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

NCT04903119 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: MCC-20-MEL-11-PMC1R01CA258751-01A1
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Metastatic Melanoma; BRAF Gene Mutation

Keywords

dose escalation; nilotinib; dabrafenib; trametinib; pharmacokinetics; CYP3A4; encorafenib; binimetinib

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Dose-Adjusted Steady State Concentration of Dabrafenib

  15 days

• Change in Nilotinib Concentration

  1 month

• Duration of Response

  12 months

Study Arms (4)

Level 1

EXPERIMENTAL

Patients in this group will receive 100mg Nilotinib PO BID.

Drug: Nilotinib 100mg; Drug: Dabrafenib; Drug: Trametinib; Drug: Encorafenib; Drug: Binimetinib

Level 2

EXPERIMENTAL

Patients in this group will receive 200mg Nilotinib PO BID.

Drug: Nilotinib 200mg; Drug: Dabrafenib; Drug: Trametinib; Drug: Encorafenib; Drug: Binimetinib

Level 3

EXPERIMENTAL

Patients in this group will receive 300mg Nilotinib PO BID.

Drug: Nilotinib 300mg; Drug: Dabrafenib; Drug: Trametinib; Drug: Encorafenib; Drug: Binimetinib

Level 4

EXPERIMENTAL

Patients in this group will receive 400mg Nilotinib PO BID.

Drug: Nilotinib 400mg; Drug: Dabrafenib; Drug: Trametinib; Drug: Encorafenib; Drug: Binimetinib

Interventions

Nilotinib 100mg DRUG

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.

Level 1

Nilotinib 200mg DRUG

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.

Level 2

Nilotinib 300mg DRUG

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.

Level 3

Nilotinib 400mg DRUG

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.

Level 4

Dabrafenib DRUG

All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.

Level 1; Level 2; Level 3; Level 4

Trametinib DRUG

All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.

Level 1; Level 2; Level 3; Level 4

Encorafenib DRUG

encorafenib will be administered orally 450mg once daily for 28 consecutive days

Level 1; Level 2; Level 3; Level 4

Binimetinib DRUG

binimetinib will be administered orally 45mg twice daily for 28 consecutive days

Level 1; Level 2; Level 3; Level 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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). NOTE: Other prior therapies are not allowed, with the exception of radiation.
• Age ≥18 years.
• ECOG performance status ≤ 1. See Appendix A.
• 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)
• Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis: collaborator
• National Cancer Institute (NCI): collaborator
• Rina Plattner: lead

Study Sites (4)

University of Iowa

Iowa City, Iowa, 52242, United States

NOT YET RECRUITING

Markey Cancer Center

Lexington, Kentucky, 40536, United States

RECRUITING

St. Luke's University Health Network

Easton, Pennsylvania, 18045, United States

RECRUITING

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

RECRUITING

MeSH Terms

Conditions

Melanoma

Interventions

nilotinib; dabrafenib; trametinib; encorafenib; binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Ruta Arays, MD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

• Rina Plattner, PhD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Heather Pavlik, RN

CONTACT

859-323-7628; heather.schroer@uky.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 26, 2021
• First Posted: May 26, 2021
• Study Start: June 1, 2022
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): June 1, 2030
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)