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Clinical Trial Results:
A Randomized, Controlled, Open-Label, Phase 2 Trial of SGI-110 and Carboplatin in Subjects with Platinum-Resistant Recurrent Ovarian Cancer

Summary
EudraCT number	2012-001576-12
Trial protocol	GB
Global end of trial date	15 Apr 2016

Results information
Results version number	v1(current)
This version publication date	06 Jul 2018
First version publication date	06 Jul 2018
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

SGI-110-02

ISRCTN number

US NCT number

NCT01696032

WHO universal trial number (UTN)

Other trial identifiers

Health Canada: CN 161678

Sponsor organisation name

Astex Pharmaceuticals, Inc.

Sponsor organisation address

4420 Rosewood Drive, Suite 200, Pleasanton, CA, United States, 94588

Public contact

Dr Harold Keer, Astex Pharmaceuticals Inc., 001 9257190741, Harold.Keer@astx.com

Scientific contact

Dr Harold Keer, Astex Pharmaceuticals Inc., 001 9257190741, Harold.Keer@astx.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

15 Apr 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Apr 2016

Was the trial ended prematurely?

Main objective of the trial

Primary Objectives: Stage 1: To assess the safety & tolerability of guadecitabine+carboplatin (G+C) and determine the maximum tolerated dose (MTD) for Stage 2. Stage 2: To assess & compare progression free survival (PFS) between G+C and treatment choice (TC) arms. Secondary Objectives: Stage 1: To determine the objective response rate (ORR) based on both measurable & detectable disease; to assess PFS at 6 months; to determine the clinical benefit rate (CBR), the duration of response (DOR), CA-125 reduction by ≥50%, overall survival (OS), & pharmacokinetics (PK) of G&C in subjects with ovarian cancer, and determine if there is a PK interaction between G&C. Stage 2: To determine & compare the ORR for G+C & TC arms based on both measurable & detectable disease; to assess & compare PFS at 6 months for G+C and TC arms; to determine & compare the CBR, DOR, CA-125 reduction by ≥50% & OS for G+C & TC arms; to determine the ORR for subjects in the TC arm who cross over to the G+C arm

Protection of trial subjects

Institutional Review Board (IRB)/Independent Ethics Committee (IEC): The protocol, amendments, informed consent forms (ICFs), and administrative letters for this study were reviewed and approved by an IRB/IEC at each study center prior to implementation. No subject was treated until the IRB/IEC had provided written approval of the study and the ICF to the investigator and the sponsor. Protocol amendments and all revisions to the ICF after initial IRB/IEC approval were submitted by the investigator to the IRB/IEC for review and approval before implementation in accordance with regulatory requirements. The IRB/IEC regulations for each region were followed at respective centers. Ethical Conduct of the Study: The study was conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, applicable local regulatory requirements, and the principles enunciated in the Declaration of Helsinki. Subject Information and Consent: The ICF(s) used for each study center complied with ICH, the principles enunciated in the Declaration of Helsinki, local regulatory requirements, and ICH GCP guidelines and was approved by the sponsor and the investigator's IRB/IEC. The investigator, or a person delegated by the investigator, explained the medical aspects of the study, including the nature and purpose of the study and the treatment, the procedures involved, and the potential benefits and risks. Other tasks in the informed consent process may have been delegated by the investigator. After having been informed that participation was voluntary and that subjects may withdraw from the study at any time, without prejudice, each subject signed the IRB/IEC-approved ICF prior to undergoing any study specific procedures and enrolment in the study.

Background therapy

Concomitant medications and therapies deemed necessary for supportive care and safety of the subject were allowed. Specifically, antibiotics were permitted to prevent or manage febrile neutropenia, granulocyte-colony stimulating factor and other white blood cell stimulating factors were permitted during Cycle 1 and onwards, and red blood cell transfusions were permitted at the discretion of the treating physician. Administration of any other anticancer agents including chemotherapy and biologic agents was not permitted. Similarly, concurrent use of other investigational drugs was not allowed.

Evidence for comparator

TC Control Group in Stage 2 was given from commercial supply of the following selections based on FDA-approved regimens or National Comprehensive Cancer Network (NCCN) Guidelines in second line and standard of care: •Topotecan (Hycamtin® or equivalent): recommended dose range of 3.5-4.0 mg/m2/week administered on Days 1, 8, and 15 of a 28-day cycle administered via IV infusion. •PLD (Doxil® or equivalent): recommended dose range of 40-50 mg/m2 IV on Day 1 of a 28-day cycle. •Paclitaxel (Taxol® or equivalent): recommended dose range of 60-80 mg/m2/week × 4 on Days 1, 8, 15, and 22 of a 28-day cycle administered via IV infusion. •Gemcitabine (Gemzar® or equivalent): recommended dose range of 800-1000 mg/m2 IV over 30 minutes on Days 1, 8, and 15 of a 28-day cycle.

Actual start date of recruitment

10 Dec 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 24

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

United States: 81

Worldwide total number of subjects

124

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

A total of 20 principal investigators at 20 study centers (12 in the US, 5 in the UK, and 3 in Canada) enrolled subjects in this study. The first subject was dosed on 10 December 2012 and the last subject completed observation on 15 April 2016.

