Nilotinib in Combination with Dabrafenib and Trametinib or Encorafenib and Binimetinib for the Treatment of BRAF V600 Mutant Metastatic or Unresectable Melanoma
This phase I trial tests the safety, side effects, and best dose of nilotinib given together with dabrafenib and trametinib (DT) or encorafenib and binimetinib (EB) in treating patients with BRAF V600 mutant melanoma that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Nilotinib, dabrafenib, trametinib, encorafenib, and binimetinib are in a class of medications called kinase inhibitors. They work by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps stop the spread of tumor cells.
Inclusion Criteria
- Patients must have histologically confirmed metastatic or unresectable melanoma. Radiological evaluation should occur within 28-days prior to enrollment initiation
- Patients must have a BRAF V600 mutation. Any Clinical Laboratory Improvement Act (CLIA)-certified mutation testing is acceptable to document mutation status
- Patients must have stable disease on dabrafenib and trametinib or on encorafenib and binimetinib for a duration of greater than or equal to 3 months OR have failed any BRAFi/MEKi regimen to qualify for the trial, including the dabrafenib/trametinib combination and/or the encorafenib/ binimetinib combination
- Patient may have had prior immunotherapy for metastatic disease or prior cellular therapy (although NOT mandatory). Other prior therapies are not allowed, with the exception of radiation
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< institutional upper limit of normal (ULN)
- Aspartate transaminase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
- Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
- Patients with known human immunodeficiency virus (HIV) on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they 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 of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target lesions selected for tumor measurements should be those where additional (e.g., palliative) treatments are not indicated or anticipated. * Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be recorded for non-nodal lesions > 10mm and short axis for nodal lesions >15 mm using conventional techniques * For patients enrolling onto the study with stable disease, it is possible they have no evidence of disease and/or do not have disease that meet RECIST 1.1 criteria if they have had clinical and radiographical response to treatment. This will be noted and monitored on subsequent surveillance imaging as per guidelines
- The effects of nilotinib, encorafenib, dabrafenib, binimetinib and trametinib on the developing human fetus are unknown, women of childbearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of nilotinib, dabrafenib, and trametinib administration
- Patients must have the ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- Patients with chronic hypokalemia or chronic hypomagnesemia. Patients can be eligible with a repeat screening, if results show repletion
- Patients with long QT syndrome or baseline QTc (Fridericia) > 470 msec in males and > 480 msec in females (ULN for each respectively)
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1 or greater than baseline) with the exception of alopecia, grade 2 fatigue, vitiligo or endocrinopathies on stable replacement therapy)
- Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study
- Untreated brain metastases are not allowed
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, encorafenib, binimetinib and trametinib
- Patients receiving any medications or substances that are strong CYP3A inhibitors are ineligible for this trial. Patients receiving any medications or substances that are strong CYP3A inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Patients receiving any medications or substances that are strong CYP2C8 inhibitors are ineligible for the dabrafenib+ trametinib. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Use of proton pump inhibitors concurrent with nilotinib is prohibited. Use of short-acting antacids or H2 blockers as an alternative to proton pump inhibitors is allowable
- 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
Additional locations may be listed on ClinicalTrials.gov for NCT04903119.
Locations matching your search criteria
United States
Kentucky
Lexington
Pennsylvania
Allentown
Tennessee
Nashville
PRIMARY OBJECTIVE:
I. To assess the toxicity and tolerability and determine the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of the combination of nilotinib hydrochloride monohydrate (nilotinib) with BRAF inhibitor and MEK inhibitor (dabrafenib and trametinib OR encorafenib and binimetinib) for BRAF mutant metastatic melanoma patients.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity of the combination of nilotinib and BRAF inhibitor and MEK inhibitor.
II. To estimate the response rate and duration of response of nilotinib in combination with dabrafenib and trametinib OR encorafenib and binimetinib in BRAF mutant melanoma patients.
III. To evaluate the pharmacokinetics of nilotinib administered concomitantly with dabrafenib and trametinib OR encorafenib and binimetinib.
EXPLORATORY OBJECTIVES:
I. To identify whether the drugs inhibit their targets, by evaluating ABL kinase activity and pERK activation.
II. To identify patients most likely to respond to therapy, by evaluating whole exome and ribonucleic acid (RNA) sequencing, and evaluating RTK signaling.
OUTLINE: This is a dose-escalation study of nilotinib in combination with dabrafenib and trametinib or with encorafenib and binimetinib.
Patients receive nilotinib orally (PO) twice a day (BID) on days 2-28 of cycle 1, and days 1-28 of subsequent cycles. Patients also receive either dabrafenib PO BID and trametinib PO once a day (QD) on days 1-28 of each cycle or encorafenib PO QD and binimetinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiogram (ECHO), computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI), blood sample collection, and tumor biopsy throughout the trial.
After completion of study treatment, patients are followed up for 4 weeks.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of Kentucky/Markey Cancer Center
Principal InvestigatorRuta Arays
- Primary IDMCC-20-MEL-11-PMC
- Secondary IDsNCI-2021-01699, 2020-092, 63739
- ClinicalTrials.gov IDNCT04903119