Description:
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.
Title
- Brief Title: Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma
- Official Title: Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma
Clinical Trial IDs
- ORG STUDY ID:
MIA2015/174
- NCT ID:
NCT02645149
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Standard therapy or clinical trial | Immunotherapy, Biological agent | BRAF / NRAS mutant melanoma |
| Matched targeted therapy | 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 | Matched targeted therapy |
| Trametinib and / or supportive care | Trametinib, Supportive care | No actionable genetic aberration/available targeted therapy |
| CDK4/6 and MEK inhibitor | Ribociclib + Trametinib | Mucosal melanoma |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| No actionable genetic aberration/available targeted therapy | Experimental | Patients with BRAF and NRAS wild type tumour for whom there is no actionable genetic aberration in tumour tissue or no available matched targeted theray. These patients will receive trametinib based upon the known MAPK excess activity in the majority of melanomas that may be inhibited by a MEK inhibitor. | - Trametinib and / or supportive care
|
| Matched targeted therapy | Experimental | Patients with BRAF and NRAS wild type tumour for whom there is a targeted therapy available, will receive targeted drug matched to gene defect in tumour. 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 trametinin, or clinical trials if available. | |
| Mucosal melanoma | Experimental | Patients with mucosal melanoma and BRAF V600 and NRAS wild type tumour will receive trametinib with ribociclib. A large proportion of mucosal melanomas (47/67, 70%) harbour alterations (CDK4 and CCND1 amplifications, as well as CDKN2A deletions) potentially responsive to CDK4/6 and MEK inhibitors. In addition, although not identified as a significantly mutated driver, a number of samples also had CDK6 amplifications (9/67, 13%) that indicates potential sensitivity to CDK4/6 inhibitors. | |
| BRAF / NRAS mutant melanoma | Other | Patients with BRAF / NRAS mutations in tumour tissue will be treated with standard approved targeted therapies (dabrafenib and trametinib) or on clinical trials, and will be followed for clinical response and survival outcomes. | - Standard therapy or clinical trial
|
Eligibility Criteria
Inclusion criteria for Inclusion in Molecular Testing Platform:
1. Newly diagnosed and treatment naïve unresectable Stage IIIB, IIIC or Stage IV melanoma
(including sub types: cutaneous, mucosal, acral, ungual, uveal and unknown primary).
2. Archival metastatic tumour tissue available for genetic testing. Archival tissue from
primary melanoma may be considered if no recent sample is available.
3. Male or female patients aged 18 or over.
4. Written informed consent for molecular genetic testing of tumour tissue (for both
standard and research tests).
Inclusion Criteria for Matched Targeted Therapy:
6. Received available standard therapies for metastatic melanoma and progressed, unable to
tolerate standard therapy, or standard therapy contraindicated.
7. Written informed consent to receive targeted therapy (if applicable) and clinical follow
up.
8. 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 9. ECOG status 0 - 2. 10. 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). 11. Life expectancy > 30
days. 12. Women of child bearing potential (WOCBP) to use contraception to avoid
pregnancy.
13. Non sterile men with female partners of CBP to use contraception to avoid
pregnancy.
14. Drug specific inclusions.
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 investigational drug or other systemic drug therapy for melanoma within 14
days or 5 half-lives from baseline, whichever is shorter.
3. Pregnant or breast feeding females.
4. Drug specific exclusions.
5. Any clinically significant gastrointestinal abnormalities which may impair intake
or absorption of the study drug
| Maximum Eligible Age: | 100 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Type and frequency of genetic aberrations in BRAF/NRAS wild-type metastatic melanoma |
| Time Frame: | For the duration of the study, estimated at 5 years. |
| Safety Issue: | |
| Description: | Genetic aberrations detected by extended molecular profiling in patients with BRAF / NRAS wild type metastatic melanoma. |
Secondary Outcome Measures
| Measure: | Proportion of patients who have BRAF/NRAS wild type melanoma |
| Time Frame: | For the duration of the study, estimated at 5 years. |
| Safety Issue: | |
| Description: | From consecutive patients with metastatic melanoma tested for common BRAF / NRAS mutations as part of standard care. |
| Measure: | Proportion of patients with complete (CR) or partial (PR) response. |
| Time Frame: | From date of targeted therapy commencement until the date of first documented objective partial or complete response per RECIST, assessed up to 60 months. |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Duration of response |
| Time Frame: | From date of first objective partial or complete response to disease progression or death, which ever is sooner, assessed up to 60 months. |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Progression free survival |
| Time Frame: | From date of targeted therapy commencement to date of objective disease progression per RECIST, assessed up to 60 months. |
| Safety Issue: | |
| Description: | The period of time from study entry to progression of disease or death |
| Measure: | Overall survival |
| Time Frame: | From date of targeted therapy commencement to date of death from any cause, assessed up to 60 months. |
| Safety Issue: | |
| Description: | The proportion of patients alive from the time of study entry |
| Measure: | Correlation of genetic aberration detected in tumour tissue with clinical response and disease progression |
| Time Frame: | From date of targeted therapy commencement to date of to partial or complete response or disease progression, assessed up to 60 months. |
| Safety Issue: | |
| Description: | Identify genetic predictors of response and progression using the extended molecular testing platform. |
| Measure: | Correlation of with genetic aberration detected in tumour tissue with age at diagnosis, site of primary tumour, chronic sun damaged skin. |
| Time Frame: | At baseline |
| Safety Issue: | |
| Description: | Identify clinicopathological correlates (e.g. age at diagnosis, site of primary tumour, chronic sun damaged skin etc.) of molecular subtypes of melanoma at baseline. |
| Measure: | Correlation of genetic aberration detected in tumour tissue with site of metastases, nodular or superficial spreading disease. |
| Time Frame: | At baseline |
| Safety Issue: | |
| Description: | Identify the differences in disease behaviour (e.g. site of metastases, nodular or superficial spreading disease) based on molecular subtypes of melanoma. |
| Measure: | Adverse events in patients receiving matched targeted therapy. |
| Time Frame: | From date of the start of targeted therapy to 30 days from discontinuation of targeted therapy |
| Safety Issue: | |
| Description: | Characterisation of adverse events by type, frequency and severity using CTCAE version 5.0 |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Not yet recruiting |
| Lead Sponsor: | Melanoma Institute Australia |
Trial Keywords
- Metastatic Melanoma
- Molecular Testing
- Targeted Therapy
Last Updated
September 1, 2021
