Denosumab + PD-1 in Subjects With Stage III/ IV Melanoma
brief summary
This is a multicenter open-label, single-arm, phase II study designed to investigate the pharmacodynamic and antitumor effects of denosumab alone and in combination with an anti-Programmed death-1 or Programmed death ligand 1 (PD1) agent (pembrolizumab or nivolumab) in patients with unresectable Programmed death-1 or Programmed death ligand 1 (PD-1/PD-L1) inhibitor-naïve regional and distant metastatic melanoma (The American Joint Committee on Cancer (AJCC) stage III/IV). The pharmacodynamic and antitumor effects will be investigated by performing translational research on peripheral blood and tumor tissue collected before and during denosumab alone and in combination with anti-PD-1 treatment.
detailed description
STUDY OBJECTIVES
Co-primary Objectives
* Assess the mechanistic (immune-mediated and/or direct antitumor effect) and pharmacodynamics effect (tissue saturation studies) of denosumab alone (i.e., after three loading doses of denosumab are given on days 1,8 and 22) in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve cutaneous melanoma (stage III/IV) by performing translational research on peripheral blood and tumor biopsy samples collected at baseline and after third loading dose of Denosumab. * Assess the immune-mediated and direct antitumor effect of denosumab in combination with anti- PD-1 agent in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve cutaneous melanoma (The American Joint Committee on Cancer (AJCC) stage III/IV) by performing translational research on peripheral blood and tumor biopsy samples collected at weeks 16, 28 and 40 of the study and comparing the results with those from baseline and after third loading dose of Denosumab.
Secondary Objectives
* Assess the safety of the denosumab-anti-PD-1 agent combination in unresectable (resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (The American Joint Committee on Cancer (AJCC) stage III/IV) by National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. * Determine antitumor response by Response evaluation criteria in solid tumors (RECIST) v1.1 criteria of the denosumab-anti- PD-1 agent combination at 16 weeks in patients with unresectable (resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (The American Joint Committee on Cancer (AJCC) stage III/IV). * Determine the 1-year Overall Survival rate of the Denosumab-anti-PD-1 agent combination in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (The American Joint Committee on Cancer (AJCC) stage III/IV). * Determine the 6-month PFS rate of the denosumab-anti-PD-1 agent combination in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naive melanoma (The American Joint Committee on Cancer (AJCC) stage III/IV).
Endpoints Co-primary Endpoints
* The immune-mediated mechanism of action of denosumab alone will be evaluated in blood and tumor samples collected at baseline and after the third loading dose of denosumab. Multiparameter flow cytometry and ELISA assays will be performed on peripheral blood/serum samples as outlinedin the protocol. Tumor biopsy samples will be evaluated by IHC and IF studies as outlined in the protocol. * The immune-mediated mechanism of action of denosumab combined with anti-PD-1 agent will be evaluated in blood and tumor samples collected at weeks 16, 28, and 40 of the study. Multi-parameter flow cytometry and ELISA assays will be performed on peripheral blood/serum samples collected at weeks 16, 28, and 40 as outlined in the protocol. Tumor biopsy samples obtained at week 16 will be evaluated by immune histochemical (IHC) and immune florescent (IF) studies as outlined in the protocol.
official title
Phase 2 Study of Denosumab in Combination With a PD-1 Inhibitor in Subjects With Stage III/IV Melanoma