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Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

Primary Purpose

Metastatic Melanoma, BRAF Gene Mutation

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Nilotinib 100mg

Nilotinib 200mg

Nilotinib 300mg

Nilotinib 400mg

Dabrafenib

Trametinib

About this trial

This is an interventional treatment trial for Metastatic Melanoma focused on measuring dose escalation, nilotinib, dabrafenib, trametinib, pharmacokinetics, CYP3A4

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Markey Cancer CenterRecruiting
St. Luke's University Health NetworkRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Level 1

Level 2

Level 3

Level 4

Arm Description

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

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

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

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

Outcomes

Primary Outcome Measures

Percentage of Patients Experiencing Dose Limiting Toxicities

Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol.

Secondary Outcome Measures

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).

Change in Nilotinib Concentration

Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29.

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.

Full Information

NCT ID

NCT04903119

First Posted

April 26, 2021

Last Updated

May 9, 2023

Sponsor

Jill M Kolesar

Collaborators

Novartis, National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT04903119

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 1, 2022 (Actual)

Primary Completion Date

December 31, 2026 (Anticipated)

Study Completion Date

March 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Jill M Kolesar

Collaborators

Novartis, National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Melanoma, BRAF Gene Mutation

Keywords

dose escalation, nilotinib, dabrafenib, trametinib, pharmacokinetics, CYP3A4

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Level 1

Arm Type

Experimental

Arm Description

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

Arm Title

Level 2

Arm Type

Experimental

Arm Description

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

Arm Title

Level 3

Arm Type

Experimental

Arm Description

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

Arm Title

Level 4

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Nilotinib 100mg

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Nilotinib 200mg

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Nilotinib 300mg

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Nilotinib 400mg

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Dabrafenib

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Trametinib

Intervention Description

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

Primary Outcome Measure Information:

Title

Percentage of Patients Experiencing Dose Limiting Toxicities

Description

Percentage of patients who experienced dose-limiting toxicities associated with Nilotinib as defined by the study protocol.

Time Frame

28 days

Secondary Outcome Measure Information:

Title

Dose-Adjusted Steady State Concentration of Dabrafenib

Description

The dose-adjusted steady state concentrations (Css) of dabrafenib will be calculated on day 8 (dabrafenib alone) compared to day 15 (dabrafenib + nilotinib).

Time Frame

15 days

Title

Change in Nilotinib Concentration

Description

Plasma concentrations of Nilotinib will be measured on day 8 (pre-Nilotinib) and day 29.

Time Frame

1 month

Title

Duration of Response

Description

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Yvonne Taul, RN

Phone

859-323-7628

Yvonne.Taul@uky.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mark Evers, MD

Organizational Affiliation

University of Kentucky

Official's Role

Principal Investigator

Facility Information:

Facility Name

Markey Cancer Center

City

Lexington

State/Province

Kentucky

ZIP/Postal Code

40536

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yvonne Taul, RN

Phone

859-323-7628

yvonne.taul@uky.edu

Facility Name

St. Luke's University Health Network

City

Easton

State/Province

Pennsylvania

ZIP/Postal Code

18045

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Amy Grossman

Phone

484-658-1788

amy.grossman@sluhn.org

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Nilotinib Plus Dabrafenib/Trametinib in Metastatic Melanoma

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