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Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

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ClinicalTrials.gov Identifier: NCT04903119
Recruitment Status : Recruiting
First Posted : May 26, 2021
Last Update Posted : January 25, 2022
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Peng Wang, MD PhD, University of Kentucky

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

Condition or disease Intervention/treatment Phase
Metastatic Melanoma BRAF Gene Mutation Drug: Nilotinib 100mg Drug: Nilotinib 200mg Drug: Nilotinib 300mg Drug: Nilotinib 400mg Drug: Dabrafenib Drug: Trametinib Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : March 2022
Estimated Primary Completion Date : December 31, 2026
Estimated Study Completion Date : March 31, 2027

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. Percentage of Patients Experiencing Dose Limiting Toxicities [ Time Frame: 28 days ]
    Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol.


Secondary Outcome Measures :
  1. Dose-Adjusted Steady State Concentration of Dabrafenib [ Time Frame: 15 days ]
    The dose-adjusted steady state concentrations (Css) of dabrafenib will be calculated on day 8 (dabrafenib alone) compared to day 15 (dabrafenib + nilotinib).

  2. Change in Nilotinib Concentration [ Time Frame: 1 month ]
    Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29.

  3. Duration of Response [ Time Frame: 12 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04903119


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

Locations
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United States, Kentucky
Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Yvonne Taul, RN    859-323-7628    yvonne.taul@uky.edu   
Sponsors and Collaborators
Peng Wang, MD PhD
Novartis
Investigators
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Principal Investigator: Peng Wang, MD University of Kentucky
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Responsible Party: Peng Wang, MD PhD, Associate Professor, University of Kentucky
ClinicalTrials.gov Identifier: NCT04903119    
Other Study ID Numbers: MCC-20-MEL-11-PMC
First Posted: May 26, 2021    Key Record Dates
Last Update Posted: January 25, 2022
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Peng Wang, MD PhD, University of Kentucky:
dose escalation
nilotinib
dabrafenib
trametinib
pharmacokinetics
CYP3A4
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Trametinib
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action