Print

Purpose

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.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Level 1 		Patients in this group will receive 100mg Nilotinib PO BID.
  • 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.
  • 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.
Experimental
Level 2 		Patients in this group will receive 200mg Nilotinib PO BID.
  • Drug: 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.
  • 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.
Experimental
Level 3 		Patients in this group will receive 300mg Nilotinib PO BID.
  • Drug: 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.
  • 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.
Experimental
Level 4 		Patients in this group will receive 400mg Nilotinib PO BID.
  • Drug: 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.
  • 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.

Recruiting Locations

UK Center for Clinical and Translational Science and nearby locations

Markey Cancer Center
Lexington, Kentucky 40536
Contact:
Yvonne Taul, RN
859-323-7628
yvonne.taul@uky.edu

More Details

NCT ID
NCT04903119
Status
Recruiting
Sponsor
Ruta Arays

Study Contact

Yvonne Taul, RN
859-323-7628
Yvonne.Taul@uky.edu

Detailed 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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.