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Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma (MatchMel)

Primary Purpose

Melanoma

Status
Recruiting
Phase
Phase 2
Locations
Australia
Study Type
Interventional
Intervention
Standard therapy or clinical trial
Matched targeted therapy
Trametinib and / or supportive care
CDK4/6 and MEK inhibitor
Compassionate Access Targeted Therapy
Sponsored by
Melanoma Institute Australia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Metastatic Melanoma, Molecular Testing, Targeted Therapy

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Westmead Hospital
  • Melanoma Institute AustraliaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Other

Arm Label

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

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

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

B. Mucosal melanoma

C. NRAS mutant melanoma

D. BRAF V600 mutant melanoma

Arm Description

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.

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.

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

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.

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.

Patients will receive standard of care treatment only.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

Proportion of patients who have BRAF/NRAS wild type melanoma
From consecutive patients with metastatic melanoma tested for common BRAF / NRAS mutations as part of standard care.
Proportion of patients with complete (CR) or partial (PR) response.
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
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
The period of time from study entry to progression of disease or death
Overall survival
The proportion of patients alive from the time of study entry
Correlation of genetic aberration detected in tumour tissue with clinical response and disease progression
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.
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.
Identify the differences in disease behaviour (e.g. site of metastases, nodular or superficial spreading disease) based on molecular subtypes of melanoma.
Adverse events in patients receiving matched targeted therapy.
Characterisation of adverse events by type, frequency and severity using CTCAE version 5.0

Full Information

First Posted
December 27, 2015
Last Updated
August 28, 2023
Sponsor
Melanoma Institute Australia
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT02645149
Brief Title
Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma
Acronym
MatchMel
Official Title
Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 22, 2021 (Actual)
Primary Completion Date
July 2027 (Anticipated)
Study Completion Date
December 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Melanoma Institute Australia
Collaborators
Novartis

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
Metastatic Melanoma, Molecular Testing, Targeted Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
1000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
A1. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, matched drug available
Arm Type
Experimental
Arm Description
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.
Arm Title
A2. Non-V600 BRAF, BRAF wildtype, NRAS wildtype. Actionable gene mutation, no matched drug available
Arm Type
Experimental
Arm Description
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.
Arm Title
A3. Non-V600 BRAF, BRAF wild type and NRAS wild type melanoma - no actionable genetic aberration
Arm Type
Experimental
Arm Description
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
Arm Title
B. Mucosal melanoma
Arm Type
Experimental
Arm Description
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.
Arm Title
C. NRAS mutant melanoma
Arm Type
Experimental
Arm Description
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.
Arm Title
D. BRAF V600 mutant melanoma
Arm Type
Other
Arm Description
Patients will receive standard of care treatment only.
Intervention Type
Drug
Intervention Name(s)
Standard therapy or clinical trial
Other Intervention Name(s)
Immunotherapy, Biological agent
Intervention Description
Patients with BRAF V600 mutations detected by standard of care tumour testing will be treated with standard approved therapies or on clinical trials.
Intervention Type
Drug
Intervention Name(s)
Matched targeted therapy
Other Intervention Name(s)
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
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Trametinib and / or supportive care
Other Intervention Name(s)
Trametinib, Supportive care
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
CDK4/6 and MEK inhibitor
Other Intervention Name(s)
Ribociclib + Trametinib
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Compassionate Access Targeted Therapy
Other Intervention Name(s)
Off label use of a matched targeted therapy currently unavailable to the study
Intervention Description
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
Primary Outcome Measure Information:
Title
Type and frequency of genetic aberrations in BRAF/NRAS wild-type metastatic melanoma
Description
Genetic aberrations detected by extended molecular profiling in patients with BRAF / NRAS wild type metastatic melanoma.
Time Frame
For the duration of the study, estimated at 5 years.
Title
Proportion of patients with BRAS/NRAS wild-type melanoma receiving targeted therapy
Description
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.
Time Frame
For the duration of the study, estimated at 5 years.
Secondary Outcome Measure Information:
Title
Proportion of patients who have BRAF/NRAS wild type melanoma
Description
From consecutive patients with metastatic melanoma tested for common BRAF / NRAS mutations as part of standard care.
Time Frame
For the duration of the study, estimated at 5 years.
Title
Proportion of patients with complete (CR) or partial (PR) response.
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.
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.
Title
Duration of response
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
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.
Title
Progression free survival
Description
The period of time from study entry to progression of disease or death
Time Frame
From date of targeted therapy commencement to date of objective disease progression per RECIST, assessed up to 60 months.
Title
Overall survival
Description
The proportion of patients alive from the time of study entry
Time Frame
From date of targeted therapy commencement to date of death from any cause, assessed up to 60 months.
Title
Correlation of genetic aberration detected in tumour tissue with clinical response and disease progression
Description
Identify genetic predictors of response and progression using the extended molecular testing platform.
Time Frame
From date of targeted therapy commencement to date of to partial or complete response or disease progression, assessed up to 60 months.
Title
Correlation of with genetic aberration detected in tumour tissue with age at diagnosis, site of primary tumour, chronic sun damaged skin.
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.
Time Frame
At baseline
Title
Correlation of genetic aberration detected in tumour tissue with site of metastases, nodular or superficial spreading disease.
Description
Identify the differences in disease behaviour (e.g. site of metastases, nodular or superficial spreading disease) based on molecular subtypes of melanoma.
Time Frame
At baseline
Title
Adverse events in patients receiving matched targeted therapy.
Description
Characterisation of adverse events by type, frequency and severity using CTCAE version 5.0
Time Frame
From date of the start of targeted therapy to 30 days from discontinuation of targeted therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria for Inclusion in Molecular Testing Platform: Newly diagnosed and treatment naïve unresectable Stage IIIB, IIIC or Stage IV melanoma (including sub types: cutaneous, mucosal, acral, ungual, uveal and unknown primary). Archival metastatic tumour tissue available for genetic testing. Archival tissue from primary melanoma may be considered if no recent sample is available. Male or female patients aged 18 or over. 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: White cell count ≥ 2.0 × 109/L Neutrophil count ≥ 1.5 × 109/L Haemoglobin ≥ 90 g/L Platelet count ≥ 100 x 109/L Total bilirubin ≤ 3.0 x ULN Alanine transaminase ≤ 3.0 x ULN Aspartate aminotransferase ≤ 3.0 x ULN 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: 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 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. Drug specific exclusions. Any clinically significant gastrointestinal abnormalities which may impair intake or absorption of the study drug
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Monica Osorio
Phone
612 9911 7296
Email
monica.osorio@melanoma.org.au
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alex Menzies
Organizational Affiliation
Melanoma Institute Australia
Official's Role
Study Chair
Facility Information:
Facility Name
Westmead Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Radhika Butala
Phone
612 8890 8935
Email
Radhika.Butala@health.nsw.gov.au
First Name & Middle Initial & Last Name & Degree
Matteo Carlino
Facility Name
Melanoma Institute Australia
City
Wollstonecraft
State/Province
New South Wales
ZIP/Postal Code
2260
Country
Australia
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Monica I Osorio
Phone
+612 9911 7296
Email
monica.osorio@melanoma.org.au
First Name & Middle Initial & Last Name & Degree
Alex Menzies
Phone
+612 9911 7200
Email
info@melanoma.org.au
First Name & Middle Initial & Last Name & Degree
Georgina Long
First Name & Middle Initial & Last Name & Degree
Alex Menzies

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34376578
Citation
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.
Results Reference
derived

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Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma

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