Denosumab + PD-1 in Subjects With Stage III/ IV Melanoma
Condition: Melanoma Stage Iii; Melanoma Stage Iv; Melanoma; Melanoma (Skin); Cutaneous Melanoma
MeSH terms: Melanoma
Study type: Interventional
Phase: Phase 2

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-PD1
      agent (pembrolizumab or nivolumab) in patients with unresectable PD-1/PD-L1 inhibitor-naïve
      regional and distant metastatic melanoma (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 day 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 (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 (AJCC
           stage III/IV) by NCI-CTCAE v.5.0.

        -  Determine antitumor response by 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 (AJCC stage III/IV).

        -  Determine the 1-year OS 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 (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 (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 third loading dose of denosumab.
           Multiparameter flow cytometry and ELISA assays will be performed on peripheral
           blood/serum samples as outlined above in section 1.10.1 Tumor biopsy samples will be
           evaluated by IHC and IF studies as outlined above in section 1.10.2 (See referenced
           sections for assay details. The investigators will estimate differences after 3 weeks of
           denosumab treatment versus baseline).

        -  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 above in section
           1.10.1. Tumor biopsy samples obtained at week 16 will be evaluated by IHC and IF studies
           as outlined above in section 1.10.2 (See referenced sections for assay details. The
           investigators will describe differences in immunomodulatory/antitumor effects observed
           with denosumab therapy with later immunomodulatory/antitumor effects observed after the
           addition of an anti PD-1 agent to denosumab).

      Secondary Endpoints

        -  AEs experienced by patients receiving denosumab-anti- PD-1 agent will be assessed per
           NCI-CTCAE v.5.0.

        -  The overall RR (CR + PR) at 16 weeks will assessed based on RECIST v1.1 criteria.

        -  Overall Survival (OS) rate at 1-year is defined as the time from day 1 of study
           treatment until death as a result of any cause within one year of initiating study
           treatment.

        -  Progression Free Survival (PFS) rate at 6 months is defined as the time from day 1 of
           treatment until disease progression or death status measured 6 months after initiating
           study treatment. Progression events will be defined per RECIST v1.1 criteria.

      Procedures

      Subjects in this trial will be given denosumab, 120 mg s.c. q4 weeks, starting on day 1 of
      study treatment. Additional loading doses of Denosumab will be administered on day 8 and day
      22 ( after Amendment 1). Nivolumab, 480 mg will be administered intravenously (IV) every 4
      weeks and initiated 21 days after the first dose of Denosumab is given. In subjects enrolled
      prior to Amendment 1 Pembrolizumab, 200 mg will be administered intravenously (IV) every 3
      weeks and initiated 21 days after the first dose of denosumab is given. Combination therapy
      with both agents will continue as long as subjects benefit from therapy for up to 1 year.
      Study therapy will be discontinued for intolerable toxicity, disease progression or for other
      reasons at the discretion of the investigator. If subjects are not withdrawn prematurely then
      their last dose of study medications will be administered approximately 49 weeks after
      denosumab was initiated.
    

Intervention name(s): Denosumab; Pembrolizumab; Nivolumab
Intervention type(s): Drug; Drug; Drug
Intervention description(s): A dose of 120 mg will be administered as a subcutaneous (s.c.) injection every 4 weeks in the upper arm, upper thigh, or abdomen. Another loading dose of 120 mg s.c. denosumab will be administered on day 8. On days when denosumab is administered on the same day as pembrolizumab, the s.c. injection should be given after the infusion of pembrolizumab is completed.; Pembrolizumab will be administered as standard of care following the institutional guidelines.The recommended dose of pembrolizumab is 200 mg administered as an IV infusion over approximately 30 minutes (range: 25 - 40 minutes) every 3 weeks until disease progression or unacceptable toxicity.; Nivolumab will be given every four weeks at a dose of 480 mg to be administered as an IV infusion per institutional guidelines.
Other intervention name(s): XGEVA; Keytruda; Opdivo
Intervention MeSH terms: Denosumab; Pembrolizumab; Nivolumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Denosumab; Pembrolizumab; Melanoma; Unresectable; Cutaneous; Nivolumab