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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

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).

Condition or disease Intervention/treatment Phase
Melanoma Drug: regorafenib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : February 2015
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma
Drug Information available for: Regorafenib

Arm Intervention/treatment
Experimental: Regorafenib
160mg regorafenib once daily with a low fat breakfast for the first 21 days of each 28-day cycle
Drug: regorafenib
160mg regorafenib once daily with a low fat breakfast for the first 21 days of each 28-day cycle

Primary Outcome Measures :
  1. disease control rate as measured by RECIST 1.1 [ Time Frame: at 8 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02501551

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Contact: Sang Joon Shin 02-2228-8138

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Korea, Republic of
Severance Hospital, Yonsei University Health System Recruiting
Seoul, Korea, Republic of, 120-752
Contact: Sang Joon Shin         
Sponsors and Collaborators
Yonsei University
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Responsible Party: Sang Joon Shin, Associate Professor, Yonsei University Identifier: NCT02501551    
Other Study ID Numbers: 4-2014-0573
First Posted: July 17, 2015    Key Record Dates
Last Update Posted: April 5, 2021
Last Verified: April 2021
Keywords provided by Sang Joon Shin, Yonsei University:
Malignant melanoma
C-KIT mutation
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas