E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
treatment of patients with metastatic and/or inoperable melanoma harboring a c-Kit mutation |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the clinical efficacy of nilotinib to DTIC, based on progression free survival (PFS), in the treatment of c-Kit mutated melanoma in patients who have not received prior therapy with TKIs. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objectives •To compare objective overall response rate (ORR) between nilotinib and DTIC. •To compare durable objective response rate (DORR) between nilotinib and DTIC. •To compare overall survival (OS) between nilotinib and DTIC. Other secondary objectives •To assess the PFS rate at 6 months (PFS6) and OS at 12 months (OS12) for nilotinib and DTIC treatment. •To assess the time to objective response (TOR) and duration of objective response (DOR) to nilotinib and DTIC treatment. •To assess the disease control rate (DCR) to nilotinib and DTIC treatment.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Histologically confirmed mucosal, acral or cutaneous melanoma. 2.Presence of a c-Kit mutation of exon 11 or 13, or mutations Y822D and Y823D of exon 17, as confirmed by the central laboratory. 3.Stage III unresectable or stage IV disease. 4.The presence of one or more measurable lesions as detected by radiological or photographic methods and assessed according to RECIST. lesions must have a size of at least 10mm at longest diameter (using a slice thickness of 5 mm). 5.WHO performance status 0 - 2. 6.At least 28 days since major surgery and 7 days since skin/tumor biopsy until start of study drug. 7.Age 18 or greater. 8.Patients must have adequate bone marrow and organ function as defined by the following laboratory values: •Biochemistry parameters within normal ranges prior to and at the latest by the day of first dosing, achieved by correction with supplements if necessary. •ALT and AST ≤ 2.5 x ULN (upper limit of normal) or ≤ 5.0 x ULN if considered due to tumor. •Alkaline phosphatase ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to tumor. •Serum bilirubin ≤ 1.5 x ULN. •Serum creatinine ≤ 1.5 x ULN •Serum amylase ≤ 1.5 x ULN and serum lipase ≤ 1.5 x ULN. •Hemoglobin ≥ 9.0 g/dL, absolute neutrophil count ≥1.5 x 109/L, platelets ≥100 x 109/L. 9.The capacity to understand the patient information sheet and the ability to provide written informed consent. 10.Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
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E.4 | Principal exclusion criteria |
1.C-Kit mutation of exons 17(except mutations Y822D or Y823D) or 18. 2.Patients with c-Kit amplifications only and no mutation. 3.Patients with any NRAS or BRAF mutation 4.Patients with known untreated or treated brain metastases as shown at the screening visit or earlier (metastatic disease M1a, M1b, M1c are allowed). 5.Patients who have had any prior treatment with TKIs or DTIC. 6.Patients receiving medications or herbal extracts which interfere with nilotinib metabolism which are not discontinued by the time of the baseline visit. 7.Impaired cardiac function, including any one of the following: •LVEF < 45% or below institutional lower limit of the normal range (which ever is higher) as determined by MUGA scan or echocardiogram. •Complete left bundle branch block. •Use of a cardiac pacemaker. •Congenital long QT syndrome. •History of or presence of significant ventricular or atrial tachyarrhythmias. •Clinically significant resting bradycardia (< 50 beats per minute). •QTc > 450 msec on screening ECG (using the QTcF formula). •Right bundle branch block plus left anterior hemiblock, bifascicular block. •Myocardial infarction within 12 months prior to randomization. •Unstable angina diagnosed or treated during the past 12 months. •Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen). 8.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive gastric or small bowel resection). 9.History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis. 10.Acute or chronic liver or renal disease considered unrelated to the tumor. 11.Other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol. 12.Patients who are currently receiving treatment with any medications that have a significant potential to prolong the QT interval. See link for list of these medications: http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm. 13. Patients currently receiving therapy with strong CYP3A4 inhibitors. See link for list of these medications: http://medicine.iupui.edu/flockhart/table.htm. 14. Patients receiving therapy with strong CYP3A4 inducers. See link for list of these medications: http://medicine.iupui.edu/flockhart/table.htm. 15. Patients who have received cytotoxic chemotherapy ≤ 4 weeks (6 weeks for nitrosurea or mitomycin-C) prior to starting study drug or who have not recovered from the side effects of such therapy. 16. Patients who have received immunotherapy ≤ 1 week prior to starting study drug or who have not recovered from the side effects of such therapy. 17. Patients who have received any investigational drug ≤ 4 weeks prior to starting study drug or who have not recovered from the side effects of such therapy. 18. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy. 19. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention. 20. Women who are pregnant, breast feeding or adults of reproductive potential not employing an effective method of birth control. Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Female patients must agree to employ an effective method of contraception during the study and for up to three months following discontinuation from the study. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.
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E.5 End points |
E.5.1 | Primary end point(s) |
PFS is defined as the time from randomization to the first documented progression or death due to any cause. |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
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.8.2.3.1 | Comparator description |
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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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
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 |
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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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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 | 2 |