Screening details

A total of 145 subjects were assessed for inclusion in the study. Of these, 124 subject were enrolled and 21 subjects failed screening assessments.

Period 1 title

Overall trial baseline period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Stage 1

Arm description

Stage 1 was a safety lead-in stage with a dose escalation design. Subjects were evaluated with the combination of G+C, given as 28-day treatment cycles: guadecitabine administered SC daily on Days 1-5, at a starting dose of 45 mg/m2/d, followed by carboplatin IV based on a targeted dose of AUC 5 on Day 8. In a dose escalation design, cohorts of 6 subjects were used to identify the optimum dose of G+C.

Arm type

Experimental

Investigational medicinal product name

Guadecitabine

Investigational medicinal product code

SGI-110

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 1: Guadecitabine 45 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 5 on Day 8 of a 28-day cycle (dose was de-escalated after Cycle 1 to 30 mg/m2 guadecitabine for 4 subjects and carboplatin was reduced for 2 subjects). Cohort 2: Guadecitabine 30 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 4 on Day 8 of a 28-day cycle.

Stage 2

Arm description

This stage was conducted as an open-label, randomized, controlled trial. Eligible subjects were randomly assigned in a 1:1 ratio to receive either (1) G+C combination treatment in 28-day cycles, or (2) TC of topotecan, pegylated liposomal doxorubicin (PLD), paclitaxel, or gemcitabine in 28-day cycles.

Arm type

Experimental and comparator

Investigational medicinal product name

Guadecitabine

Investigational medicinal product code

SGI-110

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Guadecitabine 30 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 4 on Day 8 of a 28-day cycle. Reference Therapy, Dose and Mode of Administration: TC of one of the following approved products using commercially available supply: topotecan, PLD, paclitaxel, or gemcitabine, in 28-day cycles selected at the investigator’s discretion, based on recommended dosing, as follows: •Topotecan: 3.5-4.0 mg/m2/wk administered on Days 1, 8, and 15 via IV infusion. •PLD: 40-50 mg/m2 administered on Day 1 via IV infusion. •Paclitaxel: 60-80 mg/m2/wk administered on Days 1, 8, 15, and 22 via IV infusion. •Gemcitabine: 800-1000 mg/m2 administered on Days 1, 8, and 15 via IV infusion.

Number of subjects in period 1	Stage 1	Stage 2
Started	21	103
Completed	20	100
Not completed	1	3
Physician decision	1	2
Consent withdrawn by subject	-	1

Baseline characteristics

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Reporting group title

Overall trial baseline period

Reporting group description

Reporting group values	Overall trial baseline period	Total
Number of subjects	124	124
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	76	76
From 65-84 years	47	47
85 years and over	1	1
Gender categorical
Units: Subjects
Female	124	124
Male	0	0

End points

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Reporting group title

Stage 1

Reporting group description

Reporting group title

Stage 2

Reporting group description

Subject analysis set title

Stage 1: G+C, 30 mg/m2

Subject analysis set type

Full analysis

Subject analysis set description

Guadecitabine 30 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 4 on Day 8 of a 28-day cycle.

Subject analysis set title

Stage 1: G+C, 45 mg/m2

Subject analysis set type

Full analysis

Subject analysis set description

Guadecitabine 45 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 5 on Day 8 of a 28-day cycle (dose was de-escalated after Cycle 1 to 30 mg/m2 guadecitabine for 4 subjects and carboplatin was reduced for 2 subjects).

Subject analysis set title

Stage 2: G+C, 30 mg/m2

Subject analysis set type

Full analysis

Subject analysis set description

Guadecitabine 30 mg/m2 SC once daily on Days 1-5 and carboplatin IV AUC 4 on Day 8 of a 28-day cycle.

Subject analysis set title

Stage 2: TC

Subject analysis set type

Full analysis

Subject analysis set description

TC of one of the following approved products using commercially available supply: topotecan, PLD, paclitaxel, or gemcitabine, in 28-day cycles selected at the investigator’s discretion, based on recommended dosing, as follows: • Topotecan: 3.5-4.0 mg/m2/wk administered on Days 1, 8, and 15 via IV infusion. • PLD: 40-50 mg/m2 administered on Day 1 via IV infusion. • Paclitaxel: 60-80 mg/m2/wk administered on Days 1, 8, 15, and 22 via IV infusion. • Gemcitabine: 800-1000 mg/m2 administered on Days 1, 8, and 15 via IV infusion.

Subject analysis set title

Stage 2: Crossover TC to G+C

Subject analysis set type

Full analysis

Subject analysis set description

Subjects initially randomized to TC who crossed over to receive 30 mg/m2 G+C after having disease progression.

Primary: Progression Free Survival

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End point title

Progression Free Survival

End point description

Progression free survival time was defined as the time interval from the date of the first dose of study medication until the earlier of disease progression or death.

End point type

Primary

End point timeframe

Subjects were treated with their assigned treatment (G+C or TC) until disease progression or unacceptable treatment-related toxicity occurred.

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	51	49
Units: days
median (confidence interval 95%)
PFS in days	114 (63 to 169)	64 (52 to 105)

Comparison of PFS

Comparison groups

Stage 2: G+C, 30 mg/m2 v Stage 2: TC

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0654

Method

Logrank

Confidence interval

Secondary: Objective Response Rate

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End point title

Objective Response Rate

End point description

The ORR was defined as the proportion of subjects who experienced an objective response (best overall response of complete response/full response or partial response, which was confirmed by a subsequent assessment at least 28 days later). Response categories were determined based on RECIST v1.1 criiteria, or on modified Rustin (CA-125) criteria if response assessment could not be made using RECIST criteria.

End point type

Secondary

End point timeframe

Subjects were treated with their assigned treatment (G+C or TC) until disease progression or unacceptable treatment-related toxicity occurred.

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	51	49
Units: Percentage
number (confidence interval 95%)
ORR (CR/FR+PR)	16 (7 to 28.6)	8 (2.3 to 19.6)

Comparison of Objective Response Rate

Comparison groups

Stage 2: TC v Stage 2: G+C, 30 mg/m2

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.358

Method

Fisher exact

Confidence interval

Secondary: Duration of response in responders

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End point title

Duration of response in responders

End point description

Duration of response is defined as the time between the date of the first documentation of complete response/full response or partial response, and the date of disease progression or date of death due to any cause, or the last adequate tumor assessment prior to the start of subsequent anti-cancer therapy including crossing over to G+C from TC arm, whichever occurred earlier. Only subjects who responded were included in the duration of response calculation.

End point type

Secondary

End point timeframe

Subjects were treated with their assigned treatment (G+C or TC) until disease progression or unacceptable treatment-related toxicity occurred.

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	21	14
Units: Days
number (confidence interval 95%)
Median duration, days	186 (147 to 241)	173 (121 to 267)

No statistical analyses for this end point

Secondary: Progression Free Survival rate at 6 months

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End point title

Progression Free Survival rate at 6 months

End point description

Progression free survival rate at 6 months is the proportion of subjects who were alive and did not have disease progression at 6 months after start of treatment.

End point type

Secondary

End point timeframe

6 months

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	51	49
Units: proportion of subjects
median (confidence interval 95%)
PFS rate at 6 months	0.37 (0.24 to 0.50)	0.11 (0.04 to 0.22)

Comparison of PFS rate at 6 months

Comparison groups

Stage 2: G+C, 30 mg/m2 v Stage 2: TC

Number of subjects included in analysis

100

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0027

Method

Logrank

Confidence interval

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as the number of days from the day the subject was administered the first dose of study treatment to the date of death (regardless of cause). Survival time was censored on the last date the subject was known to be alive or lost to follow-up before reaching the event of death.

End point type

Secondary

End point timeframe

Subjects were treated with their assigned treatment (G+C or TC) until disease progression or unacceptable treatment-related toxicity occurred.

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	51	49
Units: days
median (confidence interval 95%)
OS in days	331 (231 to 415)	221 (145 to 372)

Comparison of Overall Survival

Comparison groups

Stage 2: TC v Stage 2: G+C, 30 mg/m2

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5852

Method

Logrank

Confidence interval

Secondary: Overall Survival Rate at 6 months

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End point title

Overall Survival Rate at 6 months

End point description

Overall survival rate at 6 months is the proportion of subjects who were alive at 6 months after the start of study treatment.

End point type

Secondary

End point timeframe

6 months

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	51	49
Units: proportion of subjects
median (confidence interval 95%)
OS rate at 6 months	0.72 (0.58 to 0.83)	0.67 (0.47 to 0.80)

Comparison of Overall Survival rate at 6 months

Comparison groups

Stage 2: TC v Stage 2: G+C, 30 mg/m2

Number of subjects included in analysis

100

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.5629

Method

Logrank

Confidence interval

Secondary: Clinical Benefit Rate

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End point title

Clinical Benefit Rate

End point description

CBR was defined as the proportion of subjects who experienced a best overall response of complete response/full response or partial response (confirmed by a subsequent assessment at least 28 days later), or documented stable disease for at least 3 months after the first dose. Response categories were determined based on RECIST v1.1 criteria, then based on modified Rustin (CA-125) criteria if assessment could not be made using RECIST criteria.

End point type

Secondary

End point timeframe

Subjects were treated with their assigned treatment (G+C or TC) until disease progression or unacceptable treatment-related toxicity occurred.

End point values	Stage 2: G+C, 30 mg/m2	Stage 2: TC
Number of subjects analysed	51	49
Units: Percentage
number (confidence interval 95%)
CBR (CR/FR+PR+stable disease)	41 (27.6 to 55.8)	29 (16.6 to 43.3)

Comparison of Clinical Benefit Rate

Comparison groups

Stage 2: G+C, 30 mg/m2 v Stage 2: TC

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.213

Method

Fisher exact

Confidence interval

Adverse events

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Timeframe for reporting adverse events

Adverse events were recorded on scheduled study days and at study follow-up.

Adverse event reporting additional description

Note: only one occurrence per preferred term is reported in the tables below.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Stage 1: G+C, 30 mg/m2

Reporting group description

Reporting group title

Stage 1: G+C, 45 mg/m2

Reporting group description

Reporting group title

Stage 2: G+C, 30 mg/m2

Reporting group description

Reporting group title

Stage 2: TC

Reporting group description

Reporting group title

Stage 2: TC to G+C, 30 mg/m2

Reporting group description

Serious adverse events	Stage 1: G+C, 30 mg/m2	Stage 1: G+C, 45 mg/m2	Stage 2: G+C, 30 mg/m2	Stage 2: TC	Stage 2: TC to G+C, 30 mg/m2
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 14 (57.14%)	4 / 6 (66.67%)	26 / 51 (50.98%)	24 / 49 (48.98%)	12 / 27 (44.44%)
number of deaths (all causes)	14	4	43	18	22
number of deaths resulting from adverse events	0	1	2	2	2
Vascular disorders
Hypotension
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Adverse drug reaction
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Fatigue
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Influenza like illness
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Elective procedure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 51 (5.88%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	0 / 51 (0.00%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Pulmonary oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
International normalised ratio increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Transaminases increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Sinus tachycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Tachycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Radicular pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	3 / 27 (11.11%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 14 (7.14%)	2 / 6 (33.33%)	1 / 51 (1.96%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Pancytopenia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Thrombocytopenia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Small intestinal obstruction
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	8 / 51 (15.69%)	4 / 49 (8.16%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 8	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	3 / 49 (6.12%)	5 / 27 (18.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	2 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	1 / 51 (1.96%)	5 / 49 (10.20%)	2 / 27 (7.41%)
occurrences causally related to treatment / all	0 / 2	0 / 2	1 / 1	4 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	0 / 51 (0.00%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	1 / 2	0 / 2	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	4 / 49 (8.16%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Large intestine perforation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Intestinal perforation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Abdominal abscess
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Portal vein thrombosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
Pyoderma gangrenosum
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Gait disturbance
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Pain in jaw
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	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
Musculoskeletal chest pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Sepsis
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	2 / 49 (4.08%)	3 / 27 (11.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 2	3 / 3
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	2 / 2
Pneumonia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Lower respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Postoperative fever
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Hyponatraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	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
Decreased appetite
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 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

