Clinical Trials Register

Summary
EudraCT Number:	2009-017918-69
Sponsor's Protocol Code Number:	AB08026
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prohibited by CA
Date on which this record was first entered in the EudraCT database:	2010-10-18
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2009-017918-69

A.3

Full title of the trial

A prospective, multicenter, randomized, open-label, active-controlled, two-parallel groups, phase 3 study to compare the efficacy and safety of masitinib at 7.5 mg/kg/day to dacarbazine in the treatment of patients with non-resectable or metastatic stage 3 or stage 4 melanoma carrying a mutation in the juxta membrane domain of c-kit

A.3.1

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

A study to compare masitinib with dacarbazine in the treatment of patients with advanced melanoma carrying a mutation in a gene called c-kit

A.3.2

Name or abbreviated title of the trial where available

Not applicable

A.4.1

Sponsor's protocol code number

AB08026

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01280565

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	Alain Moussy
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	33147.20.23.11
B.5.5	Fax number	33147.20.24.11

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
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	Masitinib mesylate
D.3.9.1	CAS number	790-299-79-5
D.3.9.2	Current sponsor code	AB1010
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Masitinib mesylate
D.3.9.1	CAS number	790-299-79-5
D.3.9.2	Current sponsor code	AB1010
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-resectable or metastatic stage 3 or stage 4 melanoma carrying a mutation in the juxta membrane domain of c-kit

E.1.1.1

Medical condition in easily understood language

Advanced melanoma

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10025671
E.1.2	Term	Malignant melanoma stage IV
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10025670
E.1.2	Term	Malignant melanoma stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Objective Response Rate (CR + PR)

E.2.2

Secondary objectives of the trial

• Overall Progression Free Survival (PFS)
• Overall Survival (OS)
• PFS rate at week 6, 12, 18, 24 and every 12 weeks
• Survival rate at week 6, 12, 18, 24 and every 12 weeks
• Other Tumour assessment:

- Overall Time To Progression (TTP)
- TTP rate at week 6, 12, 18, 24 and every 12 weeks
- Best response rate and Disease control rate (CR + PR + SD)
- Duration of response
• Quality of life assessment at week 6, 12, 18 and 24 and every 12 weeks
- ECOG performance status
- EORTC QLQ-C30
• Safety profile using the NCI CTCAE v4.02 classification

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient >18 years old, male or female, weighting more than 40 kg and BMI>18 kg/m²
2. histologically or cytologically confirmed non-resectable or metastatic stage 3 (non-resectable IIIB or IIIC, AJCC TNM staging system 7th edition) or stage 4 melanoma
3. detectable c-kit JM mutation(mutation in exon 9, 11 or 13)confirmed by DNA or RNA sequencing, which is expected to be mainly found after screening of mucosal or acral melanoma or melanoma on skin with chronic sun-induced damages (defined by a microscopically marked elastosis involving the skin surrounding their primary melanoma)
4. measurable disease according to RECIST
5. ECOG ≤ 2
6. life expectancy > 3 months
7. adequate organ function
• ANC ≥ 1.5 x 109/L
• Haemoglobin ≥ 10 g/dL
• Platelets (PLT) ≥ 75 x 109/L
• AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases)
• Gamma GT ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastases)
• Bilirubin ≤ 1.5 x ULN (≤ 3 x ULN in case of liver metastases)
• Normal Creatinine or if abnormal creatinine, creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula)
• Albuminaemia ≥ 1 x LLN
• Urea ≤ 2 x ULN
• 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. Female patient of childbearing potential , who agrees to use two highly effective methods (1for the patient and 1 for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception include:
• A documented placement of an IUD or IUS and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository)
• Documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used
• Double barrier method: Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
• Any other contraceptive method with a documented failure rate of <1% per year
• Abstinence
Male patients must use medically acceptable methods of contraception if his female partner is pregnant, from the time of the first administration of the study drug until three months following administration of the last dose of study drug. Acceptable methods include:
• Condom;
• If you have undergone surgical sterilization (vasectomy with documentation of azoospermia) a condom should also be used.
Male patients must use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. The acceptable methods of contraception are as follows:
• Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;
• Surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);
• Your female partner uses oral contraceptives (combination oestrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);
• Medically prescribed topically-applied transdermal contraceptive patch and a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);
• Your female partner has undergone documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used;
• Your female partner has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository);
• Abstinence.
9. Patient able and willing to comply with study visits and procedures as per protocol
10. 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.
11. 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.
12. Patient affiliated to a social security regimen.

E.4

Principal exclusion criteria

1. Pregnant, or nursing female patient
2. Patient with other malignancies from which the patient has been continuously disease-free for < 3 years, with the exception of melanoma, cervical carcinoma in situ, basal cell or squamous cell skin cancer, ductal or lobular carcinoma in situ of the breast
3. Patient with active brain metastases are not eligible. Patients with treated brain metastases are eligible if :
(a) presence of 3 brain lesions or less
(b) lesion(s) diameter is ≤ 2 cm
(c) radiation therapy (gamma knife) was completed ≥ 4 weeks prior to baseline
(d) surgery was completed ≥4 weeks prior to baseline
(e) lesions assessed by follow-up scan (or MRI if MRI performed before brain therapy) ≥ 1 month after brain therapy are considered under control at baseline
4. Patient refractory to dacarbazine defined as patient presenting with disease progression within 3 months from the start of a previous dacarbazine therapy.
5. Prior treatment with a tyrosine kinase c-kit inhibitor
6. Patient with cardiac disorders defined by at least one of the following conditions:
• Patient with recent cardiac history (within 6 months) of:
o Acute coronary syndrome
o Acute heart failure (class III or IV of the NYHA classification)
o 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 judgment of the investigator, or symptomatic hypertension
7. Patient with clinically uncontrolled infectious diseases including HIV or AIDS-related illness
8. Major surgery or radiation therapy within four weeks of starting the study treatment
9. Patient with an history of poor compliance or an history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
WASH-OUT
10. Previous radiotherapy, chemotherapy and/or previous adjuvant therapy with interferon, vaccines or therapy with IL-2 or GM-CSF within 4 weeks prior to baseline. Those patients will require a four weeks wash-out period before baseline. Similarly, any previous treatment with an investigational agent will require a wash-out period of four weeks before baseline

E.5 End points

E.5.1

Primary end point(s)

Objective Response Rate (CR + PR)

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary analysis is the percentage of Objective Response Rate (CR + PR) estimated as the number of patients with documented partial response or complete response defined according to RECIST, divided by the number of randomized patients, in patients with no previous treatment line for melanoma.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

week 6, 12, 18 and 24 and every 12 weeks

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

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

dacarbazine

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

Austria

Belgium

Canada

Czech Republic

Germany

Greece

Hungary

India

Italy

Romania

Russian Federation

Serbia

Slovakia

South Africa

Spain

Turkey

Ukraine

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

24 weeks of treatment can be continued until disease progression

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