This is an open-label Phase I trial designed to determine the phase 2 recommended dose (RP2D) of belinostat in combination with nivolumab with or without ipilimumab.
Overall, the trial will assess dosing and safety of two regimens in the study population: * The double regimen: belinostat in combination with nivolumab; * The triplet regimen: belinostat in combination with nivolumab and ipilimumab. The trial will consist of two parts: Part 1 will establish the RP2D of belinostat in combination with nivolumab (doublet regimen) and Part 2 will assess the safety of the RP2D of belinostat in combination with nivolumab (doublet regimen) and ipilimumab (triplet regimen). In Part 1, the recommended phase 2 dose of belinostat will be determined by using an single-patient accelerated titration design confirmed by a modified 3+3 design. Once the RP2D of belinostat is confirmed in Part 1, Part 2 will open to the expansion of the doublet regimen and begin assessing the triplet regimen. The assessment of safety for the triplicate regimen will follow a Bayesian approach as described in the Statistical Analysis section and Appendix 2. Due to the expected contrast in toxicity profiles between immediate toxicity from belinostat at various dose levels and immune mediated toxicity from the doublet and the triplet regimens, the definition of dose-limiting toxicities and the DLT evaluation periods will differ for each regimen (doublet vs. triplicate). Patients will be managed according to the regimen administered. Statistical Hypotheses: Belinostat in combination with nivolumab alone and with ipilimumab is safe and effective in patients with previously treated metastatic or advanced carcinomas with or without ARID1A loss of function (lof) mutations.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Doublet Regimen Dose levels for Part 1: Belinostat Dose Level 1 (starting dose) 500 mg/m2 Dose Level 2 750 mg/m2 Dose Level 3 1000 mg/m2
Doublet Regimen Dose levels for Part 1 Nivolumab Dose Level 1 (starting dose) 360 mg Dose Level 2 360 mg Dose Level 3 360 mg
Triplet and Doublet Regimen Dose Levels for Phase 2 Ipilimumab Doublet Dose n/a Triplet Dose 1 mg/kg
rate of dose limiting toxicities (DLTs) during defined DLT period
assess the recommended phase 2 dose of belinostat in combination with nivolumab in patients with advanced solid tumors harboring ARID1A mutations.
Time frame: 9-12 months
rate of intolerable refractory immune mediated adverse events assessed during the defined DLT evaluation period
assess the safety and tolerability of belinostat in combination with nivolumab with and without ipilimumab in patients with advanced solid tumors.
Time frame: 12-18 months
frequency and characterization of Adverse Events (AE)
assess the safety of belinostat in combination with nivolumab with or without ipilimumab in patients with advanced solid tumors
Time frame: up to 5 years
• The rate of clinical benefit defined as the proportion of evaluable patients achieving stable disease, a partial response, or a complete response per RECIST 1.1 criteria
assess the efficacy of belinostat in combination with nivolumab with or without ipilimumab in patients with advanced solid tumors
Time frame: up to 5 years
• Objective response rate (ORR) as defined as the proportion of evaluable patients achieving a partial response or a complete response per RECIST 1.1 criteria.
assess the efficacy of belinostat in combination with nivolumab with or without ipilimumab in patients with advanced solid tumors
Time frame: up to 5 years
• Duration of response (DoR) as defined as the time from documented tumor response to disease progression as defined by RECIST 1.1.
assess the efficacy of belinostat in combination with nivolumab with or without ipilimumab in patients with advanced solid tumors
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Triplet and Doublet Regimen Dose Levels for Phase 2 Nivolumab Doublet Dose 360 mg IV Triplet Dose 3 mg/kg
Triplet and Doublet Regimen Dose Levels for Phase 2 Belinostat Doublet Dose RP2D Triplet Dose RP2D
Time frame: up to 5 years
• Progression-free survival (PFS) as defined as the time from the initiation of study therapy to disease progression per RECIST 1.1, initiation of alternative therapy, or death from any cause.
assess the efficacy of belinostat in combination with nivolumab with or without ipilimumab in patients with advanced solid tumors
Time frame: up to 5 years
Overall survival (OS)
assess the efficacy of belinostat in combination with nivolumab with or without ipilimumab in patients with advanced solid tumors
Time frame: up to 5 years