A Phase II Trial of Sunitinib and Nivolumab for KIT-mutated Advanced Melanoma

Curtin and Bastian in 2006 first described KIT mutations in melanoma. Although uncommon in non-acral cutaneous melanoma, these mutations are frequent in mucosal and acral melanomas. The KIT mutations in melanoma are similar to the KIT mutations in gastrointestinal intestinal stromal sarcomas (GIST) and these are believed to be driver mutations. In melanomas these mutations occur in an exclusive pattern in tumors without NRAS, BRAF, or GNAQ mutations. There is evidence that stage four melanoma patients with KIT mutations have a worse prognosis than other patients with similar stage and primary site.

Both imatinib and sunitinib are FDA approved for treatment of patients with GIST; these and other oral tyrosine kinase KIT inhibitors have been studied in melanoma patients with KIT mutations. Imatinib is the best studied with objective responses in 20% of patients in a multicenter trial, considerably lower than the efficacy seen in GIST. Sunitinib has the theoretical advantage of anti-angiogenic activity as well as anti -KIT activity and demonstrated objective responses in three of four patients in a small trial sponsored by Pfizer.(see citation).

Immunotherapy has a major role in the treatment of metastatic melanoma, with the approval and use of both Interleukin-2 and ipilimumab because of the ability of immunotherapy to produce durable responses and prolonged survival in a minority, but a significant number, of patients . Both sunitinib and ipilimumab have intestinal perforation as an unusual but very significant toxicity, which argues against using those two agents in combination. The anti-PD-1 antibody Nivolumab, however, is an immunologic agent that yields rapid and durable responses in melanoma with less colitis and less risk of intestinal perforation than ipilimumab. Nivolumab was FDA approved in December 2014 and NCCN guidelines include it as a first-line option.

Combining KIT receptor inhibition with sunitinib with immunotherapy with Nivolumab is an attractive investigational approach as the combination should produce complementary and perhaps synergistic efficacy.

Asim et al reported at ASCO in June 2014 a phase one study of sunitinib and nivolumab for the treatment of metastatic renal cell cancer. Sunitinib (50 mg/day x 4 week, off 2 weeks and nivolumab at 2mg/kg or 5mg/kg q 3 weeks was administered to 33 patients. No dose-limiting toxicities were seen but grade 3-4 AEs were seen in 24 of 33 patients. The most common AEs were elevated ALT (18%), hypertension (15%) and hyponatremia (15%). Objective responses sere seen in 52% (17/33) indicating an "encouraging activity and a manageable safety profile" in patients with renal cell cancer. The Nivolumab dose of 5mg/kg Q 3 weeks (1.67mg/kg/week) on that study is slightly above the usual dose of 3mg/kg Q 2 weeks (1.5mg/kg/week).

Study Design:

This is an open-label multi-center phase 2 study of sunitinib and Nivolumab in combination in patients with KIT mutated metastatic melanoma. Study to begin after FDA approval of nivolumab Total number of study subjects will be approximately 12-18 patients.

Objectives

Primary objective:

1. To describe the preliminary clinical efficacy of sunitinib when given in combination with nivolumab to patients with KIT-mutated melanoma
2. To describe the immunologic effects of sunitinib when administered in combination with Nivolumab

Co-primary endpoints:

1. Objective response using RECIST 1.1 immune modified response criteria
2. Progression-free survival using immune-modified response criteria

Secondary endpoints:

1. Toxicities using CTAE criteria
2. Changes in peripheral blood total lymphocyte counts and T and B cell count
3. Overall survival The trial is sponsored by the California Pacific Medical Center Research Institute and the sunitinib will be provided by Pfizer. Commercial sources will be used for the nivolumab, whose use is in accord with NCCN guidelines.