0	1	6	1
Nasopharyngitis
subjects affected / exposed	9 / 62 (14.52%)	14 / 60 (23.33%)	8 / 50 (16.00%)	12 / 61 (19.67%)	7 / 60 (11.67%)	8 / 58 (13.79%)
occurrences all number	21	20	14	17	12	11
Oral herpes
subjects affected / exposed	2 / 62 (3.23%)	1 / 60 (1.67%)	4 / 50 (8.00%)	0 / 61 (0.00%)	3 / 60 (5.00%)	2 / 58 (3.45%)
occurrences all number	2	1	6	0	3	2
Urinary tract infection
subjects affected / exposed	2 / 62 (3.23%)	4 / 60 (6.67%)	3 / 50 (6.00%)	2 / 61 (3.28%)	4 / 60 (6.67%)	2 / 58 (3.45%)
occurrences all number	2	4	5	2	6	2
Viral upper respiratory tract infection
subjects affected / exposed	3 / 62 (4.84%)	1 / 60 (1.67%)	2 / 50 (4.00%)	0 / 61 (0.00%)	9 / 60 (15.00%)	2 / 58 (3.45%)
occurrences all number	3	1	4	0	11	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	9 / 62 (14.52%)	6 / 60 (10.00%)	6 / 50 (12.00%)	2 / 61 (3.28%)	5 / 60 (8.33%)	4 / 58 (6.90%)
occurrences all number	11	8	6	3	5	5

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

01 Feb 2017

AM1: The IMP palbociclib obtained marketing authorization in November 2016 Therefore, Palbociclib was commercially available and prescribed by the investigators since March 2017. The patient population was extended to 360 pre- and perimenopausal patients in 85 sites, scheduled for palliative treatment with the combination of Palbociclib and Letrozole for first- and later-line and the combination partners Anastrozole for first line, Exemestane for first-line or fulvestrant for first- and later-line after prior endocrine therapy. The recruitment period was extended from 12 to 28 months until December 2018. The ICF was amended (v5.0 dated 06 Feb 2017) due to changes in the SmPC Ibrance® (11/2016).

17 Dec 2018

AM2: Implementation of an interim analysis (fulvestrant treatment groups); implementation of a modified per protocol analysis population (mPP); submission of SmPC Ibrance® (07/2018).

15 Apr 2020

AM3: Implementation of an additional patient leaflet / informed consent form no. 1 (v2.0 dated 15 Apr 2020) due to safety changes in the SmPC Ibrance® (11/2019);

10 Sep 2020

AM4: Amendment to the study protocol: Implementation of an addendum to the study protocol (Addendum v1.0 dated 10 Sep 2020). Implementation of an additional patient leaflet / informed consent form no.2 (v1.0 dated 10 Sep 2020) due to the change of the formulation of Ibrance® from capsule to film coated (SmPC (06/2020)).

09 May 2022

AM5: Implementation of an additional patient leaflet / informed consent form (no. 3 (v2.0 dated 09 May 2022) due to safety changes in the SmPC Ibrance® (07/2021).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Exploratory trial: no randomization; descriptive analysis; no formal comparison between the treatment arms.

http://www.ncbi.nlm.nih.gov/pubmed/27959613
http://www.ncbi.nlm.nih.gov/pubmed/29360932
http://www.ncbi.nlm.nih.gov/pubmed/26947331

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Clinical Benefit Rate (CBR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Primary: Clinical Benefit Rate (CBR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Primary: Best Overall Response Rate (BOR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Primary: Best Overall Response Rate (BOR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Clinical Benefit Rate (CBR) - Patients with measurable disease (IA)

Secondary: Clinical Benefit Rate (CBR) - Patients with measurable disease (IA)

Secondary: Clinical Benefit Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

Secondary: Clinical Benefit Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

Secondary: Clinical Benefit Rate by change in FACT-B Total Score - All patients [(measurable and non-measurable disease (IA)]

Secondary: Clinical Benefit Rate by change in FACT-B Total Score - All patients [(measurable and non-measurable disease (IA)]

Secondary: Physicians Assessment of Global Health Status

Secondary: Physicians Assessment of Global Health Status

Secondary: Best Overall Response Rate (BOR) - Patients with measurable disease (IA)

Secondary: Best Overall Response Rate (BOR) - Patients with measurable disease (IA)

Secondary: Best Overall Response Rate (BOR) - All patients [(measurable and non-measurable disease (IA)]

Secondary: Best Overall Response Rate (BOR) - All patients [(measurable and non-measurable disease (IA)]

Secondary: Overall Response Rate (ORR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Overall Response Rate (ORR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Overall Response Rate (ORR) - Patients with measurable disease (IA)

Secondary: Overall Response Rate (ORR) - Patients with measurable disease (IA)

Secondary: Overall Response Rate (ORR) - All patients [measurable and non-measurable disease (IA)]

Secondary: Overall Response Rate (ORR) - All patients [measurable and non-measurable disease (IA)]

Secondary: Disease Control Rate (DCR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Disease Control Rate (DCR) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Disease Control Rate (CBR) - Patients with measurable disease (IA)

Secondary: Disease Control Rate (CBR) - Patients with measurable disease (IA)

Secondary: Disease Control Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

Secondary: Disease Control Rate (CBR) - All patients [measurable and non-measurable disease (IA)]

Secondary: Progression Free Survival (PFS) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Progression Free Survival (PFS) - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: Progression Free Survival (PFS) - Patients with measurable disease (IA)

Secondary: Progression Free Survival (PFS) - Patients with measurable disease (IA)

Secondary: Progression Free Survival (PFS) - All patients [measurable and non-measurable disease (IA)]

Secondary: Progression Free Survival (PFS) - All patients [measurable and non-measurable disease (IA)]

Secondary: Overall Survival (OS) - Patients with measurable disease

Secondary: Overall Survival (OS) - Patients with measurable disease

Secondary: Overall Survival (OS) - All patients (measurable and non-measurable disease)

Secondary: Overall Survival (OS) - All patients (measurable and non-measurable disease)

Secondary: 1-Year PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: 1-Year PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: 1-Year PFS Rate - Patients with measurable disease (IA)

Secondary: 1-Year PFS Rate - Patients with measurable disease (IA)

Secondary: 1-Year PFS Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 1-Year PFS Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 2-y PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: 2-y PFS Rate - Patients with measurable disease (calculated acc. to RECIST 1.1)

Secondary: 2-y PFS Rate - Patients with measurable disease (IA)

Secondary: 2-y PFS Rate - Patients with measurable disease (IA)

Secondary: 2-y PFS Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 2-y PFS Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 1-y Overall Survival Rate - Patients with measurable disease

Secondary: 1-y Overall Survival Rate - Patients with measurable disease

Secondary: 1-y Overall Survival Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 1-y Overall Survival Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 2-y Overall Survival Rate - Patients with measurable disease

Secondary: 2-y Overall Survival Rate - Patients with measurable disease

Secondary: 2-y OS Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: 2-y OS Rate - All patients [measurable and non-measurable disease (IA)]

Secondary: Treatment details - Treatment duration (All patients, FAS)

Secondary: Treatment details - Treatment duration (All patients, FAS)

Secondary: Treatment details - Treatment modifications (All patients, FAS / mPP)

Secondary: Treatment details - Treatment modifications (All patients, FAS / mPP)

Secondary: Treatment details - Reason for treatment modification [Palbociclib - All patients, FAS / mPP)]

Secondary: Treatment details - Reason for treatment modification [Palbociclib - All patients, FAS / mPP)]

Secondary: Treatment details - Relative dose intensity overall (SAF)

Secondary: Treatment details - Relative dose intensity overall (SAF)

Secondary: Patient Reported Outcome (FAS) - FACT-B Trial Outcome Index

Secondary: Patient Reported Outcome (FAS) - FACT-B Trial Outcome Index

Secondary: Patient Reported Outcome (FAS) - FACT-G Total Score

Secondary: Patient Reported Outcome (FAS) - FACT-G Total Score

Secondary: Patient Reported Outcome (FAS) - FACT-B Total Score