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Clinical Trial Results:
A Phase II, Double-blind, Placebo Controlled, Randomized Study to Assess the Efficacy and Safety of 2 Doses of ZD6474 (Vandetanib) in Combination With FOLFOX vs FOLFOX Alone for the Treatment of Colorectal Cancer in Patients Who Have Failed Therapy With an Irinotecan and Fluoropyrimidine Regimen

Summary
EudraCT number	2006-005022-23
Trial protocol	FR HU ES
Global end of trial date	11 Nov 2016

Results information
Results version number	v1(current)
This version publication date	15 Dec 2017
First version publication date	15 Dec 2017
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

D4200C00047

ISRCTN number

US NCT number

NCT00500292

WHO universal trial number (UTN)

Sponsor organisation name

Genzyme Corporation

Sponsor organisation address

500 Kendall Street, Cambridge, MA , United States, 02142

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.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

11 Nov 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Nov 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to assess the efficacy of ZD6474 (vandetanib) in combination with oxaliplatin, leucovorin, fluorouracil (5-FU) combination regimen (FOLFOX) vs FOLFOX alone for the treatment of subjects with colorectal cancer that have failed prior treatment with irinotecan and fluoropyrimidine by assessment of disease progression.

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Mar 2007

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

Hungary: 27

Country: Number of subjects enrolled

Taiwan: 18

Country: Number of subjects enrolled

Korea, Republic of: 22

Country: Number of subjects enrolled

Slovakia: 14

Worldwide total number of subjects

104

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

First subject randomised 19 March 2007, last subject randomised 11 Nov 2007, data cut off date 8 March 2008. 109 subjects were enrolled in the study.

Screening details

109 subjects were enrolled/screened to the study but only 104 subjects were entered treatment/randomized. Completed subjects refers to ongoing study treatment at data cut-off date 8 March 2008.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Vandetanib 100 mg Plus FOLFOX

Arm description

Vandetanib 100 mg plus FOLFOX

Arm type

Experimental

Investigational medicinal product name

Vandetanib

Investigational medicinal product code

ZD6474

Other name

ZACTIMA™

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Vandetanib 100 mg tablet, once daily.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin 85 mg/m^2 IV infusion over 120 minutes.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Leucovorin 400 mg/m^2 IV infusion over 120 minutes.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU 400 mg/m^2 IV bolus over 2-4 minutes and then 2400 mg/m^2 continuous IV infusion over 46 hours.

Vandetanib 300 mg Plus FOLFOX

Arm description

Vandetanib 300 mg plus FOLFOX

Arm type

Experimental

Investigational medicinal product name

Vandetanib

Investigational medicinal product code

ZD6474

Other name

ZACTIMA™

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Vandetanib 300 mg tablet, once daily.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin 85 mg/m^2 IV infusion over 120 minutes.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Leucovorin 400 mg/m^2 IV infusion over 120 minutes.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU 400 mg/m^2 IV bolus over 2-4 minutes and then 2400 mg/m^2 continuous IV infusion over 46 hours.

Placebo Plus FOLFOX

Arm description

Placebo plus FOLFOX

Arm type

Placebo

Investigational medicinal product name

Placebo (matched to vandetanib)

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo (matched to vandetanib) tablet, once daily.

Investigational medicinal product name

Oxaliplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Oxaliplatin 85 mg/m^2 IV infusion over 120 minutes.

Investigational medicinal product name

Leucovorin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Leucovorin 400 mg/m^2 IV infusion over 120 minutes.

Investigational medicinal product name

5-Fluorouracil

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

5-FU 400 mg/m^2 IV bolus over 2-4 minutes and then 2400 mg/m^2 continuous IV infusion over 46 hours.

