Clinical Trials /

Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

NCT04903119

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma
  • 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 IDs

  • ORG STUDY ID: MCC-20-MEL-11-PMC
  • NCT ID: NCT04903119

Conditions

  • Metastatic Melanoma
  • BRAF Gene Mutation

Interventions

DrugSynonymsArms
Nilotinib 100mgLevel 1
Nilotinib 200mgLevel 2
Nilotinib 300mgLevel 3
Nilotinib 400mgLevel 4
DabrafenibLevel 1
TrametinibLevel 1

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Level 1ExperimentalPatients in this group will receive 100mg Nilotinib PO BID.
  • Nilotinib 100mg
  • Dabrafenib
  • Trametinib
Level 2ExperimentalPatients in this group will receive 200mg Nilotinib PO BID.
  • Nilotinib 200mg
  • Dabrafenib
  • Trametinib
Level 3ExperimentalPatients in this group will receive 300mg Nilotinib PO BID.
  • Nilotinib 300mg
  • Dabrafenib
  • Trametinib
Level 4ExperimentalPatients in this group will receive 400mg Nilotinib PO BID.
  • Nilotinib 400mg
  • Dabrafenib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed metastatic or unresectable melanoma

          -  Patients must have a BRAF V600 mutation

          -  Patients must have failed 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Patients Experiencing Dose Limiting Toxicities
Time Frame:28 days
Safety Issue:
Description:Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol.

Secondary Outcome Measures

Measure:Dose-Adjusted Steady State Concentration of Dabrafenib
Time Frame:15 days
Safety Issue:
Description:The dose-adjusted steady state concentrations (Css) of dabrafenib will be calculated on day 8 (dabrafenib alone) compared to day 15 (dabrafenib + nilotinib).
Measure:Change in Nilotinib Concentration
Time Frame:1 month
Safety Issue:
Description:Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29.
Measure:Duration of Response
Time Frame:12 months
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Peng Wang, MD PhD

Trial Keywords

  • dose escalation
  • nilotinib
  • dabrafenib
  • trametinib
  • pharmacokinetics
  • CYP3A4

Last Updated

June 8, 2021