Molecular Profiling and Matched Targeted Therapy for Patients With Unresectable Advanced or Metastatic Melanoma

NCT02645149 | Completed Phase 2 DMC

• 1 other identifier: MIA2015/174
• Study Type: interventional
• Target: 216
• Locations: 1 country
• Sites: 2

Brief Summary

This is a patient oriented translational research project aiming to improve clinical outcomes for patients with BRAF and NRAS wild-type unresectable Stage III or Stage IV metastatic melanoma who have progressed on, or are unable to receive standard therapy (in general, immunotherapy). Consecutive patients seen at three major clinics and fitting the broad eligibility criteria will be invited to participate. The approach is designed to test the impact of different targeted drugs on different mutations in a single type of cancer. In this project, patients will have tumour tissue genetically profiled to determine which mutation(s) are present, and will then be assigned to receive a matched drug expected to target the mutation(s) in the tumour. Where multiple targets are identified in one patient, or where multiple potential therapies would be appropriate for a single tumour mutation, the treating clinician may determine the appropriate therapeutic approach after consultation with the study team, using the latest version of library of matched therapies.

Conditions

Melanoma

Keywords

Metastatic Melanoma; Molecular Testing; Targeted Therapy

Outcome Measures

Primary Outcomes (2)

• Type and frequency of genetic aberrations in BRAF/NRAS wild-type metastatic melanoma

  Genetic aberrations detected by extended molecular profiling in patients with BRAF / NRAS wild type metastatic melanoma.

  For the duration of the study, estimated at 5 years.

• Proportion of patients with BRAS/NRAS wild-type melanoma receiving targeted therapy

  Patients able to receive matched targeted therapy as a result of genetic aberrations detected with extended molecular profiling, from a pool of all BRAF / NRAS wild type patients.

  For the duration of the study, estimated at 5 years.

Secondary Outcomes (9)

• Proportion of patients who have BRAF/NRAS wild type melanoma

  For the duration of the study, estimated at 5 years.

• Proportion of patients with complete (CR) or partial (PR) response.

  From date of targeted therapy commencement until the date of first documented objective partial or complete response per RECIST, assessed up to 60 months.

• Duration of response

  From date of first objective partial or complete response to disease progression or death, which ever is sooner, assessed up to 60 months.

• Progression free survival

  From date of targeted therapy commencement to date of objective disease progression per RECIST, assessed up to 60 months.

• Overall survival

  From date of targeted therapy commencement to date of death from any cause, assessed up to 60 months.

Study Arms (6)

A1. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, matched drug available

EXPERIMENTAL

Patients will receive targeted drug matched to the actionable gene mutation detected on NGS testing. If a patient cannot receive the matched targeted therapy because of the existence of one or more drug specific exclusion criteria, an alternative matched therapy may be assigned, or trametinib, or clinical trials if available.

Drug: Matched targeted therapy

A2. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, no matched drug available

EXPERIMENTAL

Patients may have an actionable aberration for which there is no current study-specific drug supply available. In this scenario, access will be sought for compassionate use of the relevant approved targeted therapy.

Drug: Compassionate Access Targeted Therapy

A3. Non-V600 BRAF, BRAF wild type and NRAS wild type melanoma - no actionable genetic aberration

EXPERIMENTAL

Patients for whom there is no actionable genetic aberration will receive trametinib, based upon the known MAPK excess activity in the majority of melanomas that may be inhibited by a MEK inhibitor

Drug: Trametinib and / or supportive care

B. Mucosal melanoma

EXPERIMENTAL

Patients will receive combined trametinib and ribociclib based on evidence to suggest that combined MEK inhibition and CDK4/6 inhibition may be effective. After failure of trametinib and ribociclib, actionable genetic aberrations from the NGS testing will be reviewed for the opportunity to use a further targeted therapy off label.

Drug: CDK4/6 and MEK inhibitor

C. NRAS mutant melanoma

EXPERIMENTAL

Patients with an NRAS mutation detected on standard gene testing only will receive combined trametinib and ribociclib based on evidence that combining MEK inhibition and CDK4/6 inhibition is a viable treatment option.

Drug: CDK4/6 and MEK inhibitor

D. BRAF V600 mutant melanoma

OTHER

Patients will receive standard of care treatment only.

Drug: Standard therapy or clinical trial

Interventions

CDK4/6 and MEK inhibitor DRUG

Patients mucosal melanoma and any genetic aberration on NGS testing may receive ribociclib + trametinib initially. After failure of trametinib and ribociclib, actionable genetic aberrations from the NGS testing will be reviewed for the opportunity to use a further targeted therapy off label. Patients with an NRAS mutation on standard of care tumour testing will also receive ribociclib + trametinib.

Also known as: Ribociclib + Trametinib

B. Mucosal melanoma; C. NRAS mutant melanoma

Compassionate Access Targeted Therapy DRUG

Patients with non-V600 BRAF, BRAF wildtype and NRAS wildtype melanoma may have an actionable aberration(s) for which there is no current study-specific drug supply. In this scenario, access will be sought for compassionate use of the off label use of the relevant regulatory approved targeted therapy

Also known as: Off label use of a matched targeted therapy currently unavailable to the study

A2. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, no matched drug available

Standard therapy or clinical trial DRUG

Patients with BRAF V600 mutations detected by standard of care tumour testing will be treated with standard approved therapies or on clinical trials.

Also known as: Immunotherapy, Biological agent

D. BRAF V600 mutant melanoma

Matched targeted therapy DRUG

Patients with tumour found to be non-V600 BRAF, BRAF wildtype and NRAS wildtype melanoma will have tumour tested further using the extended molecular testing platform designed for this project. Patients will first receive standard therapy(ies) for non-V600 BRAF, wildtype and NRAS wildtype melanoma until disease progression or intolerable drug toxicities. Followed by a targeted therapy matched to the genetic aberration detected in their tumour on NGS testing.

Also known as: ALK - Ceritinib, BRAF fusion - Trametinib, CCND1 - Ribociclib + Trametinib, CDK4/6 - Ribociclib + Trametinib, CDKN2A - Ribociclib + Trametinib, GNA11 - Trametinib, GNAQ - Trametinib, HRAS - Trametinib, KIT - Pazopanib, KRAS - Trametinib, MAP2K1 - Trametinib, NF1 - Trametinib, MET - Ceritinib, RAS - Ribociclib + Trametinib, ROS1 - Ceritinib

A1. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, matched drug available

Trametinib and / or supportive care DRUG

Patients with non-V600 BRAF, BRAF wildtype and NRAS wildtype melanoma for whom there is no actionable genetic aberration found on extended molecular testing, may receive trametinib (if not already administered as part of standard care) and/or supportive care.

Also known as: Trametinib, Supportive care

A3. Non-V600 BRAF, BRAF wild type and NRAS wild type melanoma - no actionable genetic aberration

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent for Part 1
• Newly diagnosed, histologically confirmedand , unresectable Stage IIIB, IIIC or Stage IV melanoma including cutaneous (including acral, ungual subtypes), ocular (including uveal and extra-uveal), mucosal, and unknown primary).
• Treatment-naïve for unresectable advanced orf metastatic melanoma (systemic treatment given in the neoadjuvant and adjuvant settings are acceptable).
• Tumour tissue available from advanced or metastatic disease. Archival tissue from primary or regional recurrent melanoma may be considered if no recent sample is available.
• Male or female patients aged 18 or over.
• Standard of care molecular tumour testing which has identified NRAS wild type, and either BRAF wild type or non-V600 BRAF mutant melanoma.
• Adequate tissue available for the Molecular Testing Platform.
• Eligibility Criteria for NGS Molecular Testing Platform (Part 1)
• Standard of care molecular tumour testing which has identified non V600 BRAF or BRAF wild type, or NRAS wild type melanoma (NRAS mutant patients are eligible for Part 2, but will not undergo NGS testing).
• Adequate tissue available per NGS specimen preparation instructions.
• Written informed consent to receive targeted therapy (if applicable) and clinical follow up.
• Patient has undergone NGS tumour testing or has NRAS or ALKati mutant melanoma on routine testing
• Histologically confirmed melanoma of any sub type with measurable disease per RECIST criteria.
• Received available standard therapies or clinical trial agents for unrectable metastatic melanoma that has progressed, unable to tolerate standard therapy, or standard therapy is contraindicated.
• Patient has an 'actionable' genetic aberration and matched targeted therapy is available. Patients with no genetic aberration or where no matched targeted therapy is available, patients will be offered trametinib

You may not qualify if:

• An expectation for the need for concurrent radiotherapy (unless safety has been established with the matched drug regimen and is directed at one anatomical region for symptom control).
• Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug.
• Any investigational drug or other systemic drug therapy for melanoma within 14 days or 5 half-lives from baseline, whichever is shorter.
• Pregnant or breast feeding females.

Sponsors & Collaborators

• Melanoma Institute Australia: lead
• Novartis: collaborator

Study Sites (2)

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Melanoma Institute Australia

Wollstonecraft, New South Wales, 2260, Australia

Location

Related Publications (1)

• Nassar KW, Hintzsche JD, Bagby SM, Espinoza V, Langouet-Astrie C, Amato CM, Chimed TS, Fujita M, Robinson W, Tan AC, Schweppe RE. Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor-Resistant Melanoma. Mol Cancer Ther. 2021 Oct;20(10):2049-2060. doi: 10.1158/1535-7163.MCT-20-1126. Epub 2021 Aug 10.

  PMID: 34376578 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Standard of Care; Clinical Trials as Topic; Immunotherapy; Biological Factors; trametinib; Palliative Care; ribociclib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Clinical Studies as Topic; Epidemiologic Study Characteristics; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Public Health; Environment and Public Health; Immunomodulation; Biological Therapy; Therapeutics; Patient Care; Health Services; Health Care Facilities Workforce and Services

Study Officials

• Alex Menzies

  Melanoma Institute Australia

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2015
• First Posted: January 1, 2016
• Study Start: November 22, 2021
• Primary Completion: November 1, 2025
• Study Completion: December 1, 2025
• Last Updated: February 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)