Nilotinib Plus Dabrafenib/Trametinib or Encorafenib/Binimetinib in Metastatic Melanoma

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

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 or with encorafenib and binimetinib. Additionally, this study will assess pharmacokinetic parameters of dabrafenib and nilotinib when used in combination.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Melanoma; BRAF Gene Mutation
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib; Drug: Nilotinib 100mg; Drug: Encorafenib; Drug: Binimetinib; Drug: Nilotinib 200mg; Drug: Nilotinib 300mg; Drug: Nilotinib 400mg

Detailed Description

This is a phase 1 dose-escalation study of nilotinib in combination with a fixed-dose of dabrafenib and trametinib or with encorafenib and binimetinib. The first week, patients will be treated with dabrafenib (150mg, twice daily) and trametinib (2mg, once daily), or encorafenib (450 mg, daily) and binimetinib (45 mg twice 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. Optional 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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Heather Pavlik, RN; Phone Number: 859-323-7628; Email: heather.schroer@uky.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Not yet recruiting
      • University of Iowa
      • Principal Investigator: Mohammed Milhem, MD
      • Contact: Mohammed Milhem, MD; Phone Number: 319-356-2324; Email: mohammed-milhem@uiowa.edu
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • Markey Cancer Center
      • Contact: Heather Pavlik, RN; Phone Number: 859-323-7628; Email: heather.schroer@uky.edu
  • Pennsylvania
    • Easton, Pennsylvania, United States, 18045
      • Recruiting
      • St. Luke's University Health network
      • Contact: Amy Grossman; Phone Number: 484-658-1788; Email: amy.grossman@sluhn.org
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt-Ingram Cancer Center
      • Contact: Douglas B Johnson; Phone Number: 800-811-8480; Email: CTIP@VUMC.ORG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

3.1.1 Patients must have histologically confirmed metastatic or unresectable melanoma.

Radiological evaluation should occur within 28 days prior to enrollment initiation.

3.1.2 Patients must have a BRAF V600 mutation. Any CLIA-certified mutation testing is acceptable to document mutation status.

3.1.3 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.

3.1.4 Patient may have had prior immunotherapy for metastatic disease or prior cellular therapy (although NOT mandatory). NOTE: Other prior therapies are not allowed, with the exception of radiation.

3.1.5 Age ≥18 years.

3.1.6 ECOG performance status ≤ 1. See Appendix A.

3.1.7 Patients must have adequate organ and marrow function as defined below: absolute neutrophil count ≥1,500/mcL platelets ≥100,000/mcL total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2 (see Appendix B)

3.1.8 Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

3.1.9 For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

3.1.10 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.

3.1.11 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.

3.1.12 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.

3.1.13 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.

3.1.14 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.

3.1.15 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.

3.1.16 Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

3.2.1 Patients with chronic hypokalemia or chronic hypomagnesemia. Patients can be eligible with a repeat screening, if results show repletion.

3.2.2 Patients with long QT syndrome or baseline QTc (Fridericia) >470 msec in males and >480 msec in females (ULN for each respectively).

3.2.3 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).

3.2.4 Patients who are receiving any other investigational therapies that could affect the primary or secondary outcomes of this study.

3.2.5 Untreated brain metastases are not allowed.

3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic composition to nilotinib, dabrafenib, encorafenib, binimetinib and trametinib.

3.2.7 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.

3.2.8 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.

3.2.9 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.

3.2.10 Use of drugs or substances known to prolong QT interval is prohibited with Nilotinib

3.2.11 Patients with uncontrolled intercurrent illness.

3.2.12 Patients with psychiatric illness/social situations that would limit compliance with study requirements.

3.2.13 Pregnant or lactating women

3.3 There are no exclusions for trial participation based on gender nor race.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Level 1; Patients in this group will receive 100mg Nilotinib PO BID.	Drug: Dabrafenib; All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.; Drug: Trametinib; All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.; Drug: Nilotinib 100mg; Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) 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.; Drug: Encorafenib; encorafenib will be administered orally 450mg once daily for 28 consecutive days; Drug: Binimetinib; binimetinib will be administered orally 45mg twice daily for 28 consecutive days
Experimental: Level 2; Patients in this group will receive 200mg Nilotinib PO BID.	Drug: Dabrafenib; All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.; Drug: Trametinib; All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.; Drug: Encorafenib; encorafenib will be administered orally 450mg once daily for 28 consecutive days; Drug: Binimetinib; binimetinib will be administered orally 45mg twice daily for 28 consecutive days; Drug: Nilotinib 200mg; Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) 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.
Experimental: Level 3; Patients in this group will receive 300mg Nilotinib PO BID.	Drug: Dabrafenib; All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.; Drug: Trametinib; All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.; Drug: Encorafenib; encorafenib will be administered orally 450mg once daily for 28 consecutive days; Drug: Binimetinib; binimetinib will be administered orally 45mg twice daily for 28 consecutive days; Drug: Nilotinib 300mg; Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) 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.
Experimental: Level 4; Patients in this group will receive 400mg Nilotinib PO BID.	Drug: Dabrafenib; All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.; Drug: Trametinib; All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.; Drug: Encorafenib; encorafenib will be administered orally 450mg once daily for 28 consecutive days; Drug: Binimetinib; binimetinib will be administered orally 45mg twice daily for 28 consecutive days; Drug: Nilotinib 400mg; Patients will begin dabrafenib (150mg PO BID) and trametinib (2mg PO once daily) or encorafenib (450 mg PO) and binimetinib (45 mg PO BID) 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Rina Plattner
• Collaborators: National Cancer Institute (NCI); Novartis
• Investigators: Principal Investigator: Ruta Arays, MD, University Of Kentucky; Principal Investigator: Rina Plattner, PhD, University Of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: April 26, 2021
• First Submitted That Met QC Criteria: May 25, 2021
• First Posted (Actual): May 26, 2021

Study Record Updates

• Last Update Posted (Actual): February 13, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: pharmacokinetics; trametinib; dabrafenib; dose escalation; CYP3A4; encorafenib; binimetinib; nilotinib
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; dabrafenib; trametinib; encorafenib; binimetinib; nilotinib
• Other Study ID Numbers: MCC-20-MEL-11-PMC; 1R01CA258751-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes