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NCT02645149

PHASE2

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

Sponsor: Melanoma Institute Australia

View on ClinicalTrials.gov

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.

Key Details

Gender

All

Age Range

18 Years - 100 Years

Study Type

INTERVENTIONAL

Enrollment

216

Start Date

2021-11-22

Completion Date

2026-03-06

Last Updated

2026-05-29

Healthy Volunteers

Conditions

Melanoma

Interventions

DRUG

Standard therapy or clinical trial

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

DRUG

Matched targeted therapy

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.

DRUG

Trametinib and / or supportive care

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.

DRUG

CDK4/6 and MEK inhibitor

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.

DRUG

Compassionate Access Targeted Therapy

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

Inclusion criteria for Part 1: 1. Written informed consent for Part 1 2. 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). 3. Treatment-naïve for unresectable advanced orf metastatic melanoma (systemic treatment given in the neoadjuvant and adjuvant settings are acceptable). 4. 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. 5. Male or female patients aged 18 or over. 6. Standard of care molecular tumour testing which has identified NRAS wild type, and either BRAF wild type or non-V600 BRAF mutant melanoma. 7. Adequate tissue available for the Molecular Testing Platform. Eligibility Criteria for NGS Molecular Testing Platform (Part 1) 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). 2. Adequate tissue available per NGS specimen preparation instructions. Inclusion Criteria for Part 2: 1. Written informed consent to receive targeted therapy (if applicable) and clinical follow up. 2. Patient has undergone NGS tumour testing or has NRAS or ALKati mutant melanoma on routine testing 3. Histologically confirmed melanoma of any sub type with measurable disease per RECIST criteria. 4. 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. 5. 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 6. ECOG status 0 - 2. 7. Adequate haematological, hepatic and renal organ function as defined by: 1. White cell count ≥ 2.0 × 109/L 2. Neutrophil count ≥ 1.5 × 109/L 3. Haemoglobin ≥ 90 g/L 4. Platelet count ≥ 100 x 109/L 5. Total bilirubin ≤ 3.0 x ULN 6. Alanine transaminase ≤ 3.0 x ULN 7. Aspartate aminotransferase ≤ 3.0 x ULN 8. Serum creatinine ≤ 1.5 x the upper limit of normal (ULN). 8. Life expectancy \> 30 days. 9. Women of child bearing potential (WOCBP) to use contraception to avoid pregnancy. 10. Non sterile men with female partners of CBP to use contraception to avoid pregnancy. Exclusion criteria for Matched Targeted Therapy: 1. 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). 2. Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug. 3. Any investigational drug or other systemic drug therapy for melanoma within 14 days or 5 half-lives from baseline, whichever is shorter. 4. Pregnant or breast feeding females. 5. Drug specific exclusions as detailed in the TGA Product Information for each drug.

Locations (2)

Westmead Hospital

Westmead, New South Wales, Australia

Melanoma Institute Australia

Wollstonecraft, New South Wales, Australia