Aim: To investigate if azacitidine and carboplatin “prime” metastatic melanoma for re-challenge with Ipilimumab and Nivolumab via stabilisation/decrease in disease burden and re-establishment of immune sensitivity.
Study Design: PRIME005 is an interventional non-randomised, single-arm, open-label phase Ib/II study to assess the feasibility of the multisite trial design and determine outcome measures required to calculate sample sizes and develop a statistical plan for a larger multi-centre Phase II study. The PRIME005 Phase Ib Stage 1 was a Bayesian Optimal Interval Design (BOIN) with 3 dose escalation steps to determine the recommended Phase 2 dose (RP2D) for azacitidine and timing of carboplatin administration.
Phase 1b recruited 8 participants. The recommended Phase 2 Dose (RP2D) to move to Stage 2, Phase II was azacitidine 40mg/m2 IVI/day for 5 days (Day 1-Day 5) followed by Carboplatin AUC 4 IVI Day 8 of 21 day cycle.
PRIME005 consists of 2 cycles of azacitidine and carboplatin over 6 weeks followed by 2 cycles of azacitidine and carboplatin combined with Ipilimumab and Nivolumab for 6 weeks. Ipilimumab and Nivolumab will be given in combination for another 2 cycles/21 days and then Ipilimumab and Nivolumab continue for 24 months or until disease progression by iRECIST.
Primary Objectives:
1. Quantify clinical benefit rate (CBR) using a composite of complete response (CR), partial response (PR) and stable disease (SD) according to RECIST 1.1 after 2 cycles of priming (1 cycle = Azacitidine IVI x 5 days followed by Carboplatin AUC 4 on Day 8).
2. Quantify CBR using a composite of iCR, iPR, iSD using iRECIST after:
i) 2 cycles of priming and immunotherapy (1 cycle = Azacitidine IVI x 5 days followed by Carboplatin AUC 4 on Day 8/21 day cycle plus Ipilimumab 1mg/kg and Nivolumab 360mg on day 15/21-day cycle)
ii) 2 cycles of immunotherapy alone (1 cycle = Ipilimumab 1mg/kg and Nivolumab 360mg on day 1/21-day cycle)