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

Non-serious adverse events	Stage 1: G+C, 30 mg/m2	Stage 1: G+C, 45 mg/m2	Stage 2: G+C, 30 mg/m2	Stage 2: TC	Stage 2: TC to G+C, 30 mg/m2
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 14 (100.00%)	6 / 6 (100.00%)	50 / 51 (98.04%)	49 / 49 (100.00%)	27 / 27 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	7 / 51 (13.73%)	6 / 49 (12.24%)	2 / 27 (7.41%)
occurrences all number	1	0	7	6	2
Embolism
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	0	2
Flushing
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 51 (1.96%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	1	1	1	3	0
Haematoma
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0	0
Hypotension
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	3 / 49 (6.12%)	3 / 27 (11.11%)
occurrences all number	0	0	1	3	3
Lymphoedema
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	0 / 51 (0.00%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	1	1	0	2	0
Deep vein thrombosis
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	0	1	1	1	0
Any event
subjects affected / exposed	2 / 14 (14.29%)	3 / 6 (50.00%)	12 / 51 (23.53%)	14 / 49 (28.57%)	7 / 27 (25.93%)
occurrences all number	2	3	12	14	7
General disorders and administration site conditions
Fatigue
subjects affected / exposed	9 / 14 (64.29%)	4 / 6 (66.67%)	33 / 51 (64.71%)	26 / 49 (53.06%)	14 / 27 (51.85%)
occurrences all number	9	4	33	26	14
Injection site reaction
subjects affected / exposed	8 / 14 (57.14%)	2 / 6 (33.33%)	23 / 51 (45.10%)	1 / 49 (2.04%)	9 / 27 (33.33%)
occurrences all number	8	2	23	1	9
Pyrexia
subjects affected / exposed	2 / 14 (14.29%)	4 / 6 (66.67%)	8 / 51 (15.69%)	3 / 49 (6.12%)	3 / 27 (11.11%)
occurrences all number	2	4	8	3	3
Oedema peripheral
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	5 / 51 (9.80%)	14 / 49 (28.57%)	3 / 27 (11.11%)
occurrences all number	2	2	5	14	3
Adverse drug reaction
subjects affected / exposed	3 / 14 (21.43%)	1 / 6 (16.67%)	2 / 51 (3.92%)	0 / 49 (0.00%)	4 / 27 (14.81%)
occurrences all number	3	1	2	0	4
Pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	4 / 49 (8.16%)	1 / 27 (3.70%)
occurrences all number	0	0	5	4	1
Chills
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	0	0	4	2	1
Hernia pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Malaise
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences all number	0	0	3	1	1
Peripheral swelling
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	0	1	0	3	0
Early satiety
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	0	0	4	2	1
Asthenia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	0	1	1	2	0
Injection site pain
subjects affected / exposed	4 / 14 (28.57%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	4	0	1	0	0
Mass
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Any event
subjects affected / exposed	13 / 14 (92.86%)	6 / 6 (100.00%)	41 / 51 (80.39%)	39 / 49 (79.59%)	22 / 27 (81.48%)
occurrences all number	13	6	41	39	22
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	10 / 51 (19.61%)	3 / 49 (6.12%)	4 / 27 (14.81%)
occurrences all number	2	0	10	3	4
Hypersensitivity
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	3 / 51 (5.88%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	3	0	0
Any event
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	12 / 51 (23.53%)	3 / 49 (6.12%)	4 / 27 (14.81%)
occurrences all number	2	1	12	3	4
Reproductive system and breast disorders
Perineal pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	0	1	0
Vaginal discharge
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	1	0	1	2	0
Vaginal ulceration
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Vulvovaginal swelling
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Pelvic pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences all number	0	0	5	1	1
Vaginal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 49 (4.08%)	3 / 27 (11.11%)
occurrences all number	0	0	2	2	3
Any event
subjects affected / exposed	4 / 14 (28.57%)	0 / 6 (0.00%)	9 / 51 (17.65%)	5 / 49 (10.20%)	4 / 27 (14.81%)
occurrences all number	4	0	9	5	4
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	14 / 51 (27.45%)	15 / 49 (30.61%)	5 / 27 (18.52%)
occurrences all number	2	1	14	15	5
Cough
subjects affected / exposed	4 / 14 (28.57%)	2 / 6 (33.33%)	7 / 51 (13.73%)	8 / 49 (16.33%)	4 / 27 (14.81%)
occurrences all number	4	2	7	8	4
Atelectasis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 51 (1.96%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	1	1	1	2	1
Haemoptysis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Nasal congestion
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	3 / 51 (5.88%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	1	1	3	3	0
Paranasal sinus hypersecretion
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences all number	0	0	3	1	1
Productive cough
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	1	0	1	3	0
Epistaxis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	5 / 51 (9.80%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	0	0	5	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	2 / 51 (3.92%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences all number	0	1	2	1	1
Pulmonary oedema
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Upper respiratory tract infection
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	2	0	2	2	1
Wheezing
subjects affected / exposed	0 / 14 (0.00%)	2 / 6 (33.33%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	0	2	0	1	0
Any event
subjects affected / exposed	6 / 14 (42.86%)	5 / 6 (83.33%)	26 / 51 (50.98%)	27 / 49 (55.10%)	9 / 27 (33.33%)
occurrences all number	6	5	26	27	9
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 14 (21.43%)	2 / 6 (33.33%)	6 / 51 (11.76%)	6 / 49 (12.24%)	1 / 27 (3.70%)
occurrences all number	3	2	6	6	1
Insomnia
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	4 / 51 (7.84%)	13 / 49 (26.53%)	3 / 27 (11.11%)
occurrences all number	2	0	4	13	3
Depression
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	4 / 51 (7.84%)	5 / 49 (10.20%)	0 / 27 (0.00%)
occurrences all number	1	0	4	5	0
Libido decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Any event
subjects affected / exposed	5 / 14 (35.71%)	2 / 6 (33.33%)	11 / 51 (21.57%)	18 / 49 (36.73%)	5 / 27 (18.52%)
occurrences all number	5	2	11	18	5
Investigations
Weight decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 51 (3.92%)	5 / 49 (10.20%)	0 / 27 (0.00%)
occurrences all number	1	0	2	5	0
Anion gap increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	4 / 51 (7.84%)	2 / 49 (4.08%)	2 / 27 (7.41%)
occurrences all number	2	0	4	2	2
Bilirubin urine present
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Blood albumin decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	2 / 51 (3.92%)	4 / 49 (8.16%)	1 / 27 (3.70%)
occurrences all number	2	0	2	4	1
Blood chloride decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Carbon dioxide decreased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Protein urine present
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Weight increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 51 (5.88%)	2 / 49 (4.08%)	2 / 27 (7.41%)
occurrences all number	2	1	3	2	2
Specific gravity urine increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Urine ketone body present
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Urine leukocyte esterase positive
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	0	1	0	1	0
Blood phosphorus decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Protein total decreased
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Any event
subjects affected / exposed	5 / 14 (35.71%)	4 / 6 (66.67%)	15 / 51 (29.41%)	15 / 49 (30.61%)	10 / 27 (37.04%)
occurrences all number	5	4	15	15	10
Blood creatinine increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	7 / 51 (13.73%)	3 / 49 (6.12%)	2 / 27 (7.41%)
occurrences all number	0	1	7	3	2
International normalised ratio increased
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	1	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 51 (3.92%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	2	0	0
Infusion related reaction
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	3 / 51 (5.88%)	0 / 49 (0.00%)	2 / 27 (7.41%)
occurrences all number	2	2	3	0	2
Procedural pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 51 (5.88%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	3	1	0
Skin abrasion
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0	0
Stoma site pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Any event
subjects affected / exposed	3 / 14 (21.43%)	2 / 6 (33.33%)	15 / 51 (29.41%)	5 / 49 (10.20%)	3 / 27 (11.11%)
occurrences all number	3	2	15	5	3
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	0	4	0	1
Sinus tachycardia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences all number	1	0	1	1	1
Any event
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	7 / 51 (13.73%)	4 / 49 (8.16%)	2 / 27 (7.41%)
occurrences all number	1	0	7	4	2
Nervous system disorders
Headache
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	9 / 51 (17.65%)	5 / 49 (10.20%)	1 / 27 (3.70%)
occurrences all number	3	0	9	5	1
Dizziness
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	5 / 51 (9.80%)	6 / 49 (12.24%)	1 / 27 (3.70%)
occurrences all number	1	0	5	6	1
Dysgeusia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	0	0	4	2	1
Neuropathy peripheral
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	4 / 49 (8.16%)	0 / 27 (0.00%)
occurrences all number	0	0	3	4	0
Paraesthesia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Tremor
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	1	1	0
Any event
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	15 / 51 (29.41%)	16 / 49 (32.65%)	7 / 27 (25.93%)
occurrences all number	3	0	15	16	7
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	7 / 14 (50.00%)	5 / 6 (83.33%)	36 / 51 (70.59%)	16 / 49 (32.65%)	18 / 27 (66.67%)
occurrences all number	7	5	36	16	18
Leukopenia
subjects affected / exposed	5 / 14 (35.71%)	2 / 6 (33.33%)	16 / 51 (31.37%)	11 / 49 (22.45%)	12 / 27 (44.44%)
occurrences all number	5	2	16	11	12
Anaemia
subjects affected / exposed	7 / 14 (50.00%)	4 / 6 (66.67%)	16 / 51 (31.37%)	25 / 49 (51.02%)	8 / 27 (29.63%)
occurrences all number	7	4	16	25	8
Thrombocytopenia
subjects affected / exposed	3 / 14 (21.43%)	6 / 6 (100.00%)	12 / 51 (23.53%)	12 / 49 (24.49%)	10 / 27 (37.04%)
occurrences all number	3	6	12	12	10
Pancytopenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	0	1	0
Any event
subjects affected / exposed	12 / 14 (85.71%)	6 / 6 (100.00%)	44 / 51 (86.27%)	35 / 49 (71.43%)	22 / 27 (81.48%)
occurrences all number	12	6	44	35	22
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences all number	1	0	0	0	1
Ear pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	1	0	0
Any event
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 51 (3.92%)	1 / 49 (2.04%)	1 / 27 (3.70%)
occurrences all number	1	0	2	1	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	10 / 14 (71.43%)	2 / 6 (33.33%)	38 / 51 (74.51%)	28 / 49 (57.14%)	12 / 27 (44.44%)
occurrences all number	10	2	38	28	12
Vomiting
subjects affected / exposed	6 / 14 (42.86%)	2 / 6 (33.33%)	32 / 51 (62.75%)	15 / 49 (30.61%)	10 / 27 (37.04%)
occurrences all number	6	2	32	15	10
Constipation
subjects affected / exposed	5 / 14 (35.71%)	4 / 6 (66.67%)	22 / 51 (43.14%)	17 / 49 (34.69%)	10 / 27 (37.04%)
occurrences all number	5	4	22	17	10
Abdominal pain
subjects affected / exposed	4 / 14 (28.57%)	2 / 6 (33.33%)	21 / 51 (41.18%)	17 / 49 (34.69%)	8 / 27 (29.63%)
occurrences all number	4	2	21	17	8
Diarrohoea
subjects affected / exposed	4 / 14 (28.57%)	1 / 6 (16.67%)	21 / 51 (41.18%)	11 / 49 (22.45%)	9 / 27 (33.33%)
occurrences all number	4	1	21	11	9
Stomatitis
subjects affected / exposed	3 / 14 (21.43%)	1 / 6 (16.67%)	11 / 51 (21.57%)	12 / 49 (24.49%)	2 / 27 (7.41%)
occurrences all number	3	1	11	12	2
Abdominal distension
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	10 / 51 (19.61%)	12 / 49 (24.49%)	4 / 27 (14.81%)
occurrences all number	1	0	10	12	4
Dyspepsia
subjects affected / exposed	3 / 14 (21.43%)	2 / 6 (33.33%)	6 / 51 (11.76%)	10 / 49 (20.41%)	3 / 27 (11.11%)
occurrences all number	3	2	6	10	3
Ascites
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	4 / 51 (7.84%)	4 / 49 (8.16%)	2 / 27 (7.41%)
occurrences all number	2	2	4	4	2
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 14 (7.14%)	2 / 6 (33.33%)	8 / 51 (15.69%)	4 / 49 (8.16%)	1 / 27 (3.70%)
occurrences all number	1	2	8	4	1
Abdominal pain upper
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	4 / 51 (7.84%)	5 / 49 (10.20%)	3 / 27 (11.11%)
occurrences all number	3	0	4	5	3
Abdominal discomfort
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	0	0	3	2	1
Abdominal pain lower
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	1 / 49 (2.04%)	3 / 27 (11.11%)
occurrences all number	0	0	3	1	3
Anorectal discomfort
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Dry mouth
subjects affected / exposed	1 / 14 (7.14%)	2 / 6 (33.33%)	1 / 51 (1.96%)	4 / 49 (8.16%)	2 / 27 (7.41%)
occurrences all number	1	2	1	4	2
Flatulence
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 51 (7.84%)	2 / 49 (4.08%)	2 / 27 (7.41%)
occurrences all number	0	0	4	2	2
Haemorrhoids
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	0	0	1	3	0
Proctalgia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	2 / 27 (7.41%)
occurrences all number	0	0	0	1	2
Toothache
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	2 / 27 (7.41%)
occurrences all number	1	0	1	1	2
Dental caries
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	0	0	1
Epigastric discomfort
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Lip dry
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Oral pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	0	0	1
Any event
subjects affected / exposed	12 / 14 (85.71%)	6 / 6 (100.00%)	48 / 51 (94.12%)	41 / 49 (83.67%)	25 / 27 (92.59%)
occurrences all number	12	6	48	41	25
Dysphagia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	0	0	0	3	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	7 / 51 (13.73%)	6 / 49 (12.24%)	0 / 27 (0.00%)
occurrences all number	2	1	7	6	0
Alopecia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	6 / 51 (11.76%)	7 / 49 (14.29%)	2 / 27 (7.41%)
occurrences all number	1	0	6	7	2
Dermatitis contact
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	0	1	0
Dry skin
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 51 (3.92%)	6 / 49 (12.24%)	2 / 27 (7.41%)
occurrences all number	1	0	2	6	2
Erythema
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	1	0	1	2	1
Hyperhidrosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	1	1	0
Night sweats
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	0	1	0
Onycholysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 51 (0.00%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	0	0	0	3	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	1	0	0	3	0
Pruritus
subjects affected / exposed	1 / 14 (7.14%)	3 / 6 (50.00%)	7 / 51 (13.73%)	0 / 49 (0.00%)	3 / 27 (11.11%)
occurrences all number	1	3	7	0	3
Rash erythematous
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Rash maculo-papular
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	1	0	0	3	0
Skin lesion
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Swelling face
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Any event
subjects affected / exposed	7 / 14 (50.00%)	4 / 6 (66.67%)	19 / 51 (37.25%)	24 / 49 (48.98%)	8 / 27 (29.63%)
occurrences all number	7	4	19	24	8
Renal and urinary disorders
Dysuria
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	5 / 51 (9.80%)	3 / 49 (6.12%)	2 / 27 (7.41%)
occurrences all number	2	0	5	3	2
Haematuria
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	1 / 51 (1.96%)	3 / 49 (6.12%)	0 / 27 (0.00%)
occurrences all number	2	0	1	3	0
Hydronephrosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	1	1	0
Micturition urgency
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	1	1	0
Pollakiuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 51 (3.92%)	2 / 49 (4.08%)	2 / 27 (7.41%)
occurrences all number	0	0	2	2	2
Urinary incontinence
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 51 (3.92%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	0	2	1	0
Urinary retention
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Any event
subjects affected / exposed	5 / 14 (35.71%)	1 / 6 (16.67%)	13 / 51 (25.49%)	11 / 49 (22.45%)	5 / 27 (18.52%)
occurrences all number	5	1	13	11	5
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	3 / 14 (21.43%)	1 / 6 (16.67%)	9 / 51 (17.65%)	8 / 49 (16.33%)	5 / 27 (18.52%)
occurrences all number	3	1	9	8	5
Arthralgia
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	11 / 51 (21.57%)	6 / 49 (12.24%)	2 / 27 (7.41%)
occurrences all number	2	0	11	6	2
Pain in extremity
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	10 / 51 (19.61%)	8 / 49 (16.33%)	3 / 27 (11.11%)
occurrences all number	0	1	10	8	3
Flank pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	3 / 27 (11.11%)
occurrences all number	1	0	0	0	3
Groin pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 51 (3.92%)	1 / 49 (2.04%)	3 / 27 (11.11%)
occurrences all number	1	0	2	1	3
Joint stiffness
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	5 / 51 (9.80%)	4 / 49 (8.16%)	3 / 27 (11.11%)
occurrences all number	1	0	5	4	3
Muscular weakness
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 51 (5.88%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	2	1	3	1	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	5 / 51 (9.80%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	1	0	5	2	1
Musculoskeletal pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	6 / 51 (11.76%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	6	0	0
Myalgia
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	3 / 51 (5.88%)	3 / 49 (6.12%)	2 / 27 (7.41%)
occurrences all number	2	0	3	3	2
Neck pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	1 / 49 (2.04%)	2 / 27 (7.41%)
occurrences all number	0	0	1	1	2
Bone pain
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	1 / 51 (1.96%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	3	0	1	0	0
Any event
subjects affected / exposed	8 / 14 (57.14%)	2 / 6 (33.33%)	27 / 51 (52.94%)	20 / 49 (40.82%)	13 / 27 (48.15%)
occurrences all number	8	2	27	20	13
Infections and infestations
Bacteriuria
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Breast cellulitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Localised infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	1	0	0	2	0
Nasopharyngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 51 (1.96%)	2 / 49 (4.08%)	2 / 27 (7.41%)
occurrences all number	0	0	1	2	2
Rhinitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 51 (5.88%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0	0
Rocky mountain spotted fever
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Urinary tract infection
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	8 / 51 (15.69%)	4 / 49 (8.16%)	3 / 27 (11.11%)
occurrences all number	2	1	8	4	3
Vaginitis bacterial
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0	0
Clostridium difficile colitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)
occurrences all number	0	1	0	0	1
Enterococcal infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Impetigo
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	0	1	1	2	0
Any event
subjects affected / exposed	7 / 14 (50.00%)	3 / 6 (50.00%)	21 / 51 (41.18%)	18 / 49 (36.73%)	10 / 27 (37.04%)
occurrences all number	7	3	21	18	10
Metabolism and nutrition disorders
Hypomagnesaemia
subjects affected / exposed	3 / 14 (21.43%)	4 / 6 (66.67%)	15 / 51 (29.41%)	8 / 49 (16.33%)	9 / 27 (33.33%)
occurrences all number	3	4	15	8	9
Decreased appetite
subjects affected / exposed	6 / 14 (42.86%)	2 / 6 (33.33%)	14 / 51 (27.45%)	13 / 49 (26.53%)	6 / 27 (22.22%)
occurrences all number	6	2	14	13	6
Hypokalaemia
subjects affected / exposed	3 / 14 (21.43%)	2 / 6 (33.33%)	6 / 51 (11.76%)	8 / 49 (16.33%)	3 / 27 (11.11%)
occurrences all number	3	2	6	8	3
Hyponatraemia
subjects affected / exposed	3 / 14 (21.43%)	1 / 6 (16.67%)	3 / 51 (5.88%)	7 / 49 (14.29%)	1 / 27 (3.70%)
occurrences all number	3	1	3	7	1
Dehydration
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	4 / 51 (7.84%)	6 / 49 (12.24%)	5 / 27 (18.52%)
occurrences all number	1	1	4	6	5
Hyperglycaemia
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 51 (1.96%)	1 / 49 (2.04%)	0 / 27 (0.00%)
occurrences all number	1	1	1	1	0
Hypoalbuminaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 51 (1.96%)	3 / 49 (6.12%)	3 / 27 (11.11%)
occurrences all number	0	1	1	3	3
Hypocalcaemia
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	2 / 51 (3.92%)	2 / 49 (4.08%)	1 / 27 (3.70%)
occurrences all number	1	1	2	2	1
Hypoglycaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	0 / 51 (0.00%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	2	0	0	2	0
Hypophosphataemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 51 (0.00%)	2 / 49 (4.08%)	0 / 27 (0.00%)
occurrences all number	0	1	0	2	0
Any event
subjects affected / exposed	9 / 14 (64.29%)	6 / 6 (100.00%)	27 / 51 (52.94%)	26 / 49 (53.06%)	18 / 27 (66.67%)
occurrences all number	9	6	27	26	18

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Were there any global substantial amendments to the protocol? Yes

23 May 2013

• Eliminated the limit of 3 prior cytotoxic treatment regimens in Stage 2 eligibility criteria. • Clarified definition of subjects who were refractory to platinum treatment as those who had never responded to prior platinum treatment. • Clarified that all subjects treated in Stage 1 would be used to determine if one objective response occurred for the study to proceed into Stage 2 and the objective response no longer needed to be confirmed since RECIST v 1.1 criteria did not require such confirmation. • Clarified that subjects could come off carboplatin treatment and continue SGI-110 alone at the investigator’s discretion after at least 4 ycles instead of 6 cycles. Clarified that, in the absence of unacceptable toxicity, subjects should continue treatment with SGI-110 until at least radiographic and clinical disease progression or until the subject needed to be treated with another anti-cancer treatment. • In Inclusion Criterion #7, added a new inclusion requirement for subjects to have platelet counts ≥ 100,000 cells/mm3 to be eligible for treatment.

18 Nov 2013

• Allowed subjects with other histotypes (endometrioid, mixed cell, or clear cell) to be enrolled. • Allowed pleural fluid to be collected for tumor cell analyses, if such collection was more feasible than tumor biopsy or ascites collection. • Allowed subjects with previous platinum hypersensitivity to be enrolled if they successfully undergo an institutional desensitization protocol. • Allowed more choices in TC arm of Stage 2, with the addition of gemcitabine as a TC option. • Allowed dose reduction for guadecitabine from 30 mg/m2 to 24 mg/m2 in the event of guadecitabine specific toxicity. • Allowed dose reduction for carboplatin by one AUC dose level.

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.

Nil.

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Clinical Trial Results:
A Randomized, Controlled, Open-Label, Phase 2 Trial of SGI-110 and Carboplatin in Subjects with Platinum-Resistant Recurrent Ovarian Cancer

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Primary: Progression Free Survival

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Clinical trials

Clinical Trial Results: A Randomized, Controlled, Open-Label, Phase 2 Trial of SGI-110 and Carboplatin in Subjects with Platinum-Resistant Recurrent Ovarian Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression Free Survival

Primary: Progression Free Survival

Secondary: Objective Response Rate

Secondary: Objective Response Rate

Secondary: Duration of response in responders

Secondary: Duration of response in responders

Secondary: Progression Free Survival rate at 6 months

Secondary: Progression Free Survival rate at 6 months

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Overall Survival Rate at 6 months

Secondary: Overall Survival Rate at 6 months

Secondary: Clinical Benefit Rate

Secondary: Clinical Benefit Rate

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, Controlled, Open-Label, Phase 2 Trial of SGI-110 and Carboplatin in Subjects with Platinum-Resistant Recurrent Ovarian Cancer