Number of subjects in period 1	Vandetanib 100 mg Plus FOLFOX	Vandetanib 300 mg Plus FOLFOX	Placebo Plus FOLFOX
Started	32	35	37
Completed	7	4	10
Not completed	25	31	27
Adverse Event	3	6	4
Other	1	1	4
Condition under investigation worsened	21	23	19
Withdrawal by Subject	-	1	-

Baseline characteristics

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Reporting group title

Vandetanib 100 mg Plus FOLFOX

Reporting group description

Vandetanib 100 mg plus FOLFOX

Reporting group title

Vandetanib 300 mg Plus FOLFOX

Reporting group description

Vandetanib 300 mg plus FOLFOX

Reporting group title

Placebo Plus FOLFOX

Reporting group description

Placebo plus FOLFOX

Reporting group values	Vandetanib 100 mg Plus FOLFOX	Vandetanib 300 mg Plus FOLFOX	Placebo Plus FOLFOX	Total
Number of subjects	32	35	37	104
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (full range (min-max))	57 (34 to 75)	58 (37 to 71)	59 (32 to 81)	-
Gender categorical
Units: Subjects
Female	16	11	13	40
Male	16	24	24	64

End points

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Reporting group title

Vandetanib 100 mg Plus FOLFOX

Reporting group description

Vandetanib 100 mg plus FOLFOX

Reporting group title

Vandetanib 300 mg Plus FOLFOX

Reporting group description

Vandetanib 300 mg plus FOLFOX

Reporting group title

Placebo Plus FOLFOX

Reporting group description

Placebo plus FOLFOX

Primary: Number of Subjects With an Objective Disease Progression Event

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End point title

Number of Subjects With an Objective Disease Progression Event ^[1]

End point description

Number of subjects with objective disease progression or death (by any cause in the absence of objective progression).

End point type

Primary

End point timeframe

RECIST tumour assessments carried out at screening and then as per site clinical practice until objective progression. The only additional mandatory tumour assessment visit is at the point of data cut-off (5 March 2008 +/-3 days)

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: Only descriptive statistics were reported, inferential statistics were not planned to be reported for primary endpoint.

End point values	Vandetanib 100 mg Plus FOLFOX	Vandetanib 300 mg Plus FOLFOX	Placebo Plus FOLFOX
Number of subjects analysed	32	35	37
Units: Subjects	23	27	24

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (up to 503 weeks) regardless of seriousness or relationship to investigational product.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Vandetanib 100 mg Plus FOLFOX

Reporting group description

Vandetanib 100 mg plus FOLFOX

Reporting group title

Vandetanib 300 mg Plus FOLFOX

Reporting group description

Vandetanib 300 mg plus FOLFOX

Reporting group title

Placebo Plus FOLFOX

Reporting group description

Placebo plus FOLFOX.

Serious adverse events	Vandetanib 100 mg Plus FOLFOX	Vandetanib 300 mg Plus FOLFOX	Placebo Plus FOLFOX
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 32 (18.75%)	10 / 35 (28.57%)	4 / 37 (10.81%)
number of deaths (all causes)	2	6	4
number of deaths resulting from adverse events	1	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Gastric
subjects affected / exposed	1 / 32 (3.13%)	0 / 35 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 32 (3.13%)	0 / 35 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 32 (3.13%)	0 / 35 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous Thrombosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 35 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina Pectoris
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Haemorrhage Intracranial
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Mucosal Inflammation
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic Reaction
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Intestinal Obstruction
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	1 / 37 (2.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Female Genital Tract Fistula
subjects affected / exposed	1 / 32 (3.13%)	0 / 35 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Toxic Epidermal Necrolysis
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device Related Infection
subjects affected / exposed	2 / 32 (6.25%)	0 / 35 (0.00%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung Abscess
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 32 (3.13%)	3 / 35 (8.57%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Staphylococcal Infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal Sepsis
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Vandetanib 100 mg Plus FOLFOX	Vandetanib 300 mg Plus FOLFOX	Placebo Plus FOLFOX
Total subjects affected by non serious adverse events
subjects affected / exposed	31 / 32 (96.88%)	32 / 35 (91.43%)	35 / 37 (94.59%)
Vascular disorders
Hypertension
subjects affected / exposed	13 / 32 (40.63%)	13 / 35 (37.14%)	5 / 37 (13.51%)
occurrences all number	13	13	8
Phlebitis
subjects affected / exposed	2 / 32 (6.25%)	1 / 35 (2.86%)	1 / 37 (2.70%)
occurrences all number	2	1	1
Phlebitis Superficial
subjects affected / exposed	2 / 32 (6.25%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences all number	2	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	4 / 32 (12.50%)	8 / 35 (22.86%)	6 / 37 (16.22%)
occurrences all number	5	8	7
Chills
subjects affected / exposed	1 / 32 (3.13%)	1 / 35 (2.86%)	2 / 37 (5.41%)
occurrences all number	1	1	2
Fatigue
subjects affected / exposed	8 / 32 (25.00%)	10 / 35 (28.57%)	15 / 37 (40.54%)
occurrences all number	9	13	23
Oedema Peripheral
subjects affected / exposed	1 / 32 (3.13%)	2 / 35 (5.71%)	1 / 37 (2.70%)
occurrences all number	1	2	1
Pyrexia
subjects affected / exposed	3 / 32 (9.38%)	5 / 35 (14.29%)	9 / 37 (24.32%)
occurrences all number	3	6	16
Immune system disorders
Drug Hypersensitivity
subjects affected / exposed	3 / 32 (9.38%)	4 / 35 (11.43%)	5 / 37 (13.51%)
occurrences all number	5	9	5
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	6 / 32 (18.75%)	1 / 35 (2.86%)	3 / 37 (8.11%)
occurrences all number	6	1	3
Dyspnoea
subjects affected / exposed	3 / 32 (9.38%)	4 / 35 (11.43%)	2 / 37 (5.41%)
occurrences all number	3	4	2
Epistaxis
subjects affected / exposed	2 / 32 (6.25%)	3 / 35 (8.57%)	4 / 37 (10.81%)
occurrences all number	2	3	4
Pharyngolaryngeal Pain
subjects affected / exposed	2 / 32 (6.25%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences all number	2	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 32 (0.00%)	3 / 35 (8.57%)	0 / 37 (0.00%)
occurrences all number	0	3	0
Confusional State
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Insomnia
subjects affected / exposed	3 / 32 (9.38%)	3 / 35 (8.57%)	3 / 37 (8.11%)
occurrences all number	3	3	3
Investigations
Electrocardiogram Qt Prolonged
subjects affected / exposed	1 / 32 (3.13%)	6 / 35 (17.14%)	1 / 37 (2.70%)
occurrences all number	1	6	1
Weight Decreased
subjects affected / exposed	3 / 32 (9.38%)	1 / 35 (2.86%)	2 / 37 (5.41%)
occurrences all number	3	1	2
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 32 (6.25%)	2 / 35 (5.71%)	3 / 37 (8.11%)
occurrences all number	2	2	3
Dysaesthesia
subjects affected / exposed	1 / 32 (3.13%)	1 / 35 (2.86%)	3 / 37 (8.11%)
occurrences all number	1	1	3
Dysgeusia
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Headache
subjects affected / exposed	2 / 32 (6.25%)	5 / 35 (14.29%)	2 / 37 (5.41%)
occurrences all number	2	5	2
Lethargy
subjects affected / exposed	2 / 32 (6.25%)	0 / 35 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Paraesthesia
subjects affected / exposed	4 / 32 (12.50%)	5 / 35 (14.29%)	3 / 37 (8.11%)
occurrences all number	4	5	3
Peripheral Sensory Neuropathy
subjects affected / exposed	16 / 32 (50.00%)	12 / 35 (34.29%)	18 / 37 (48.65%)
occurrences all number	22	15	31
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	4 / 32 (12.50%)	5 / 35 (14.29%)	5 / 37 (13.51%)
occurrences all number	4	5	8
Neutropenia
subjects affected / exposed	13 / 32 (40.63%)	11 / 35 (31.43%)	13 / 37 (35.14%)
occurrences all number	21	18	17
Thrombocytopenia
subjects affected / exposed	16 / 32 (50.00%)	18 / 35 (51.43%)	13 / 37 (35.14%)
occurrences all number	29	28	18
Eye disorders
Vision Blurred
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)
occurrences all number	0	2	1
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	2 / 32 (6.25%)	3 / 35 (8.57%)	2 / 37 (5.41%)
occurrences all number	2	3	2
Abdominal Pain
subjects affected / exposed	2 / 32 (6.25%)	3 / 35 (8.57%)	10 / 37 (27.03%)
occurrences all number	2	3	10
Abdominal Pain Upper
subjects affected / exposed	2 / 32 (6.25%)	1 / 35 (2.86%)	4 / 37 (10.81%)
occurrences all number	2	1	5
Constipation
subjects affected / exposed	6 / 32 (18.75%)	3 / 35 (8.57%)	6 / 37 (16.22%)
occurrences all number	7	4	7
Diarrhoea
subjects affected / exposed	16 / 32 (50.00%)	22 / 35 (62.86%)	16 / 37 (43.24%)
occurrences all number	22	35	23
Epigastric Discomfort
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Flatulence
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Gingival Bleeding
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Nausea
subjects affected / exposed	13 / 32 (40.63%)	15 / 35 (42.86%)	24 / 37 (64.86%)
occurrences all number	25	17	41
Rectal Haemorrhage
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Stomatitis
subjects affected / exposed	8 / 32 (25.00%)	11 / 35 (31.43%)	10 / 37 (27.03%)
occurrences all number	8	15	11
Toothache
subjects affected / exposed	0 / 32 (0.00%)	1 / 35 (2.86%)	2 / 37 (5.41%)
occurrences all number	0	1	2
Vomiting
subjects affected / exposed	9 / 32 (28.13%)	5 / 35 (14.29%)	14 / 37 (37.84%)
occurrences all number	11	6	20
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	3 / 32 (9.38%)	2 / 35 (5.71%)	3 / 37 (8.11%)
occurrences all number	3	2	3
Alopecia
subjects affected / exposed	3 / 32 (9.38%)	1 / 35 (2.86%)	3 / 37 (8.11%)
occurrences all number	3	1	3
Dermatitis Acneiform
subjects affected / exposed	1 / 32 (3.13%)	5 / 35 (14.29%)	1 / 37 (2.70%)
occurrences all number	1	5	1
Dry Skin
subjects affected / exposed	2 / 32 (6.25%)	2 / 35 (5.71%)	1 / 37 (2.70%)
occurrences all number	2	2	1
Hyperhidrosis
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Palmar-Plantar Erythrodysaesthesia Syndrome
subjects affected / exposed	3 / 32 (9.38%)	3 / 35 (8.57%)	1 / 37 (2.70%)
occurrences all number	3	3	1
Photosensitivity Reaction
subjects affected / exposed	3 / 32 (9.38%)	7 / 35 (20.00%)	1 / 37 (2.70%)
occurrences all number	3	8	1
Pigmentation Disorder
subjects affected / exposed	1 / 32 (3.13%)	2 / 35 (5.71%)	1 / 37 (2.70%)
occurrences all number	1	2	1
Pruritus
subjects affected / exposed	1 / 32 (3.13%)	2 / 35 (5.71%)	3 / 37 (8.11%)
occurrences all number	1	2	3
Rash
subjects affected / exposed	7 / 32 (21.88%)	7 / 35 (20.00%)	3 / 37 (8.11%)
occurrences all number	7	7	3
Urticaria
subjects affected / exposed	1 / 32 (3.13%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	1	0	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)
occurrences all number	0	2	1
Haematuria
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	0 / 37 (0.00%)
occurrences all number	0	2	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	5 / 32 (15.63%)	4 / 35 (11.43%)	4 / 37 (10.81%)
occurrences all number	5	4	4
Musculoskeletal Pain
subjects affected / exposed	2 / 32 (6.25%)	0 / 35 (0.00%)	1 / 37 (2.70%)
occurrences all number	2	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 32 (0.00%)	2 / 35 (5.71%)	1 / 37 (2.70%)
occurrences all number	0	2	1
Nasopharyngitis
subjects affected / exposed	4 / 32 (12.50%)	1 / 35 (2.86%)	2 / 37 (5.41%)
occurrences all number	4	1	2
Pharyngitis
subjects affected / exposed	2 / 32 (6.25%)	1 / 35 (2.86%)	0 / 37 (0.00%)
occurrences all number	2	1	0
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	10 / 32 (31.25%)	11 / 35 (31.43%)	9 / 37 (24.32%)
occurrences all number	13	17	23
Decreased Appetite
subjects affected / exposed	0 / 32 (0.00%)	0 / 35 (0.00%)	2 / 37 (5.41%)
occurrences all number	0	0	2

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Were there any global substantial amendments to the protocol? No

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.

Primary results are complemented by Sanofi following sponsorship transfer from Astra Zeneca to Sanofi in May 2016, only SAEs are updated per protocol.

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Primary: Number of Subjects With an Objective Disease Progression Event

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Substantial protocol amendments (globally)

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