Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma
- Conditions
- Melanoma
- Interventions
- Drug: CDK4/6 and MEK inhibitorDrug: Matched targeted therapyDrug: Standard therapy or clinical trialDrug: Compassionate Access Targeted Therapy
- Registration Number
- NCT02645149
- Lead Sponsor
- Melanoma Institute Australia
- 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.
- Detailed Description
Current standard of care testing covers mutations in the BRAF and NRAS genes. The comprehensive gene testing platform to be used in this project is designed to interrogate the entire coding sequence of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer. These genes are known to be somatically altered in solid cancers based on recent scientific and clinical literature. The test panel will be used on melanoma tissue from patients pre-screened as having BRAF and NRAS wild-type melanoma. The extent of testing will be updated to reflect new discoveries in melanoma tumourigenesis and availability of new therapies as the project proceeds. Testing will be performed on formalin-fixed and paraffin-embedded samples of metastatic tissue. Archival tissue from primary or regional recurrent melanoma may be considered if no recent sample is available or possible.
All new patients with unresectable Stage III or IV melanoma seen at each participating site will be invited to participate. Following written consent, all patients will undergo the standard testing for BRAF and NRAS mutations. Patients found to have mutations in either gene will receive standard treatment with dabrafenib and / or trametinib and no further molecular testing.
Patients with wild type versions of BRAF and NRAS genes will have tumour tissue sent for the extended gene testing platform. These patients will first receive standard of care therapy for wild type BRAF / NRAS melanoma, where possible. Once standard therapies have been exhausted (because of disease progression or intolerable adverse events), patients will then receive a targeted therapy matched for their genetic result, if applicable. The selection of targeted therapy will be based on clinical evidence of activity in other solid tumours harbouring similar mutations and / or in at least Phase I testing in melanoma. The table of matched therapies will be modified and extended as new findings from clinical research become available. Patients may be included in specific clinical trials of targeted therapies if available, e.g. a MEK inhibitor combined with an MDM2 inhibitor (AMG232) for BRAF and TP53 wild-type melanoma or a MEK inhibitor combined with a CDK4/6 inhibitor for BRAF wild-type melanoma.
The extensive molecular profiling platform is fully validated and will be conducted by an external provider accredited by an authority with the responsibility to award Laboratory Accreditation at private and public facilities.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1000
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description A3. Non-V600 BRAF, BRAF wild type and NRAS wild type melanoma - no actionable genetic aberration Trametinib and / or supportive care 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 B. Mucosal melanoma CDK4/6 and MEK inhibitor 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. A1. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, matched drug available Matched targeted therapy 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. D. BRAF V600 mutant melanoma Standard therapy or clinical trial Patients will receive standard of care treatment only. A2. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, no matched drug available Compassionate Access Targeted Therapy 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. C. NRAS mutant melanoma CDK4/6 and MEK inhibitor 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.
- Primary Outcome Measures
Name Time Method Proportion of patients with BRAS/NRAS wild-type melanoma receiving targeted therapy For the duration of the study, estimated at 5 years. 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.
Type and frequency of genetic aberrations in BRAF/NRAS wild-type metastatic melanoma For the duration of the study, estimated at 5 years. Genetic aberrations detected by extended molecular profiling in patients with BRAF / NRAS wild type metastatic melanoma.
- Secondary Outcome Measures
Name Time Method Adverse events in patients receiving matched targeted therapy. From date of the start of targeted therapy to 30 days from discontinuation of targeted therapy Characterisation of adverse events by type, frequency and severity using CTCAE version 5.0
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. Proportion of patients who received matched targeted therapy as a result of genetic aberrations detected with extended molecular profiling who had a complete (CR) or partial (PR) response.
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. For patients experiencing a complete or partial response to study treatment, the amount of time from this outcome to the time that disease progression or death occurs
Progression free survival From date of targeted therapy commencement to date of objective disease progression per RECIST, assessed up to 60 months. The period of time from study entry to progression of disease or death
Overall survival From date of targeted therapy commencement to date of death from any cause, assessed up to 60 months. The proportion of patients alive from the time of study entry
Proportion of patients who have BRAF/NRAS wild type melanoma For the duration of the study, estimated at 5 years. From consecutive patients with metastatic melanoma tested for common BRAF / NRAS mutations as part of standard care.
Correlation of genetic aberration detected in tumour tissue with clinical response and disease progression From date of targeted therapy commencement to date of to partial or complete response or disease progression, assessed up to 60 months. Identify genetic predictors of response and progression using the extended molecular testing platform.
Correlation of with genetic aberration detected in tumour tissue with age at diagnosis, site of primary tumour, chronic sun damaged skin. At baseline Identify clinicopathological correlates (e.g. age at diagnosis, site of primary tumour, chronic sun damaged skin etc.) of molecular subtypes of melanoma at baseline.
Correlation of genetic aberration detected in tumour tissue with site of metastases, nodular or superficial spreading disease. At baseline Identify the differences in disease behaviour (e.g. site of metastases, nodular or superficial spreading disease) based on molecular subtypes of melanoma.
Trial Locations
- Locations (2)
Melanoma Institute Australia
🇦🇺Wollstonecraft, New South Wales, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia