E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
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 | 19.1 |
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 |
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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 - 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 v4.02 classification |
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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 and with a Body Mass Index (BMI)>18 kg/m² 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(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. Patient with measurable disease according to RECIST 5. Patient with ECOG ≤ 2 6. Patient with life expectancy > 3 months 7. Patient with adequate organ function · Absolute neutrophils count (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 AB08026 Study Protocol - AB08026 - Version 6.0/AT02 dated 09 January 2015 Page 4 of 121 Confidential · Proteinuria < 30 mg/dL on dipstick; in case of proteinuria ≥ 30 mg/dL, 24-hour proteinuria ≤ 1.5 g/24 h 8. Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to 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. Acceptable forms of contraception include: o A 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) o Documented tubal ligation (female sterilization). In addition, a barrier method used with spermicidal foam/gel/film/cream/suppository) should also be used o Double barrier method with spermicidal foam/gel/film/cream/suppository o Any other contraceptive method with a documented failure rate of <1% per year o 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: o Condom; o 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: o Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; o 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); o 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); o 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); o 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; o 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); o Abstinence. Abstinence when this is in line with the preferred and usual lifestyle of the patient. 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. 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. |
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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 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: - 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 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 |
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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 · Objective Response Rate (CR + PR) Secondary endpoint · 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 · 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 v4.0 classification · 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 | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 | Information not present in EudraCT |
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 |
Brazil |
Canada |
China |
India |
Serbia |
South Africa |
Turkey |
United States |
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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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The end of trial will be when the required number of events is reached. More information are provided in protocol. |
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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 |