Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

Metastatic Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04903119
• Other study ID #: MCC-20-MEL-11-PMC
• Secondary ID: 1R01CA258751-01A
• Status: Recruiting
• Phase: Phase 1
• Start date: June 1, 2022
• Est. completion date: March 31, 2027

Study information

• Verified date: February 2024
• Source: University of Kentucky
• Contact: Yvonne Taul, RN
• Phone: 859-323-7628
• Email: Yvonne.Taul[@]uky.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 15
• Est. completion date: March 31, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have histologically confirmed metastatic or unresectable melanoma

• Patients must have a BRAF V600 mutation

• Patients must have failed or have stable disease on 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

Related Conditions & MeSH terms

• BRAF Gene Mutation
• Melanoma
• Metastatic Melanoma

Intervention

Drug:
• Nilotinib 100mg
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.
• Nilotinib 200mg
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.
• Nilotinib 300mg
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.
• Nilotinib 400mg
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.
• Dabrafenib
All patients will begin dabrafenib (150mg PO BID) on day one and will continue for 28 days.
• Trametinib
All patients will begin trametinib (2mg PO once daily) on day one and will continue for 28 days.

Locations

Country	Name	City	State
United States	St. Luke's University Health Network	Easton	Pennsylvania
United States	Markey Cancer Center	Lexington	Kentucky
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee

Sponsors (3)

Lead Sponsor	Collaborator
Jill M Kolesar	National Cancer Institute (NCI), Novartis

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Change in Nilotinib Concentration	Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29.	1 month
Secondary	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