A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma

Study Overview
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Brief Summary
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Phase 1b/2a, open-label, sequential dose escalation and expansion study of AMG 232 in combination with trametinib and dabrafenib in subjects with metastatic melanoma followed by a direct comparison of AMG 232 combined with trametinib and dabrafenib versus trametinib combined with dabrafenib alone.

Detailed Description
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The study will be conducted in 3 parts: Part 1 - Dose Escalation, Part 2 - Dose Expansion and Part 3, a randomized Phase 2a. In both part 1 and 2, subjects will be enrolled open-label into 1 of 2 arms. For both Arm 1 and Arm 2, the part 1 dose escalation is aimed at determining an AMG 232 maximum tolerated dose (MTD) with a fixed dose of the combination drug(s) and evaluating safety, tolerability, pharmacokinetics and pharmacodynamics of each combination. Part 2 dose expansion will enroll subjects to receive therapy with a dose and schedule of AMG 232 selected from the corresponding part 1 dose escalation. In part 2 subjects will be enrolled to confirm safety and tolerability and to assess clinical activity prior to proceeding to Part 3, Phase 2a. In Phase 2a, Subjects will be randomized open-label in a 1:1 ratio to receive AMG 232 in combination with trametinib plus dabrafenib versus trametinib plus dabrafenib alone. Only Part 1 of the study was enrolled and the study did not proceed into Phase 2.

Official Title
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A Phase 1b/2a Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 232 Combined With Trametinib and Dabrafenib or Trametinib in Adult Subjects With Metastatic Cutaneous Melanoma

Conditions
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Oncology, Advanced Malignancy, Advanced Solid Tumors, Cancer, Oncology Patients, Tumors, Melanoma

Intervention / Treatment
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* Drug: AMG 232
* Drug: Trametinib
* Drug: Dabrafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically or cytologically confirmed metastatic cutaneous or mucosal melanoma, Able to swallow and retain orally administered medication, Adequate hematological, renal, hepatic, and coagulation laboratory assessments Exclusion Criteria: Clinically significant bleeding within 4 weeks of screening, Current use of warfarin, factor Xa inhibitors, and direct thrombin inhibitors, Infection requiring anti-infective treatments within 1 week of study enrollment, Anti-tumor therapy, Major surgery within 28 days

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AMG 232 with Trametinib and Dabrabenib<br>Arm 1 of Part 1 and 2 and Part 3 | Drug: AMG 232<br>* Given as an oral tablet in escalating doses<br>Drug: Trametinib<br>* Trametinib is an anti-cancer agent<br>Drug: Dabrafenib<br>* Dabrafenib is an anti-cancer agent<br>|
| Experimental: AMG 232 with Trametinib<br>Arm 2 of Part 1 and 2 | Drug: AMG 232<br>* Given as an oral tablet in escalating doses<br>Drug: Trametinib<br>* Trametinib is an anti-cancer agent<br>|
| Active Comparator: Trametinib and Dabrafenib<br>Part 3 | Drug: Trametinib<br>* Trametinib is an anti-cancer agent<br>Drug: Dabrafenib<br>* Dabrafenib is an anti-cancer agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject incidence of treatment-emergent adverse events, Results of safety laboratory tests, vital sign measurements, ECG measurements, PK parameters; Progression-free Survival Rate | Incidence and grade of treatment-emergent adverse events, including dose-limiting toxicities; AMG 232, trametinib, dabrafenib, and metabolite PK parameters; progression-free Survival | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to and duration of overall response and duration of stable disease measured by CT or MRI and assessed per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, Progression-free and Overall Survival | Objective Tumor Response | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic melanoma