Clinical Trials Register

Summary
EudraCT Number:	2013-000490-79
Sponsor's Protocol Code Number:	AB12006
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-07-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2013-000490-79

A.3

Full title of the trial

A prospective, multicenter, randomized, double blind, placebo-controlled, 2-parallel groups, phase 3 study to compare the efficacy and safety of masitinib in combination with FOLFIRI (irinotecan, 5-fluorouracil and folinic acid) to placebo in combination with FOLFIRI in second line treatment of patients with metastatic colorectal cancer.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A specially designed study conducted at many medical sites to compare whether Masitinib, in combination with a currently available medicine called Folfiri, to placebo in combination with Folfiri, is safe and effective in second line treatment of patients with advanced colorectal cancer.

A.3.2

Name or abbreviated title of the trial where available

AB12006

A.4.1

Sponsor's protocol code number

AB12006

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AB Science
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AB Science
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AB Science
B.5.2	Functional name of contact point	Clinical Study Project Manager
B.5.3	Address:
B.5.3.1	Street Address	3 Avenue George V
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75008
B.5.3.4	Country	France
B.5.4	Telephone number	+33 147 20 32 00
B.5.5	Fax number	+33 147 20 24 11
B.5.6	E-mail	olivier.eydoux@abscience.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Masitinib mesylate
D.3.2	Product code	AB1010
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	none
D.3.9.1	CAS number	790-299-79-5
D.3.9.3	Other descriptive name	MASITINIB MESYLATE
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	119.3 to 238.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Metastatic colorectal cancer

E.1.1.1

Medical condition in easily understood language

Cancer in the colon or rectum which has spread to other parts of the body.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10052362
E.1.2	Term	Metastatic colorectal cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the overall survival (OS) defined as the time from the randomisation to the date of documented death, of masitinib at 6mg/Kg/day in combination with standard therapy FOLFIRI (irinotecan, 5-fluorouracil and folinic acid) to matching placebo in combination with standard therapy FOLFIRI in second line treatment of patients with metastatic colorectal cancer.

E.2.2

Secondary objectives of the trial

To compare the efficacy (Progression Free Survival), the safety and the quality of life of masitinib at 6mg/Kg/day in combination with standard therapy FOLFIRI (irinotecan, 5-fluorouracil and folinic acid) to matching placebo in combination with standard therapy FOLFIRI in second line treatment of patients with metastatic colorectal cancer.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Although not a true sub-study, the protocol allows for 3 optional studies (Two pharmacogenomic analysis - DNA & RNA and Severe Neutropenia/Skin Toxicity where deemed appropriate by the Inv.), in order to define efficacy or safety genomic predictive criteria. For these sub-studies separate consents will be required.

In the event of severe neutropenia or skin toxicity; additional blood samples are drawn for genetic analysis in order to better understand why patients are presenting those side effects. The objectives of this sub-study is to evaluate potential relationships between the genes, efficacy and safety of the study treatment. Participation to this additional study will require additional laboratory blood sampling.

The first pharmacogenomic ancillary study aims at finding potential DNA mutations that might explain short or long survival, side effects and treatment response. Available tumour biopsies of patients will be collected at baseline (no biopsy is required by the study protocol but only the one used for diagnosis would be collected).

For the second pharmacogenomic ancillary study, specific blood samples will be drawn at baseline, week 2 and week 16 visit in order to identify potential variations of biomarkers (by RNA analysis) and to correlate them to the effectiveness or non-effectiveness (efficiency or non-efficiency) of the study treatment.

E.3

Principal inclusion criteria

1. Patient with non-resectable metastatic colorectal cancer with histological or cytological documentation of adenocarcinoma of the colon or rectum;
2. Metastatic disease not amenable to surgical resection with curative intent;
3. Patient in second line treatment after progression according to RECIST criteria following administration of a standard chemotherapy regimen for treatment of metastatic disease;
4. Patient with measurable lesions according to RECIST criteria (version 1.1) with spiral CT scan and defined as ≥ 10 mm in longest diameter and 2X the slice thickness for extra nodal lesions and/or >15 mm in short axis diameter for nodal lesions;
5. Patient eligible for a standard second line therapy with FOLFIRI;
6. Patient with ECOG ≤ 2;
7. Patient with adequate organ function:
- Absolute neutrophils count (ANC) ≥ 1.5 x 10EE9/L,
- Haemoglobin ≥ 10 g/dl,
- Platelets (PLT) ≥ 75 x 10EE9/L,
- AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases),
- GammaGT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases),
- Bilirubin ≤ 1.5 x ULN,
- Normal Creatinine or if abnormal creatinine, creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula),
- Albumin > 1 x LLN,
- Proteinuria < 30 mg/dL (1+) on the dipstick. If proteinuria is ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours;
8. Patient with life expectancy > 3 months;
9. Female or male patient ≥ 18;
10. Patient weight >40 kg and BMI > 18;
11. Females of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) within seven days prior to the initiation of treatment. Females of childbearing potential must have used simultaneously two highly effective methods of contraception (strongly recommended that one of the two forms of contraception be non hormonal such as condom plus spermicide, condom plus diaphragm with spermicide, or have
a vasectomized partner) or use an intrauterine device or must have been sexually abstinent for at least four weeks prior to or at least one menstrual cycle prior to (whichever is longer) the
negative pregnancy test through entry the study and for 3 months after the last treatment intake. Sexual abstinence or effective contraception must be used for at least one month prior to the initiation of therapy, during therapy, and for at least three months following discontinuation of therapy. This protocol defines a female of childbearing potential as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least 24 consecutive months;
12. Male patients with female partners of childbearing potential must agree to sexual abstinence or to practice two reliable forms of effective contraception used simultaneously (strongly recommended that one of the two forms of contraception be non-hormonal such
as condom plus spermicide, condom plus diaphragm with spermicide, or partner with tubal ligation) or partner may use an intrauterine device, during the entire period of study treatment and for at least three months after treatment is discontinued;
13. Male patients with female sexual partners who are pregnant, possibly pregnant or who could become pregnant during the study must agree to use condoms during sexual intercourse during the entire period of study treatment and for at least three month after the last dose of study treatment;
14. Patient able and willing to comply with study procedures as per protocol;
15. Patient able to understand, sign, and date the written informed consent form at the screening visit prior to any protocol-specific procedures are performed. If the patient is deemed by the treating physician to be cognitively impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable, the designated legal guardian must sign the informed consent;
16. Patient able to understand the patient card and to follow the patient card procedures in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity during the first 2 months of treatment.

