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Clinical Trial Results:
A Multicentre Phase II Study of Adavosertib plus Chemotherapy in Patients with Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Summary
EudraCT number	2015-000886-30
Trial protocol	GB NL
Global end of trial date	13 Dec 2018

Results information
Results version number	v1(current)
This version publication date	05 Apr 2023
First version publication date	05 Apr 2023
Other versions

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

D6010C00004

ISRCTN number

US NCT number

NCT02272790

WHO universal trial number (UTN)

Other trial identifiers

Sarah Cannon Development Innovations, LLC: GYN 49

Sponsor organisation name

AstraZeneca, Global Medicines Development - Oncology

Sponsor organisation address

City House, 132-134 Hills Road, Cambridge, United Kingdom, CB2 1PG

Public contact

Pejvack Motlagh, MD, AstraZeneca, +44 0 7384 799 850, pejvack.motlagh@astrazeneca.com

Scientific contact

Pejvack Motlagh, MD, AstraZeneca, +44 0 7384 799 850, pejvack.motlagh@astrazeneca.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

04 Jun 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Dec 2018

Global end of trial reached?

Yes

Global end of trial date

13 Dec 2018

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial was to evaluate the objective response rate (ORR) of AZD1775 in combination with carboplatin, paclitaxel, gemcitabine, or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Protection of trial subjects

The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonisation (ICH) Good Clinical Practice guidance, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. Precautions were taken to preserve confidentiality and prevent genetic data being linked to the identity of the subject. An Institutional Review Board (IRB) or Ethics Committee reviewed and approved the study protocol, as well as the Informed Consent Form document and other written information provided to the subjects.

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Feb 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 84

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

Netherlands: 1

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This multi-center study was conducted at 20 sites: 18 in the USA, 1 in Canada, and 1 in The Netherlands. Ninety-four (94) patients received treatment. The first patient started treatment on 2 Feb 2015; the final patients were still receiving treatment and were censored at the time of database lock on 14 Dec 2018.

Screening details

One hundred twenty-six (126) patients consented and underwent screening; 94 patients passed screening, whereas 32 patients failed screening tests and were not eligible. The Full Analysis Set consists of 94 patients.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The study was not blinded

Are arms mutually exclusive

Yes

Arm A

Arm description

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm type

Experimental

Investigational medicinal product name

Adavosertib

Investigational medicinal product code

Adavosertib

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles.

Investigational medicinal product name

Gemcitabine

Investigational medicinal product code

Other name

Gemzar

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm B

Arm description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles. Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Taxol

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Investigational medicinal product name

Adavosertib

Investigational medicinal product code

Adavosertib

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles.

Arm C

Arm description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Arm type

Experimental

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Investigational medicinal product name

Adavosertib

Investigational medicinal product code

Adavosertib

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 21 day cycles.

Arm C2

Arm description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Arm type

Experimental

Investigational medicinal product name

Adavosertib

Investigational medicinal product code

Adavosertib

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Paraplatin

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Arm D-175 mg

Arm description

Adavosertib 175 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Arm type

Experimental

Investigational medicinal product name

Pegylated Liposomal Doxorubicin

Investigational medicinal product code

Other name

PLD

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Investigational medicinal product name

Adavosertib

Investigational medicinal product code

Adavosertib

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adavosertib 175 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles.

Arm D-225 mg

Arm description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Arm type

Experimental

Investigational medicinal product name

Pegylated Liposomal Doxorubicin

Investigational medicinal product code

Other name

PLD

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Investigational medicinal product name

Adavosertib

Investigational medicinal product code

Adavosertib

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles.

Number of subjects in period 1	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Started	9	38	23	12	6	6
Completed	9	38	23	12	6	6

Baseline characteristics

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Reporting group title

Arm A

Reporting group description

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Reporting group title

Arm B

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles. Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Reporting group title

Arm C

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Reporting group title

Arm C2

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Reporting group title

Arm D-175 mg

Reporting group description

Adavosertib 175 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Reporting group title

Arm D-225 mg

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Reporting group values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg	Total
Number of subjects	9	38	23	12	6	6	94
Age categorical
Units: Subjects
Adults (18-64 years)	5	26	14	8	3	3	59
≥ 65 years	4	12	9	4	3	3	35
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.6 ( 9.75 )	60.9 ( 8.16 )	62.1 ( 11.29 )	60.3 ( 6.96 )	57.3 ( 14.58 )	61.0 ( 7.16 )	-
Sex: Female, Male
Units: Subjects
Female	9	38	23	12	6	6	94
Male	0	0	0	0	0	0	0
Age, Categorical
Units: Subjects
< 65	5	26	14	8	3	3	59
≥ 65	4	12	9	4	3	3	35
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0
Asian	0	5	0	0	0	0	5
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	2	4	2	0	0	0	8
White	7	24	20	10	6	6	73
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	0	5	1	2	0	0	8
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	1	6	2	2	0	1	12
Not Hispanic or Latino	8	31	21	10	5	5	80
Unknown or Not Reported	0	1	0	0	1	0	2
ECOG Performance Status
ECOG Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out light or sedentary work; 2 = Ambulatory and capable of all self care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, cannot carry on any self care. Totally confined to bed or chair; 5 = Dead.
Units: Subjects
PS = 0	5	19	13	4	1	3	45
PS = 1	4	19	10	8	5	3	49
PS = 2	0	0	0	0	0	0	0
PS = 3	0	0	0	0	0	0	0
PS = 4	0	0	0	0	0	0	0
Local or Regional Recurrence
Units: Subjects
Yes	5	26	17	9	4	6	67
No	4	12	6	3	2	0	27
Distant Metastases
Units: Subjects
Yes	3	29	11	12	5	5	65
No	6	9	12	0	1	1	29
Histology
Units: Subjects
Serous Epithelial Carcinoma	9	33	21	12	4	6	85
Endometrioid Carcinoma	0	1	0	0	0	0	1
Clear Cell Epithelial Carcinoma	0	2	1	0	1	0	4
Transitional Cell/Brenner Carcinoma	0	0	0	0	0	0	0
Squamous Cell Epithelial Carcinoma	0	0	0	0	0	0	0
Undifferentiated Epithelial Carcinoma	0	0	0	0	0	0	0
Mucinous Epithelial Carcinoma	0	0	0	0	1	0	1
Mixed Epithelial Carcinoma	0	1	0	0	0	0	1
Missing	0	1	1	0	0	0	2
Histological Grade
Units: Subjects
G1 - Well Differentiated	1	1	0	2	0	0	4
G2 - Moderately Differentiated	0	1	1	0	0	0	2
G3 - Poorly Differentiated	5	28	15	9	5	3	65
G4 - Undifferentiated	0	3	2	0	1	1	7
GX - Grade cannot be assessed or Not Applicable	2	3	3	1	0	2	11
Missing	1	2	2	0	0	0	5
Stage at Initial Diagnosis
Units: Subjects
IC	0	1	0	0	0	0	1
IIC	0	0	0	0	1	0	1
III	0	1	1	0	0	0	2
IIIA	0	1	0	0	1	0	2
IIIB	0	2	0	0	1	0	3
IIIC	6	14	14	4	1	5	44
IV	3	18	8	8	2	1	40
Missing	0	1	0	0	0	0	1
Metastatic Disease
Units: Subjects
Yes	7	37	19	12	5	6	86
No	2	1	4	0	1	0	8
Prior Systemic Therapy
Units: Subjects
Yes	9	38	23	12	6	6	94
No	0	0	0	0	0	0	0
Number of prior treatment regimens
Units: Subjects
No. of subjects with no prior treatment regimens	0	0	0	0	0	0	0
No. of subjects with 1 prior treatment regimen	3	12	8	4	3	2	32
No. of subjects with 2 prior treatment regimens	6	16	9	5	3	4	43
No. of subjects with 3 prior treatment regimens	0	10	6	2	0	0	18
No. of subjects with >3 prior treatment regimens	0	0	0	1	0	0	1
Disease setting for most recent prior regimen
Units: Subjects
Adj/Neoadj in Localized disease (Stage I or II)	0	1	0	0	1	0	2
Adjuvant in advanced disease (Stage III or IV)	4	14	13	4	3	1	39
Neoadjuvant in advanced disease (Stage III or IV)	0	3	2	2	0	1	8
Metastatic	5	19	8	6	2	4	44
Missing	0	1	0	0	0	0	1
Best overall response to most recent prior regimen
Units: Subjects
Complete Response (CR)	0	0	0	0	1	2	3
Partial Response (PR)	0	2	1	1	0	1	5
Non-CR/Non-PD	0	1	0	0	0	0	1
Stable Disease (SD)	2	4	1	2	1	0	10
Progressive Disease (PD)	2	9	5	4	1	2	23
Not Evaluable	0	1	0	0	0	0	1
Not Applicable	5	21	16	5	3	1	51
Reason most recent prior regimen ended
Units: Subjects
Completed planned treatment	4	14	10	5	3	2	38
Progressive Disease	5	19	10	7	2	3	46
Toxicity	0	3	1	0	1	1	6
Other	0	2	2	0	0	0	4
Prior Surgery
Units: Subjects
Yes	8	35	22	11	6	6	88
No	1	3	1	1	0	0	6
Prior Radiotherapy
Units: Subjects
Yes	0	1	0	0	0	0	1
No	9	37	23	12	6	6	93
Region of Enrollment
Units: Subjects
United States	7	30	23	12	6	6	84
Canada	2	7	0	0	0	0	9
Netherlands	0	1	0	0	0	0	1
Time from 1st positive biopsy for disease to consent for this study (mean)
Units: Weeks
arithmetic mean (standard deviation)	52.0 ( 11.83 )	70.9 ( 46.42 )	62.3 ( 24.68 )	86.1 ( 55.67 )	61.4 ( 23.88 )	65.8 ( 20.82 )	-
Time from 1st positive biopsy for disease to consent for this study (median)
Units: Weeks
median (full range (min-max))	49.9 (35.9 to 77.1)	54.9 (31.4 to 250.4)	54.1 (30.0 to 113.6)	74.9 (25.1 to 241.0)	62.9 (30.6 to 87.4)	71.1 (41.1 to 90.0)	-
Time from local/regional recurrence to consent for this study (mean)
Sixty-seven (67) patients has a local or regional recurrence.
Units: Weeks
arithmetic mean (standard deviation)	12.2 ( 14.98 )	34.3 ( 51.20 )	20.6 ( 20.23 )	47.0 ( 57.13 )	39.3 ( 27.78 )	5.2 ( 3.61 )	-
Time from local/regional recurrence to consent for this study (median)
Sixty-seven (67) patients has a local or regional recurrence.
Units: Weeks
median (full range (min-max))	6.1 (3.0 to 38.9)	18.6 (0.6 to 200.4)	16.6 (1.6 to 70.6)	15.4 (0.9 to 177.9)	37.7 (7.6 to 74.3)	5.6 (0.4 to 10.0)	-
Time from end of most recent prior systemic therapy to consent for this trial (mean)
Units: Weeks
arithmetic mean (standard deviation)	11.0 ( 9.54 )	14.4 ( 15.45 )	10.5 ( 7.81 )	15.4 ( 15.12 )	12.9 ( 11.36 )	13.4 ( 12.08 )	-
Time from end of most recent prior systemic therapy to consent for this trial (median)
Units: Weeks
median (full range (min-max))	5.4 (2 to 25)	6.9 (1 to 82)	6.9 (0 to 27)	9.4 (2 to 53)	10.5 (2 to 32)	12.2 (1 to 36)	-
Weight (mean)
Units: Kilograms
arithmetic mean (standard deviation)	73.5 ( 21.56 )	73.2 ( 15.89 )	75.7 ( 19.25 )	70.6 ( 9.45 )	70.2 ( 14.11 )	65.7 ( 8.61 )	-
Weight (median)
Units: Kilograms
median (full range (min-max))	69.6 (47.6 to 124.1)	69.6 (47.4 to 117.6)	71.5 (44.8 to 114.0)	67.7 (56.9 to 85.1)	68.2 (56.2 to 95.1)	67.8 (51.1 to 74.4)	-
Systolic Blood Pressure (mean)
Units: mmHg
arithmetic mean (standard deviation)	130.0 ( 15.23 )	125.2 ( 13.37 )	127.7 ( 10.65 )	122.3 ( 6.40 )	125.2 ( 17.22 )	127.5 ( 9.35 )	-
Systolic Blood Pressure (median)
Units: mmHg
median (full range (min-max))	130.0 (109.0 to 153.0)	126.5 (100.0 to 159.0)	128.0 (110.0 to 153.0)	121.0 (115.0 to 137.0)	120.0 (112.0 to 159.0)	126.5 (113.0 to 142.0)	-
Diastolic Blood Pressure (mean)
Units: mmHg
arithmetic mean (standard deviation)	76.2 ( 10.96 )	76.7 ( 7.74 )	74.8 ( 8.03 )	74.4 ( 8.26 )	73.0 ( 6.66 )	78.7 ( 6.02 )	-
Diastolic Blood Pressure (median)
Units: mmHg
median (full range (min-max))	78.0 (62.0 to 90.0)	78.0 (59.0 to 93.0)	75.0 (61.0 to 95.0)	73.5 (62.0 to 87.0)	74.0 (63.0 to 83.0)	77.5 (73.0 to 89.0)	-
Body Surface Area (mean)
Units: m²
arithmetic mean (standard deviation)	1.8 ( 0.25 )	1.8 ( 0.19 )	1.8 ( 0.22 )	1.8 ( 0.13 )	1.8 ( 0.18 )	1.7 ( 0.10 )	-
Body Surface Area (median)
Units: m²
median (full range (min-max))	1.8 (1.5 to 2.3)	1.8 (1.4 to 2.3)	1.8 (1.4 to 2.3)	1.7 (1.6 to 2.0)	1.7 (1.6 to 2.1)	1.7 (1.5 to 1.8)	-
Age Continuous \|
Units: years
median (full range (min-max))	63.0 (46 to 72)	60.0 (45 to 76)	62.0 (34 to 85)	58.5 (52 to 76)	58.5 (40 to 72)	60.5 (54 to 70)	-

Subject analysis set title

Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set included all patients who received at least one dose of study treatment.

Subject analysis sets values	Full Analysis Set
Number of subjects	94
Age categorical
Units: Subjects
Adults (18-64 years)	59
≥ 65 years	35
Age Continuous
Units: years
arithmetic mean (standard deviation)	60.7 ( 9.30 )
Sex: Female, Male
Units: Subjects
Female	94
Male	0
Age, Categorical
Units: Subjects
< 65	59
≥ 65	35
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0
Asian	5
Native Hawaiian or Other Pacific Islander	0
Black or African American	8
White	73
More than one race	0
Unknown or Not Reported	8
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	12
Not Hispanic or Latino	80
Unknown or Not Reported	2
ECOG Performance Status
ECOG Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out light or sedentary work; 2 = Ambulatory and capable of all self care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, cannot carry on any self care. Totally confined to bed or chair; 5 = Dead.
Units: Subjects
PS = 0	45
PS = 1	49
PS = 2	0
PS = 3	0
PS = 4	0
Local or Regional Recurrence
Units: Subjects
Yes	67
No	27
Distant Metastases
Units: Subjects
Yes	65
No	29
Histology
Units: Subjects
Serous Epithelial Carcinoma	85
Endometrioid Carcinoma	1
Clear Cell Epithelial Carcinoma	4
Transitional Cell/Brenner Carcinoma	0
Squamous Cell Epithelial Carcinoma	0
Undifferentiated Epithelial Carcinoma	0
Mucinous Epithelial Carcinoma	1
Mixed Epithelial Carcinoma	1
Missing	2
Histological Grade
Units: Subjects
G1 - Well Differentiated	4
G2 - Moderately Differentiated	2
G3 - Poorly Differentiated	65
G4 - Undifferentiated	7
GX - Grade cannot be assessed or Not Applicable	11
Missing	5
Stage at Initial Diagnosis
Units: Subjects
IC	1
IIC	1
III	2
IIIA	2
IIIB	3
IIIC	44
IV	40
Missing	1
Metastatic Disease
Units: Subjects
Yes	86
No	8
Prior Systemic Therapy
Units: Subjects
Yes	94
No	0
Number of prior treatment regimens
Units: Subjects
No. of subjects with no prior treatment regimens	0
No. of subjects with 1 prior treatment regimen	32
No. of subjects with 2 prior treatment regimens	43
No. of subjects with 3 prior treatment regimens	18
No. of subjects with >3 prior treatment regimens	1
Disease setting for most recent prior regimen
Units: Subjects
Adj/Neoadj in Localized disease (Stage I or II)	2
Adjuvant in advanced disease (Stage III or IV)	39
Neoadjuvant in advanced disease (Stage III or IV)	8
Metastatic	44
Missing	1
Best overall response to most recent prior regimen
Units: Subjects
Complete Response (CR)	3
Partial Response (PR)	5
Non-CR/Non-PD	1
Stable Disease (SD)	10
Progressive Disease (PD)	23
Not Evaluable	1
Not Applicable	51
Reason most recent prior regimen ended
Units: Subjects
Completed planned treatment	38
Progressive Disease	46
Toxicity	6
Other	4
Prior Surgery
Units: Subjects
Yes	88
No	6
Prior Radiotherapy
Units: Subjects
Yes	1
No	93
Region of Enrollment
Units: Subjects
United States	84
Canada	9
Netherlands	1
Time from 1st positive biopsy for disease to consent for this study (mean)
Units: Weeks
arithmetic mean (standard deviation)	68.0 ( 38.93 )
Time from 1st positive biopsy for disease to consent for this study (median)
Units: Weeks
median (full range (min-max))	54.9 (25.1 to 250.4)
Time from local/regional recurrence to consent for this study (mean)
Sixty-seven (67) patients has a local or regional recurrence.
Units: Weeks
arithmetic mean (standard deviation)	28.6 ( 41.11 )
Time from local/regional recurrence to consent for this study (median)
Sixty-seven (67) patients has a local or regional recurrence.
Units: Weeks
median (full range (min-max))	13.0 (0.4 to 200.4)
Time from end of most recent prior systemic therapy to consent for this trial (mean)
Units: Weeks
arithmetic mean (standard deviation)	13.1 ( 12.75 )
Time from end of most recent prior systemic therapy to consent for this trial (median)
Units: Weeks
median (full range (min-max))	7.6 (0 to 82)
Weight (mean)
Units: Kilograms
arithmetic mean (standard deviation)	72.8 ( 16.12 )
Weight (median)
Units: Kilograms
median (full range (min-max))	69.7 (44.8 to 124.1)
Systolic Blood Pressure (mean)
Units: mmHg
arithmetic mean (standard deviation)	126.1 ( 12.16 )
Systolic Blood Pressure (median)
Units: mmHg
median (full range (min-max))	126.0 (100.0 to 159.0)
Diastolic Blood Pressure (mean)
Units: mmHg
arithmetic mean (standard deviation)	75.8 ( 7.99 )
Diastolic Blood Pressure (median)
Units: mmHg
median (full range (min-max))	76.0 (59.0 to 95.0)
Body Surface Area (mean)
Units: m²
arithmetic mean (standard deviation)	1.8 ( 0.19 )
Body Surface Area (median)
Units: m²
median (full range (min-max))	1.7 (1.4 to 2.3)
Age Continuous \|
Units: years
median (full range (min-max))	60.0 (34 to 85)

End points

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Reporting group title

Arm A

Reporting group description

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Reporting group title

Arm B

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles. Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Reporting group title

Arm C

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Reporting group title

Arm C2

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Reporting group title

Arm D-175 mg

Reporting group description

Adavosertib 175 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Reporting group title

Arm D-225 mg

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Subject analysis set title

Full Analysis Set

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set included all patients who received at least one dose of study treatment.

Primary: Objective Response Rate (ORR)

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End point title

Objective Response Rate (ORR) ^[1]

End point description

Objective response rate is defined as the proportion of patients achieving a complete or partial tumour response according to RECIST v1.1 criteria.

End point type

Primary

End point timeframe

Throughout the duration of the study (up to 19 months)

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: The study protocol did not specify statistical analysis for this primary endpoint.

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	1	11	7	8	2	1

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title

Disease Control Rate (DCR)

End point description

The Disease Control Rate is defined as the proportion of patients achieving a complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1 criteria.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	3	27	19	12	3	5

No statistical analyses for this end point

Secondary: Duration of Response (DoR)

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End point title

Duration of Response (DoR)

End point description

Duration of Response (DoR) is defined as the time from first documented tumour response until the date of documented progression or death from any cause.

End point type

Secondary

End point timeframe

Throughout the duration of the study, approximately 19 months.

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	1	11	7	8	2	1
Units: Months
median (confidence interval 95%)	4.4 (0 to 99999.9)	12.0 (3.7 to 99999.9)	0 (0 to 99999.9)	10.4 (5.8 to 99999.9)	0 (0 to 99999.9)	0 (0 to 99999.9)

No statistical analyses for this end point

Secondary: Progression Free Survival (Median, 80% CI)

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End point title

Progression Free Survival (Median, 80% CI)

End point description

Progression-free survival (PFS) was defined as the elapsed time from date of first dose of adavosertib until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. Progression-free survival was derived based on scan/assessment dates, not visit dates.

End point type

Secondary

End point timeframe

Throughout the Study, Approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Months
median (confidence interval 80%)	1.7 (1.6 to 5.5)	5.5 (3.8 to 7.1)	4.2 (3.9 to 5.6)	12.0 (8.6 to 13.1)	2.7 (1.7 to 99999.9)	0 (0 to 99999.9)

No statistical analyses for this end point

Secondary: Progression Free Survival (Median, 95% CI)

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End point title

Progression Free Survival (Median, 95% CI)

End point description

End point type

Secondary

End point timeframe

Throughout the Study, Approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Months
median (confidence interval 95%)	1.7 (0.3 to 5.5)	5.5 (3.7 to 7.4)	4.2 (2.8 to 8.9)	12.0 (2.7 to 99999.9)	2.7 (0.5 to 99999.9)	0 (0 to 99999.9)

No statistical analyses for this end point

Secondary: Overall Survival (Median, 80% CI)

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End point title

Overall Survival (Median, 80% CI)

End point description

Overall survival (OS) was defined as the elapsed time from the date of first dose of adavosertib until death due to any cause. Any patient not known to have died at the time of the analysis was censored based on the last recorded date on which the patient was known to be alive.

End point type

Secondary

End point timeframe

Throughout the Study, Approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Months
median (confidence interval 80%)	16.0 (6.7 to 99999.9)	99999.9 (15.6 to 99999.9)	8.9 (8.0 to 99999.9)	19.2 (12.4 to 19.2)	3.8 (2.0 to 6.2)	0 (0 to 99999.9)

No statistical analyses for this end point

Secondary: Overall Survival (Median, 95% CI)

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End point title

Overall Survival (Median, 95% CI)

End point description

End point type

Secondary

End point timeframe

Throughout the Study, Approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Months
median (confidence interval 95%)	16.0 (2.2 to 99999.9)	99999.9 (11.6 to 99999.9)	8.9 (8.0 to 99999.9)	19.2 (12.4 to 19.2)	6.2 (2.0 to 99999.9)	0 (0 to 99999.9)

No statistical analyses for this end point

Secondary: Gynecologic Cancer Intergroup (GCIG) CA-125 Response

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End point title

Gynecologic Cancer Intergroup (GCIG) CA-125 Response

End point description

The GCIG CA-125 response is defined as the proportion of patients achieving a 50% reduction in CA-125 levels from baseline, if baseline level is ≥2 x the upper limit of normal (ULN) within 2 weeks prior to starting treatment. Response must be confirmed and maintained for at least 28 days.

End point type

Secondary

End point timeframe

Throughout the study, approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	8	28	15	11	4	4
Units: Percent
number (confidence interval 90%)	25.0 (4.6 to 60.0)	53.6 (36.6 to 69.9)	26.7 (9.7 to 51.1)	63.6 (35.0 to 86.5)	25.0 (1.3 to 75.1)	25.0 (1.3 to 75.1)

No statistical analyses for this end point

Secondary: Treatment-emergent adverse events (TEAEs).

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End point title

Treatment-emergent adverse events (TEAEs).

End point description

The number and proportion of patients experiencing at least one treatment-related adverse event (TEAE). Severity Grade 1 = Mild; Severity Grade 2 = Moderate; Severity Grade 3 = Severe; Severity Grade 4 = Life Threatening; Severity Grade 5 = Fatal

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants
Participants with at least one TEAE Grade 1.	0	2	0	0	0	0
Participants with at least one TEAE Grade 2.	1	1	5	0	3	4
Participants with at least one TEAE Grade 3.	2	19	10	4	3	0
Participants with at least one TEAE Grade 4.	6	15	8	8	0	2
Participants with at least one TEAE Grade 5.	0	1	0	0	0	0

No statistical analyses for this end point

Secondary: Treatment-emergent adverse events (TEAEs) Related to Adavosertib

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End point title

Treatment-emergent adverse events (TEAEs) Related to Adavosertib

End point description

The number and proportion of patients experiencing at least one treatment-related adverse event (TEAE) related to adavosertib.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants
Participants with at least one TEAE Grade 1.	0	3	2	0	0	0
Participants with at least one TEAE Grade 2.	1	4	5	0	5	4
Participants with at least one TEAE Grade 3.	3	16	7	4	1	0
Participants with at least one TEAE Grade 4.	5	14	8	8	0	2
Participants with at least one TEAE Grade 5.	0	1	0	0	0	0

No statistical analyses for this end point

Secondary: Treatment-emergent adverse events (TEAEs) Related to Chemotherapy

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End point title

Treatment-emergent adverse events (TEAEs) Related to Chemotherapy

End point description

The number of patients experiencing at least one treatment-related adverse event (TEAE) related to chemotherapy.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants
Participants with at least one TEAE Grade 1.	0	4	0	0	0	0
Participants with at least one TEAE Grade 2.	1	5	6	0	5	4
Participants with at least one TEAE Grade 3.	3	13	8	4	1	0
Participants with at least one TEAE Grade 4.	5	15	8	8	0	2
Participants with at least one TEAE Grade 5.	0	1	0	0	0	0

No statistical analyses for this end point

Secondary: Serious Adverse Events

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End point title

Serious Adverse Events

End point description

The number of patients experiencing at least one serious adverse event (SAE).

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants
Pts. with ≥ one serious TEAE related to AZD1775.	0	8	9	7	1	1
Pts. with ≥ one serious TEAE related to Chemo.	0	8	9	7	1	1

No statistical analyses for this end point

Secondary: Serious Adverse Events Leading to Death

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End point title

Serious Adverse Events Leading to Death

End point description

The number of patients experiencing at least one serious adverse event (SAE) leading to death.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants
No. with STEAE related to AZD1775 leading to death	0	1	0	0	0	0
No. with STEAE related to chemo leading to death	0	1	0	0	0	0

No statistical analyses for this end point

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation

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End point title

Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation

End point description

The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment discontinuation.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	0	6	5	1	0	0

No statistical analyses for this end point

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction

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End point title

Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction

End point description

The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to dose reduction.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	2	18	5	11	0	0

No statistical analyses for this end point

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption

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End point title

Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption

End point description

The number of patients experiencing at least one treatment-related adverse event related to adavosertib leading to treatment interruption.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	8	30	10	11	0	1

No statistical analyses for this end point

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation

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End point title

Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation

End point description

The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment discontinuation.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	0	6	5	1	0	0

No statistical analyses for this end point

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction

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End point title

Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction

End point description

The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to dose reduction.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	6	19	8	11	0	0

No statistical analyses for this end point

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption

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End point title

Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption

End point description

The number of patients experiencing at least one treatment-related adverse event related to chemotherapy leading to treatment interruption.

End point type

Secondary

End point timeframe

Throughout the duration of the study (up to 19 months)

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Participants	8	28	12	9	0	1

No statistical analyses for this end point

Secondary: Single Dose Adavosertib Cmax

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End point title

Single Dose Adavosertib Cmax ^[2]

End point description

Maximum plasma concentration of adavosertib after a single oral dose (Cycle 1 Day 1) in combination with IV infusion of commonly used chemotherapy agents, including gemcitabine, paclitaxel, and carboplatin.

End point type

Secondary

End point timeframe

8 hours

Notes
[2] - 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: Single Dose Cmax was only calculated in Arms B and C. Sufficient data were not available to calculate this parameter in other arms.

End point values	Arm B	Arm C
Number of subjects analysed	7	6
Units: nM
geometric mean (geometric coefficient of variation)	533.8 ( 37.29 )	556.6 ( 56.39 )

No statistical analyses for this end point

Secondary: Multiple Dose Adavosertib Cmax

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End point title

Multiple Dose Adavosertib Cmax ^[3]

End point description

Maximum plasma concentration of adavosertib after a multiple oral doses (Cycle 1 Day 3) in combination with IV infusion of 40 mg/m² pegylated liposomal doxorubicin.

End point type

Secondary

End point timeframe

3 Days

Notes
[3] - 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: Multiple dose pharmacokinetics were calculated only in Arm D-175 mg and Arm D-225 mg.

End point values	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	5	2
Units: nM
geometric mean (geometric coefficient of variation)	4135 ( 65.8 )	23530 ( 30.15 )

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival

End point description

End point type

Secondary

End point timeframe

Throughout the Study, Approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Months
median (confidence interval 90%)	16.0 (2.2 to 99999.9)	99999.9 (11.6 to 99999.9)	8.9 (6.5 to 99999.9)	19.2 (12.4 to 19.2)	6.2 (2.0 to 99999.9)	0 (0 to 99999.9)

No statistical analyses for this end point

Secondary: Single Dose Adavosertib tmax

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End point title

Single Dose Adavosertib tmax ^[4]

End point description

The time to reach maximum plasma concentration of adavosertib after a single oral dose (Cycle 1 Day 1) in combination with IV infusion of commonly used chemotherapy agents, including gemcitabine, paclitaxel, and carboplatin.

End point type

Secondary

End point timeframe

8 hours

Notes
[4] - 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: Single Dose tmax was only calculated in Arms B and C. Sufficient data were not available to calculate this parameter in other arms.

End point values	Arm B	Arm C
Number of subjects analysed	7	6
Units: hours
median (full range (min-max))	4.08 (1.97 to 8.00)	3.15 (1.75 to 4.07)

No statistical analyses for this end point

Secondary: Progression Free Survival

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End point title

Progression Free Survival

End point description

Progression-Free Survival (PFS) was defined as the elapsed time from the date of first dose of adavosertib until confirmed progressive disease or death due to any cause.

