Clinical Trials /

Molecular Profiling and Matched Targeted Therapy for Patients With Metastatic Melanoma

NCT02645149

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 4

Trial Eligibility

Document

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

  • Melanoma

Interventions

DrugSynonymsArms
Standard therapy or clinical trialChemotherapy, Immunotherapy, Biological agentStandard therapy or clinical trial
Matched targeted therapyAKT gene - Everolimus, ALK - Ceritinib or Crizotinib, ATM - Olaparib, BRAF fusion - Trametinib, BRCA1 - Olaparib, BRCA2 - Olaparib, CCND1 - Palbociclib, CCND3 - Palbociclib, CDK4 - Palbociclib, CDKN2A - Palbociclib, EGFR - Erlotinib, Gefitinib or Lapatinib, ERBB2 - Lapatinib, ERBB3 - Lapatinib, ERBB4 - Lapatinib, FBXW7 - Everolimus, FGF/R - Sorafenib, GNA11 - Sorafenib or Trametinib, GNAQ - Sorafenib or Trametinib, HGF - Cabozantinib, HGF - Crizotinib, HRAS - Sorafenib or Trametinib, IDH1 - Vorinostat, KDR - Cabozantinib or Ramucirumab, KIT - Dasatinib, Imatinib, Nilotinib, Pazopanib, Regorafenib, Sorafenib or Sunitinib, KRAS - Sorafenib or Trametinib, MAP2K1 - Palbociclib or Trametinib, MET - Crizotinib, mTOR - Everolimus, NF1 - Everolimus, Sorafenib or Trametinib, PDGFR - Imatinib, PIK3CA - Everolimus, PTEN - Everolimus, RICTOR - Everolimus, STK11 - Everolimus, TP53 - Bortezomib or PalbociclibMatched targeted therapy
Trametinib and / or supportive careTrametinib, Supportive careTrametinib and / or supportive care

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

NameTypeDescriptionInterventions
Standard therapy or clinical trialOtherPatients with BRAF and NRAS wild type tumour for whom there is no actionable genetic aberration in tumour tissue. 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.
  • Standard therapy or clinical trial
Matched targeted therapyOtherPatients 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 these patients will be treated per standard therapy / clinical trial arm.
  • Matched targeted therapy
Trametinib and / or supportive careOtherPatients with BRAF V600 and NRAS mutations will be treated with standard approved therapies or on clinical trials, and will be followed for clinical response and survival outcomes.
  • Trametinib and / or supportive care

Eligibility Criteria

        Inclusion criteria for Inclusion in Molecular Testing Platform:

          1. Newly diagnosed and treatment naïve unresectable Stage IIIB, IIIC or Stage IV
             melanoma.

          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).

          5. Standard of care molecular tumour testing which has identified BRAF / NRAS wild type
             tumour tissue.

             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. ECOG status 0 - 2.

          9. 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).

         10. Life expectancy > 30 days.

         11. Women of child bearing potential (WOCBP) to use contraception to avoid pregnancy.

         12. Non sterile men with female partners of CBP to use contraception to avoid pregnancy.

         13. 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).

          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.
      
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.

Details

Phase:Phase 4
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Melanoma Institute Australia

Trial Keywords

  • Metastatic Melanoma
  • Molecular Testing
  • Targeted Therapy

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