Study interventions
toxicity, toxicities, bleeding, tumour
DISEASE PROGRESSION, BLEEDING, ADVERSE EVENTS, TUMOUR, GASTRIC OUTLET OBSTRUCTION
In INTEGRATE IIa, participants enrolled in Arm A will receive regorafenib 160 mg (4 × 40 mg tablets) orally once daily on days 1 to 21 of a 28-day cycle until disease progression, unacceptable toxicities, day 1 treatment delay of more than 28 days or withdrawal of consent. Participants enrolled in Arm B will receive matching placebo. Missed or vomited tablets cannot be compensated for by treatment later.In INTEGRATE IIb, participants enrolled in the experimental arm of the study will receive regorafenib and nivolumab. Regorafenib will be self-administered orally once daily at a dose of 90 mg (3 × 30 mg tablets) on days 1 to 21 of a 28-day cycle until disease progression, unacceptable toxicities, day 1 treatment delay of more than 28 days or withdrawal of consent. Only one dose level reduction of regorafenib is permitted (90 mg to 60 mg) for management of regorafenib related adverse events. If regorafenib is not tolerated at a dose of 60 mg, regorafenib will be discontinued. Nivolumab will be administered intravenously at a dose of 240 mg on day 1 of a 14-day cycle until disease progression or prohibitive adverse events as per protocol or up to 24 infusions or 2 years maximum treatment duration. After 2 months, nivolumab can be administered at a dose of 480 mg on day 1 of a 28-day cycle. If a delay in nivolumab administration is required when a treatment cycle has commenced, nivolumab cannot be delayed more than 12 days for the 14-day schedule, and not more than 20 days for the 28-day schedule. If nivolumab needs to be delayed more than 12 weeks from last treatment date due to toxicity, nivolumab will be discontinued permanently. The continuation of regorafenib monotherapy is permitted despite permanent discontinuation of nivolumab. Participants enrolled in the control arm will receive investigator’s choice of chemotherapy with either docetaxel 60-75 mg/mAll participants in INTEGRATE IIa and INTEGRATE IIb will receive best supportive care which includes any intervention to preserve comfort and dignity such as stent insertion for gastric outlet obstruction, radiation to a bleeding primary tumour and use of any concomitant medications considered necessary for participant’s wellbeing including antiemetics, antidiarrhoeals, anti-inflammatory agents and analgesics.