E.4

Principal exclusion criteria

1. Patient intolerant to one of these treatments: irinotecan, 5-fluorouracil (5-FU), folinic acid;
2. More than 1 prior chemotherapy regimens for metastatic colorectal cancer;
3. Pregnant, intent to be pregnant, or nursing female patient;
4. Patient with any chronic inflammatory bowel disease;
5. Patient treated for a cancer other than colorectal cancer within five years before enrolment, with the exception of basal cell carcinoma or cervical cancer in situ;
6. Patient required to receive other therapy than FOLFIRI for second line metastatic colorectal cancer;
7. Patient with an hepatic involvement > 50%;
8. Patient with active central nervous system (CNS) metastasis or history of CNS metastases;
9. Patient with an active infection (Human immunodeficiency virus infection and/or hepatitis B or C infection);
10. Patient presenting with cardiac disorders defined by at least one of the following conditions:
- Patient with recent cardiac history (within 6 months) of:
-Acute coronary syndrome,
-Acute heart failure (class III or IV of the NYHA classification),
-Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death),
· Patient with cardiac failure class III or IV of the NYHA classification;
· Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block);
· Syncope without known aetiology within 3 months;
· Uncontrolled severe hypertension, according to the judgement of the investigator, or symptomatic hypertension;
11. Patient with a history of poor compliance or of drug/alcohol abuse, or excessive alcohol beverage consumption, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
12. Patient receiving or requiring any prohibited medication (Section 6.3.2 of the Protocol).
WASH OUT
13. Any previous treatment with an investigational agent or chemotherapy or biological agent will require a wash-out period of four weeks prior to baseline.

E.5 End points

E.5.1

Primary end point(s)

Overall Survival (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Defined as time from first randomisation to date of documented death.

E.5.2

Secondary end point(s)

• Survival rate is defined as the rate of patients alive at each time point.
• Overall Progression Free Survival (PFS) is defined as the delay between the date of randomization to the date of documented progression or any cause of death during the study. Progression will be assessed by CT scan according to RECIST criteria.
• PFS rate is defined as the rate of patients without progression or death at each time point.
• Overall Time To Progression (TTP) is defined as the time from the date of randomization to the date of documented
progression defined according to RECIST criteria.
• TTP rate is defined as the rate of patients without documented progression at each time point.
• Best Response is defined as the best response (CR or PR or SD or PD) defined according to RECIST criteria recorded from the start of the treatment until end of study.
• Best Response rate is defined as the number of patients achieving the Best Response divided by the total number of
patients in the population of analysis.
• Objective response rate (CR + PR) is defined as the number of patients with documented partial response or complete response defined according to RECIST, divided by the number of randomized patients.
• Disease control rate (CR + PR + SD) is defined as the number of patients with documented partial response, complete response or stable disease defined according to RECIST criteria, divided by the number of patients randomized at each time point.
• Pharmacogenomic assessment (Relationship between genomic data and overall survival.
• Quality of Life;
- Shift table (baseline versus worst status) of ECOG Performance Status, that represents the patient’s health status.
- Change in absolute value and percentage between baseline and each time point for EORTC QLQC30, questionnaire developed to assess the quality of life of cancer patients.
- Evolution of analgesic intake.
- Change in absolute value and percentage between baseline and each time point for pain measurement (numerical scale).
Safety
• Safety of the study treatment will be assessed on occurrence of adverse events (AEs), intake of concomitant treatments, per treatment arising changes in physical examination, vital signs (blood pressure, pulse rate and body temperature), ECG, clinical laboratory tests (biochemistry, haematology) and urinary analysis.

E.5.2.1

Timepoint(s) of evaluation of this end point

Data collected between Baseline, Week 8 and every 8 weeks after W8 and at the end of study visit.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Austria

Canada

China

Czech Republic

France

Germany

Greece

Hong Kong

Hungary

India

Italy

Korea, Republic of

Malaysia

Mexico

Montenegro

Morocco

Peru

Philippines

Romania

Russian Federation

Serbia

Singapore

Slovakia

South Africa

Spain

Taiwan

Tunisia

Ukraine

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Patient treated until disease progression, limiting toxicity or withdrawal of consent. Follow up continued until death of patient

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1