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 |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective is 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. |
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E.2.2 | Secondary objectives of the trial |
Assessing the tolerance of mastinib versus dacarbazine in the same patients population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient ≥ 18 years old, male or female, weighting more than 40 kg 2. Patient with 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. Patient with detectable c-kit JM mutation 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. Patient with measurable disease according to RECIST 5. Patient with ECOG ≤ 2 6. Patient with life expectancy ≥ 12 weeks 7. Patient with adequate organ function ·Absolute neutrophil count (ANC) ≥ 1.5 x 109/L ·Haemoglobin ≥ 10 g/dL ·Platelets (PLT) ≥ 100 x 109/L ·AST/ALT ≤ 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) ·Creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula) ·Albuminaemia ≥ 0.75 x LLN ·Urea ≤ 2 x ULN ·Proteinuria < 30 mg/dL on dipstick; in case of proteinuria ≥ 30 mg/dL, 24-hour proteinuria ≤ 1.5 g/24 h 8. Man or woman of child bearing potential, (entering the study after a menstrual period and who have a negative pregnancy test) must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for three months after the last treatment intake 9. Patient able and willing to comply with study procedures as per protocol 10. Patient able to understand, and willing to sign, and date the written informed consent form at screening visit prior to any protocol-specific procedures |
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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 a disease progression after 3 months of dacarbazine therapy. 5. Prior treatment with a tyrosine kinase c-kit inhibitor 6.Patient with grade III/IV cardiac problems as defined by the New York Heart Association Criteria (i.e., congestive heart failure, myocardial infarction within six months before baseline) 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The tumor response and progression will be assessed by CT scan using modified RECIST criteria (m-RECIST).
Primary endpoint · Overall Progression Free Survival (PFS) Secondary endpoint · Overall Survival (OS) · Survival rate at week 6, 12, 18, 24 and every 12 weeks ·Tumour assessment · PFS rate at week 6, 12, 18, 24 and every 12 weeks · Overall Time To Progression (TTP) · TTP rate at week 6, 12, 18, 24 and every 12 weeks · Best response rate, Objective response rate (CR + PR) and Disease control rate (CR + PR + SD) ·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 v4.0 classification |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 25 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 70 |
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 | No |
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 |
India |
Mexico |
Serbia |
Turkey |
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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
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24 weeks of treatment which may be continued until progression of disease. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |