Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

Study Overview
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Brief Summary
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This is a phase 1 dose-escalation study of nilotinib in combination with fixed-dose dabrafenib and trametinib regimen for patients with metastatic or unresectable melanoma carrying a BRAF V600 mutation and have relapsed on a BRAF/MEK inhibitor therapy. The goal is to assess the toxicity and tolerability and determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of the combination of nilotinib with dabrafenib and trametinib. Additionally, this study will assess pharmacokinetic parameters of dabrafenib and nilotinib when used in combination.

Detailed Description
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This is a phase 1 dose-escalation study of nilotinib in combination with a fixed-dose of dabrafenib and trametinib. The first week, patients will be treated with dabrafenib (150mg, twice daily) and trametinib (2mg, once daily). After 7 days, when both drugs have achieved steady-state levels and there is maximal induction of CYP3A4, nilotinib will be added, and all three drugs dosed concurrently for the rest of the study. Plasma pharmacokinetic (PKs) samples for dabrafenib and nilotinib will be obtained at baseline, weekly for the first four weeks, and at regular study visits for the duration of the trial. Tissue core biopsies and correlative plasma samples will be obtained at baseline, and 2 weeks after the start of nilotinib.

Official Title
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A Phase 1 Study of Nilotinib in Combination With Dabrafenib and Trametinib in BRAF V600 Mutant Metastatic Melanoma After Progression on BRAF/MEK Inhibition

Conditions
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Metastatic Melanoma, BRAF Gene Mutation

Intervention / Treatment
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* Drug: Nilotinib 100mg
* Drug: Nilotinib 200mg
* Drug: Nilotinib 300mg
* Drug: Nilotinib 400mg
* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed metastatic or unresectable melanoma Patients must have a BRAF V600 mutation Patients must have failed any BRAFi/MEKi regimen to qualify for the trial Age ≥18 years ECOG performance status ≤ 1 Patients must have adequate organ and marrow function Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible HBV viral load must be undetectable on suppressive therapy, if indicated. Patients must have an undetectable HCV viral load. Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks or longer after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment women of childbearing potential and men must agree to use adequate contraception Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patients with chronic hypokalemia or chronic hypomagnesemia Patients with long QT syndrome or baseline QTc (Fridericia) >470 msec in males and >480 msec in females Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study Untreated brain metastases History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, and trametinib. Patients receiving any medications or substances that are strong CYP3A or CYP2C8 inhibitors or substances that are strong CYP3A inducers Use of Proton pump inhibitors concurrent with nilotinib Use of drugs or substances known to prolong QT interval is prohibited with Nilotinib Patients with uncontrolled intercurrent illness. Patients with psychiatric illness/social situations that would limit compliance with study requirements. Pregnant or lactating women Other prior malignancy active within 2 years, except for localized prostate cancer, cervical carcinoma in situ, non-melanoma carcinoma of the skin, stage 1 differentiated thyroid cancer or ductal carcinoma in situ of the breast that has/have undergone curative surgery or radiation

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Level 1<br>Patients in this group will receive 100mg Nilotinib PO BID. | Drug: Nilotinib 100mg<br>* Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 100mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.<br>Drug: Dabrafenib<br>* All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.<br>Drug: Trametinib<br>* All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.<br>|
| Experimental: Level 2<br>Patients in this group will receive 200mg Nilotinib PO BID. | Drug: Nilotinib 200mg<br>* Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 200mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.<br>Drug: Dabrafenib<br>* All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.<br>Drug: Trametinib<br>* All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.<br>|
| Experimental: Level 3<br>Patients in this group will receive 300mg Nilotinib PO BID. | Drug: Nilotinib 300mg<br>* Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 300mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.<br>Drug: Dabrafenib<br>* All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.<br>Drug: Trametinib<br>* All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.<br>|
| Experimental: Level 4<br>Patients in this group will receive 400mg Nilotinib PO BID. | Drug: Nilotinib 400mg<br>* Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) on day one and will continue for 28 days. After 7 days, nilotinib will be added at 400mg PO BID and will continue for 21 days. For each subsequent cycle, nilotinib will be given for 28 days.<br>Drug: Dabrafenib<br>* All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.<br>Drug: Trametinib<br>* All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Experiencing Dose Limiting Toxicities | Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Adjusted Steady State Concentration of Dabrafenib | The dose-adjusted steady state concentrations (Css) of dabrafenib will be calculated on day 8 (dabrafenib alone) compared to day 15 (dabrafenib + nilotinib). | 15 days | 
| Change in Nilotinib Concentration | Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29. | 1 month | 
| Duration of Response | Duration of overall response will be determined by the time measurement criteria are met for complete response (CR) or partial response (PR) - whichever is first recorded - until the first date that recurrent or progressive disease is objectively documented. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dose escalation, nilotinib, dabrafenib, trametinib, pharmacokinetics, CYP3A4