Clinical Trials /

Regorafenib, C-kit Mutated Malignant Melanoma, 2nd Line Therapy

NCT02501551

Description:

This is a phase II trial of regorafenib in patients with metastatic melanoma harboring c-Kit mutations and/or amplifications of c-Kit gene copy number. The primary end point is disease control rate (DCR), and the secondary end points are safety, response rate (RR), progression free survival (PFS), and overall survival (OS).

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Regorafenib, C-kit Mutated Malignant Melanoma, 2nd Line Therapy
  • Official Title: A Phase II Study to Evaluate the Efficacy of Regorafenib in C-kit Mutated Metastatic Malignant Melanoma Failed First-Line Dacarbazine, Temozolomide or Immune Therapy

Clinical Trial IDs

  • ORG STUDY ID: 4-2014-0573
  • NCT ID: NCT02501551

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
regorafenibRegorafenib

Purpose

This is a phase II trial of regorafenib in patients with metastatic melanoma harboring c-Kit mutations and/or amplifications of c-Kit gene copy number. The primary end point is disease control rate (DCR), and the secondary end points are safety, response rate (RR), progression free survival (PFS), and overall survival (OS).

Detailed Description

      The incidence of melanoma is rising globally and mortality is increasing faster than most
      other cancers. Recent advances in the molecular biology of melanoma have uncovered several
      potential therapeutic targets in melanoma. It has been observed that 81% of melanomas arising
      from non-chronic sun-damaged skin have an oncogenic BRAF or NRAS mutation, whereas such
      mutations are far less frequent in chronic sun-damaged skin melanomas, acral melanomas, or
      mucosal melanomas. In contrast, c-Kit mutations are more common in mucosal and acral
      melanomas, which can also be accompanied by an increase in c-Kit copy numbers.

      Asian populations, the most common melanoma subtypes are acral and mucosal melanoma, which
      comprise greater than 70% of all melanomas, a rate that is much higher than that seen in
      white populations (6% to 7%). KIT mutations or amplification are reported about 20% in acral
      or mucosal melanomas (JAMA. 2011;305(22):2327-2334). Therefore, c-Kit mutations are likely
      the most common kind of genetic mutations in Asians, and the investigation of c-Kit
      inhibitors is a high priority in this population.

      Imatinib mesylate (Gleevec, formerly STI571; Novartis Pharmaceuticals, Basel, Switzerland),
      is a selective inhibitor, targeting Abl as well as c-Kit and the platelet-derived growth
      factor receptor. Imatinib demonstrated significant activity in patients with metastatic
      melanoma harboring genetic c-Kit aberrations, with an overall response rate of 29% (J Clin
      Oncol 2011;29:2904-9) Regorafenib (BAY 73-4506) is a novel, orally active, diphenylurea
      multikinase inhibitor of VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, RAF-1, BRAF and p38
      MAP kinase. Regorafenib provide a significant improved PFS and OS in patients with GIST and
      colorectal cancer, respectively (Lancet 2013; 381: 295-302, Lancet 2013; 381: 303-12).
      Especially, inhibitory activity of regorafenib is most effective in c-kit mutated tumors.
      Therefore, regorafenib has a chance to significant activity in melanoma with c-kit mutations.
      However, no clinical trials have been published for regorafenib in the patients with melanoma
      who harbor c-Kit mutations.

      NCCN recommend ipilimumab, high-dose interleukin-2, and vemurafenib or dabrafenib for BRAF
      mutated tumor as a preferred regimen, and imatinib for c-kit mutated tumors, dacarbazine,
      temozolomide, and paclitaxel as other active regimens. In Korea, ipilimumab is not available
      yet and imatinib for c-kit mutated tumors is not used legally. Thus, regorafenib could be
      used for c-kit mutated tumor in clinical trial setting.
    

Trial Arms

NameTypeDescriptionInterventions
RegorafenibExperimental160mg regorafenib once daily with a low fat breakfast for the first 21 days of each 28-day cycle
  • regorafenib

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically proven melanoma with stage IV or unresectable stage
             III disease

          2. c-kit mutations

          3. performance status of 0, 1, and 2

          4. Have progressed after 1 previous systemic treatment containing dacarbazine,
             temozolomide, or immunotherapy for metastatic melanoma

          5. Patients with central nervous system metastasis must have stable neurologic function
             without evidence of central nervous system progression within 8 weeks

          6. Measurable disease or non-measurable but evaluable disease, according to the Response
             Evaluation Criteria in Solid Tumors v1.1

        Exclusion Criteria:

          1. Major surgery or radiation therapy within 4 weeks of starting the study treatment

          2. History of or known carcinomatous meningitis, or evidence of symptomatic
             leptomeningeal disease

          3. Have received greater than or equal to 2 previous chemotherapy-containing systemic
             treatment regimens

          4. Patients with BRAF or NRAS mutation

          5. Prior therapy with a c-kit inhibitor

          6. Significant history of cardiac disease, myocardial infarction, or current cardiac
             ventricular arrhythmias requiring medication

          7. Major surgery within 4 weeks before start of study treatment

          8. Active gastrointestinal bleeding

          9. Patients treated with co-administration of a strong CYP3A4 inducers

         10. Adequate Hematologic, Biochemical, and Organ Function
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:disease control rate as measured by RECIST 1.1
Time Frame:at 8 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Yonsei University

Trial Keywords

  • Malignant melanoma
  • C-KIT mutation

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