A Study of AMNN107 in the Treatment of Metastatic and/or Inoperable Melanoma Harboring a c-Kit Mutation

Study Overview
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Brief Summary
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The purpose of this study is to determine whether nilotinib is efficacious in the treatment of metastatic and/or inoperable melanoma harboring a c-Kit mutation.

Detailed Description
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This trial began as a multi-center, randomized, Phase III, controlled trial for nilotinib vs (DTIC) dacarbazine to assess the efficacy and safety of nilotinib (400 mg bid) in patients with c-Kit mutated metastatic and/or inoperable melanoma. The study was open to patients with mucosal or acral melanoma. Due to substantial difficulties identifying and recruiting eligible patients, the trial design was altered from a randomized, two-arm, Phase III study to a single-arm, Simon two-stage Phase II study with protocol Amendment 2 (27-Jul-2011). While the original protocol required the recruitment of 120 patients, this amendment required the study to recruit only 41 patients (patients randomized to nilotinib prior to Amendment 2 were to be counted in this total, but those randomized to dacarbazine ( DTIC ) DTIC were not). Patients randomized to DTIC were allowed to cross-over to nilotinib, either immediately or at the time of progression.

Official Title
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The TEAM Trial (Tasigna Efficacy in Advanced Melanoma): A Phase II, Open Label, Multi-center, Single-arm Study to Assess the Efficacy of Tasigna ® in the Treatment of Patients With Metastatic and/or Inoperable Melanoma Harboring a c-Kit Mutation

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Nilotinib
* Drug: DTIC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Histologically confirmed mucosal or acral 2. Presence of a c-Kit mutation of exon 9, 11 or 13, or mutations Y822D and mutations D820Y, 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 1.0. Lesions must have a size of at least 10mm at longest diameter (using a slice thickness of 5 mm)or double the slice thickness to be considered a target lesion. Target lesions should not be selected in previously irradiated fields unless there is clear evidence of progression 5. WHO performance status 0 - 2 Exclusion Criteria: C-Kit mutation of exons 17(except mutations D820Y, Y822D or Y823D) or any other exon not allowed by the inclusion criteria Patients with c-Kit amplifications only and no mutation Patients with any history of brain metastases Patients who have had any prior treatment with TKIs Patients receiving medications or herbal extracts which interfere with nilotinib metabolism which are not discontinued by the time of the baseline visit Acute or chronic liver or renal disease considered unrelated to melanoma Other protocol-defined inclusion/exclusion criteria may have applied.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>400 mg twice daily | Drug: Nilotinib<br>* Nilotinib was provided as 200 mg hard gelatin capsules for oral use.<br>* Other names: AMN107;|
| Active Comparator: DTIC<br>850 mg/m2 IV every 3 weeks | Drug: DTIC<br>* DTIC was supplied locally as sterile powder for i.v. infusion.<br>* Other names: Dacarbazine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the proportion of participants with a best overall response (BOR) of a confirmed complete response or partial response (CR+PR) determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) based on local investigators' assessment (CT/MRI/photography). Per RECIST, CR: disappearance of all target lesions, all non-target lesions, and no new lesion; PR: a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no unequivocal progression of non-TLs, and no new lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments at least 4 weeks apart. | End of study (up to 39 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Durable Overall Response Rate (DORR) | DORR was defined as the rate of best overall response (CR+PR) lasting at least 12 weeks determined by RECIST v1.0 based on local investigators' assessment (CT/MRI/photography). The duration of ORR responders is computed from the date of first documented response (CR/PR) to the date of first documented progression or death due to underlying disease. Per RECIST, CR: disappearance of all target lesions, all non-target lesions, and no new lesion; PR: a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no worsening of non-TLs, and no new lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments at least 4 weeks apart. | End of study (up to 39 months) | 
| Progression Free Survival (PFS) | PFS was defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Progression is defined using RECIST v1.0, as a >=20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or unequivocal progression of non-target lesions. | End of study (up to 39 months) | 
| Overall Survival (OS) | OS was defined as the time from the date of the start of treatment to the date of death due to any cause. | End of study (up to 39 months) | 
| Time to Objective Response (TOR) | TOR was defined as the time between the start date of treatment until first documented confirmed response of CR or PR determined by RECIST v1.0 based on local investigators' assessment (CT/MRI/photography). Per RECIST, CR: disappearance of all target lesions, all non-target lesions, and no new lesion; PR: a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no unequivocal progression of non-TLs, and no new lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments at least 4 weeks apart. | End of study (up to 39 months) | 
| Disease Control Rate (DCR) | DCR was defined as the proportion of participants with an overall response of CR of any duration, PR of any duration, or stable disease (SD) for a minimum of 12 weeks from start of treatment. Per RECIST, CR: disappearance of all target lesions, all non-target lesions, and no new lesion; PR: a >=30% decrease in the sum of the longest dimensions of the target lesions (TLs) taking as a reference the baseline sum, no unequivocal progression of non-TLs, and no new lesions; PD, a >=20% increase in TLs, clearly worsening of non-TLs, or emergence of new lesions; SD: no change or small changes that do not meet previously given criteria for CR, PR or PD. | End of study (up to 39 months) | 
| PFS Rate | PFS was defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Progression is defined using RECIST v1.0, as a >=20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or unequivocal progression of non-target lesions. | End of study (up to 39 months) | 
| OS Rate | OS was defined as the time from the date of the start of treatment to the date of death due to any cause. | End of study (up to 39 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, AMN107, c-Kit, c-Kit mutated metastatic and/or inoperable melanoma