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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02501551
Recruitment Status : Recruiting
First Posted : July 17, 2015
Last Update Posted : April 5, 2021
Information provided by (Responsible Party):
Sang Joon Shin, Yonsei University

Tracking Information
First Submitted Date  ICMJE March 5, 2015
First Posted Date  ICMJE July 17, 2015
Last Update Posted Date April 5, 2021
Study Start Date  ICMJE February 2015
Estimated Primary Completion Date May 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2015)
disease control rate as measured by RECIST 1.1 [ Time Frame: at 8 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Regorafenib, C-kit Mutated Malignant Melanoma, 2nd Line Therapy
Official Title  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE Drug: regorafenib
160mg regorafenib once daily with a low fat breakfast for the first 21 days of each 28-day cycle
Study Arms  ICMJE Experimental: Regorafenib
160mg regorafenib once daily with a low fat breakfast for the first 21 days of each 28-day cycle
Intervention: Drug: regorafenib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 16, 2015)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2022
Estimated Primary Completion Date May 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sang Joon Shin 02-2228-8138
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02501551
Other Study ID Numbers  ICMJE 4-2014-0573
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sang Joon Shin, Yonsei University
Study Sponsor  ICMJE Yonsei University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Yonsei University
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP