Overview
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.
Description
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.
Eligibility
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