End point type

Secondary

End point timeframe

Throughout the Study, Approximately 4 years

End point values	Arm A	Arm B	Arm C	Arm C2	Arm D-175 mg	Arm D-225 mg
Number of subjects analysed	9	38	23	12	6	6
Units: Months
median (confidence interval 95%)	1.7 (0.3 to 5.5)	5.5 (3.7 to 7.4)	4.2 (2.8 to 8.9)	12.0 (2.7 to 99999.9)	2.7 (0.5 to 99999.9)	0 (0 to 99999.9)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Throughout the study, approximately 19 months

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Arm A

Reporting group description

Adavosertib 175 mg orally QD on Days 1, 2, 8, 9, 15, and 16 of 28 day cycles. Gemcitabine 800 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Reporting group title

Arm B

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 28 day cycles. Paclitaxel 80 mg/m² IV on Days 1, 8, and 15 of 28 day cycles.

Reporting group title

Arm D-175 mg

Reporting group description

Adavosertib 175 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Reporting group title

Arm C2

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3, 8-10, and 15-17 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Reporting group title

Arm D-225 mg

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 28 day cycles. Pegylated liposomal doxorubicin 40 mg/m² IV on Day 1 of 28 day cycles.

Reporting group title

Arm C

Reporting group description

Adavosertib 225 mg orally BID (5 doses over 3 days) on Days 1-3 of 21 day cycles. Carboplatin AUC 5 IV on Day 1 of 21 day cycles.

Serious adverse events	Arm A	Arm B	Arm D-175 mg	Arm C2	Arm D-225 mg	Arm C
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 9 (44.44%)	17 / 38 (44.74%)	2 / 6 (33.33%)	8 / 12 (66.67%)	1 / 6 (16.67%)	12 / 23 (52.17%)
number of deaths (all causes)	5	12	3	2	0	9
number of deaths resulting from adverse events	0	1	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 9 (11.11%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Pyrexia
subjects affected / exposed	1 / 9 (11.11%)	1 / 38 (2.63%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Anaphylactic Reaction
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (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
Immune system disorders
Chest Pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 23 (4.35%)
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
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (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
Pulmonary Embolism
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wheezing
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Platelet Count Decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil Count Decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Gastrointestinal Stoma Complication
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
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
Infusion Related Reaction
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial Fibrillation
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Nervous system disorders
Transient Ischaemic Attack
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Blood and lymphatic system disorders
Febrile Neutropenia
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 0	5 / 5	0 / 0	1 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	4 / 23 (17.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	2 / 12 (16.67%)	1 / 6 (16.67%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Thrombocytopenia
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	5 / 12 (41.67%)	0 / 6 (0.00%)	3 / 23 (13.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 6	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Abdominal Pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
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
Diarrhoea
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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 Obstruction
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (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
Nausea
subjects affected / exposed	1 / 9 (11.11%)	1 / 38 (2.63%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 1	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small Intestinal Obstruction
subjects affected / exposed	2 / 9 (22.22%)	3 / 38 (7.89%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 3	0 / 6	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 9 (11.11%)	1 / 38 (2.63%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 1	1 / 1	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Skin Ulcer
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (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
Musculoskeletal and connective tissue disorders
Flank Pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 38 (0.00%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 4	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
Kidney Infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Cellulitis
subjects affected / exposed	1 / 9 (11.11%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Liver Abscess
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Neutropenic Sepsis
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Paraspinal Abscess
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Sepsis
subjects affected / exposed	1 / 9 (11.11%)	0 / 38 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Septic Shock
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Urinary Tract Infection
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Vascular Device Infection
subjects affected / exposed	0 / 9 (0.00%)	1 / 38 (2.63%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (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
Metabolism and nutrition disorders
Type 2 Diabetes Mellitus
subjects affected / exposed	0 / 9 (0.00%)	0 / 38 (0.00%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (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	Arm A	Arm B	Arm D-175 mg	Arm C2	Arm D-225 mg	Arm C
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	38 / 38 (100.00%)	6 / 6 (100.00%)	12 / 12 (100.00%)	6 / 6 (100.00%)	23 / 23 (100.00%)
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	3 / 9 (33.33%)	2 / 38 (5.26%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	3	2	0	0	0	0
Aspartate Aminotransferase Increased
subjects affected / exposed	1 / 9 (11.11%)	4 / 38 (10.53%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	3	11	0	0	0	0
Blood Alkaline Phosphatase Increased
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	0	5	0	1	0	3
Blood Creatinine Increased
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	3	0	1	0	2
Neutrophil Count Decreased
subjects affected / exposed	4 / 9 (44.44%)	13 / 38 (34.21%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	5 / 23 (21.74%)
occurrences all number	16	64	0	0	0	17
Platelet Count Decreased
subjects affected / exposed	2 / 9 (22.22%)	7 / 38 (18.42%)	0 / 6 (0.00%)	0 / 12 (0.00%)	1 / 6 (16.67%)	5 / 23 (21.74%)
occurrences all number	10	12	0	0	1	19
Weight Decreased
subjects affected / exposed	1 / 9 (11.11%)	3 / 38 (7.89%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	1	3	1	0	0	2
White Blood Cell Count Decreased
subjects affected / exposed	2 / 9 (22.22%)	11 / 38 (28.95%)	1 / 6 (16.67%)	0 / 12 (0.00%)	1 / 6 (16.67%)	4 / 23 (17.39%)
occurrences all number	10	64	1	0	1	17
Nervous system disorders
Dysgeusia
subjects affected / exposed	1 / 9 (11.11%)	4 / 38 (10.53%)	1 / 6 (16.67%)	4 / 12 (33.33%)	0 / 6 (0.00%)	3 / 23 (13.04%)
occurrences all number	1	4	1	4	0	4
Dizziness
subjects affected / exposed	0 / 9 (0.00%)	2 / 38 (5.26%)	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 6 (33.33%)	3 / 23 (13.04%)
occurrences all number	0	2	0	1	3	5
Headache
subjects affected / exposed	1 / 9 (11.11%)	8 / 38 (21.05%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	7 / 23 (30.43%)
occurrences all number	1	8	0	1	0	9
Peripheral Sensory Neuropathy
subjects affected / exposed	0 / 9 (0.00%)	8 / 38 (21.05%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	14	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 9 (33.33%)	24 / 38 (63.16%)	3 / 6 (50.00%)	9 / 12 (75.00%)	2 / 6 (33.33%)	13 / 23 (56.52%)
occurrences all number	12	82	4	48	2	45
Thrombocytopenia
subjects affected / exposed	1 / 9 (11.11%)	9 / 38 (23.68%)	0 / 6 (0.00%)	11 / 12 (91.67%)	0 / 6 (0.00%)	11 / 23 (47.83%)
occurrences all number	3	12	0	90	0	33
Neutropenia
subjects affected / exposed	4 / 9 (44.44%)	12 / 38 (31.58%)	1 / 6 (16.67%)	11 / 12 (91.67%)	2 / 6 (33.33%)	5 / 23 (21.74%)
occurrences all number	14	25	1	51	8	14
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 9 (33.33%)	23 / 38 (60.53%)	3 / 6 (50.00%)	8 / 12 (66.67%)	5 / 6 (83.33%)	17 / 23 (73.91%)
occurrences all number	5	33	6	11	5	30
Oedema, Peripheral
subjects affected / exposed	0 / 9 (0.00%)	10 / 38 (26.32%)	0 / 6 (0.00%)	5 / 12 (41.67%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	10	0	5	0	0
Pyrexia
subjects affected / exposed	4 / 9 (44.44%)	8 / 38 (21.05%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences all number	4	11	3	0	0	1
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	2 / 9 (22.22%)	2 / 38 (5.26%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	3 / 23 (13.04%)
occurrences all number	3	2	1	0	0	3
Abdominal Pain
subjects affected / exposed	2 / 9 (22.22%)	8 / 38 (21.05%)	1 / 6 (16.67%)	1 / 12 (8.33%)	2 / 6 (33.33%)	8 / 23 (34.78%)
occurrences all number	2	12	2	4	3	9
Constipation
subjects affected / exposed	1 / 9 (11.11%)	4 / 38 (10.53%)	2 / 6 (33.33%)	4 / 12 (33.33%)	0 / 6 (0.00%)	5 / 23 (21.74%)
occurrences all number	1	4	2	4	0	7
Diarrhoea
subjects affected / exposed	3 / 9 (33.33%)	31 / 38 (81.58%)	1 / 6 (16.67%)	6 / 12 (50.00%)	5 / 6 (83.33%)	16 / 23 (69.57%)
occurrences all number	3	67	1	11	9	33
Dyspepsia
subjects affected / exposed	1 / 9 (11.11%)	3 / 38 (7.89%)	0 / 6 (0.00%)	1 / 12 (8.33%)	2 / 6 (33.33%)	2 / 23 (8.70%)
occurrences all number	1	3	0	1	2	2
Stomatitis
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	2 / 6 (33.33%)	1 / 12 (8.33%)	1 / 6 (16.67%)	2 / 23 (8.70%)
occurrences all number	0	3	4	2	1	2
Nausea
subjects affected / exposed	5 / 9 (55.56%)	23 / 38 (60.53%)	4 / 6 (66.67%)	10 / 12 (83.33%)	4 / 6 (66.67%)	19 / 23 (82.61%)
occurrences all number	9	49	5	12	7	38
Gastrointestinal Reflux Disease
subjects affected / exposed	0 / 9 (0.00%)	4 / 38 (10.53%)	3 / 6 (50.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences all number	0	4	3	0	0	2
Vomiting
subjects affected / exposed	4 / 9 (44.44%)	19 / 38 (50.00%)	3 / 6 (50.00%)	4 / 12 (33.33%)	0 / 6 (0.00%)	13 / 23 (56.52%)
occurrences all number	7	41	3	9	0	24
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 9 (0.00%)	5 / 38 (13.16%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	3 / 23 (13.04%)
occurrences all number	0	5	0	1	0	3
Dyspnoea
subjects affected / exposed	1 / 9 (11.11%)	10 / 38 (26.32%)	0 / 6 (0.00%)	4 / 12 (33.33%)	1 / 6 (16.67%)	4 / 23 (17.39%)
occurrences all number	1	12	0	6	2	4
Epistaxis
subjects affected / exposed	1 / 9 (11.11%)	2 / 38 (5.26%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	1	2	0	1	0	4
Oropharyngeal Pain
subjects affected / exposed	1 / 9 (11.11%)	2 / 38 (5.26%)	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	3	0	2	0	1
Nasal Congestion
subjects affected / exposed	0 / 9 (0.00%)	5 / 38 (13.16%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	0	7	0	0	0	2
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	2 / 9 (22.22%)	1 / 38 (2.63%)	1 / 6 (16.67%)	0 / 12 (0.00%)	1 / 6 (16.67%)	3 / 23 (13.04%)
occurrences all number	4	1	1	0	1	5
Alopecia
subjects affected / exposed	0 / 9 (0.00%)	6 / 38 (15.79%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	6	1	1	0	0
Rash
subjects affected / exposed	3 / 9 (33.33%)	2 / 38 (5.26%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	3	2	2	1	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 9 (11.11%)	6 / 38 (15.79%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	1	6	1	1	0	5
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	1 / 9 (11.11%)	6 / 38 (15.79%)	1 / 6 (16.67%)	3 / 12 (25.00%)	0 / 6 (0.00%)	4 / 23 (17.39%)
occurrences all number	1	6	1	3	0	5
Arthralgia
subjects affected / exposed	2 / 9 (22.22%)	1 / 38 (2.63%)	0 / 6 (0.00%)	3 / 12 (25.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	2	1	0	3	0	2
Pain in Extremity
subjects affected / exposed	1 / 9 (11.11%)	4 / 38 (10.53%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	1	4	0	0	0	0
Myalgia
subjects affected / exposed	0 / 9 (0.00%)	6 / 38 (15.79%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	6	0	0	0	0
Bone Pain
subjects affected / exposed	1 / 9 (11.11%)	1 / 38 (2.63%)	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences all number	1	1	0	2	0	2
Infections and infestations
Urinary Tract Infection
subjects affected / exposed	0 / 9 (0.00%)	6 / 38 (15.79%)	1 / 6 (16.67%)	1 / 12 (8.33%)	1 / 6 (16.67%)	2 / 23 (8.70%)
occurrences all number	0	9	1	1	2	3
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	2 / 9 (22.22%)	7 / 38 (18.42%)	1 / 6 (16.67%)	1 / 12 (8.33%)	0 / 6 (0.00%)	5 / 23 (21.74%)
occurrences all number	3	9	1	1	0	5
Hypokalaemia
subjects affected / exposed	1 / 9 (11.11%)	4 / 38 (10.53%)	1 / 6 (16.67%)	3 / 12 (25.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	1	6	1	4	0	8
Hypoalbuminaemia
subjects affected / exposed	0 / 9 (0.00%)	6 / 38 (15.79%)	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	18	0	2	0	0
Hyperglycaemia
subjects affected / exposed	1 / 9 (11.11%)	6 / 38 (15.79%)	1 / 6 (16.67%)	0 / 12 (0.00%)	0 / 6 (0.00%)	3 / 23 (13.04%)
occurrences all number	2	12	1	0	0	3
Dehydration
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	0 / 6 (0.00%)	0 / 12 (0.00%)	0 / 6 (0.00%)	2 / 23 (8.70%)
occurrences all number	0	3	0	0	0	4
Hypophosphataemia
subjects affected / exposed	0 / 9 (0.00%)	3 / 38 (7.89%)	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	0 / 23 (0.00%)
occurrences all number	0	5	0	2	0	0
Hyponatraemia
subjects affected / exposed	1 / 9 (11.11%)	4 / 38 (10.53%)	0 / 6 (0.00%)	1 / 12 (8.33%)	0 / 6 (0.00%)	1 / 23 (4.35%)
occurrences all number	7	6	0	1	0	1
Hypomagnesaemia
subjects affected / exposed	1 / 9 (11.11%)	8 / 38 (21.05%)	0 / 6 (0.00%)	2 / 12 (16.67%)	0 / 6 (0.00%)	6 / 23 (26.09%)
occurrences all number	1	13	0	3	0	8

More information

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Were there any global substantial amendments to the protocol? Yes

06 Oct 2014

Amendment 1 changed adavosertib dosing to occur concurrently with chemotherapy and clarified the conduct of the study. Additional guidance and clarification on DLT criteria, TP53 mutation testing, and study windows were provided. Additional dose-limiting criteria were included for Part 1 of the study (Grade 3 thrombocytopenia with bleeding as a haematologic DLT).

18 May 2015

Amendment 2 clarified eligibility criteria in patients with prior adjuvant therapy and reduced the starting dose of gemcitabine from 1000 mg/² to 800 mg/². In addition, the text was updated to better clarify the study conduct.

29 Jun 2015

Amendment 3 changed the restrictions and the inclusion criteria for the study, including clarifying allowable number of treatment regimens, types of treatment, and stage of disease. This amendment also identified corrections to the edition numbering to bring it back into alignment.

04 Dec 2015

Amendment 4 updated the study design to an open-label, four-arm lead-in safety and two-arm efficacy study. Enrolment was stopped in Arm A (adavosertib plus gemcitabine) and Arm B (adavosertib plus paclitaxel) beyond the safety cohorts. A treatment arm was added to evaluate safety and efficacy of adavosertib plus PLD (Arm D). In addition, proof of TP53 mutation prior to enrolment was no longer required.

17 Aug 2016

Amendment 5 aligned the CSP with the most recent adavosertib safety information, and removed the expansion cohort of Arm D (adavosertib plus PLD).

20 Jan 2017

Amendment 6 expanded Arm B (adavosertib plus paclitaxel) to further assess efficacy, and Arm C (adavosertib plus carboplatin; referred as Arm C2) to optimise the dosing schedule for prolonged adavosertib exposure. Mandatory PK assessments were added for patients in the expansion cohorts and an optional PGx assessment was added for all patients.

19 Jun 2017

Amendment 7 clarified the inclusion and exclusion criteria relating to allowable prior treatments and patients with a history of Torsades de pointes. The schedule for cfDNA collections was modified for treatment Arm B and Arm C, and text regarding ‘Best Regimen’ was removed from tumour response assessments.

14 Feb 2018

Amendment 8 provided new dose modification guidance for the management of haematological events.

05 Sep 2018

Amendment 9 clarified study procedures and analysis relating to the addition of the FPV for patients who continued to receive adavosertib ± chemotherapy after the time of primary data cut-off.

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.

In some cases the median or confidence interval limits could not be calculated. If the upper limit of the confidence interval could not be calculated 99999.9 was entered.

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Clinical trials

Clinical Trial Results: A Multicentre Phase II Study of Adavosertib plus Chemotherapy in Patients with Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Objective Response Rate (ORR)

Primary: Objective Response Rate (ORR)

Secondary: Disease Control Rate (DCR)

Secondary: Disease Control Rate (DCR)

Secondary: Duration of Response (DoR)

Secondary: Duration of Response (DoR)

Secondary: Progression Free Survival (Median, 80% CI)

Secondary: Progression Free Survival (Median, 80% CI)

Secondary: Progression Free Survival (Median, 95% CI)

Secondary: Progression Free Survival (Median, 95% CI)

Secondary: Overall Survival (Median, 80% CI)

Secondary: Overall Survival (Median, 80% CI)

Secondary: Overall Survival (Median, 95% CI)

Secondary: Overall Survival (Median, 95% CI)

Secondary: Gynecologic Cancer Intergroup (GCIG) CA-125 Response

Secondary: Gynecologic Cancer Intergroup (GCIG) CA-125 Response

Secondary: Treatment-emergent adverse events (TEAEs).

Secondary: Treatment-emergent adverse events (TEAEs).

Secondary: Treatment-emergent adverse events (TEAEs) Related to Adavosertib

Secondary: Treatment-emergent adverse events (TEAEs) Related to Adavosertib

Secondary: Treatment-emergent adverse events (TEAEs) Related to Chemotherapy

Secondary: Treatment-emergent adverse events (TEAEs) Related to Chemotherapy

Secondary: Serious Adverse Events

Secondary: Serious Adverse Events

Secondary: Serious Adverse Events Leading to Death

Secondary: Serious Adverse Events Leading to Death

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Discontinuation

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Dose Reduction

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption

Secondary: Treatment-Related Adverse Events Related to Adavosertib Leading to Treatment Interruption

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Discontinuation

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Dose Reduction

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption

Secondary: Treatment-Related Adverse Events Related to Chemotherapy Leading to Treatment Interruption

Secondary: Single Dose Adavosertib Cmax

Secondary: Single Dose Adavosertib Cmax

Secondary: Multiple Dose Adavosertib Cmax

Secondary: Multiple Dose Adavosertib Cmax

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Single Dose Adavosertib tmax

Secondary: Single Dose Adavosertib tmax

Secondary: Progression Free Survival

Secondary: Progression Free Survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicentre Phase II Study of Adavosertib plus Chemotherapy in Patients with Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer