169TiP - Colorectal carcinoma: Low dose immunotherapy in upfront metastatic d/MMR patients (CLOUD study)

Background

Patients with microsatellite instability (MSI) solid tumors are equisitely sensitive to immune-checkpoint inhibitors (ICIs). The pharmacokinetics data as well as early efficacy data have shown that low dose- ICIs (LD-ICIs) may have similar efficacy to standard dose in MSI solid tumors. While standard dose pembrolizumab as well as the combination of nivolumab and ipililumab are effective therapeutic options in advanced colorectal cancers (mCRC), it may not be feasible in a majority of patients in low income countries (LICs) and lower middle income countries (LMICs). With this background, the current study aims to evaluate the efficacy of LD-Nivolumab in mCRC.

Trial Design

The CLOUD study is planned as a single-arm, open-label, prospective, phase 2 superiority study. Adults aged >= 18 years with adequate end-organ function and Eastern Cooperative Oncology Group performance status (PS) 0-1 diagnosed with treatment naïve unresectable or metastatic colorectal adenocarcinoma (patients could have received previous adjuvant chemotherapy for colorectal cancer if the earlier treatment had been completed at least 6 months before enrolement) with MSI status (on Polymerase Chain reaction or Next Generation Sequencing) or deficient mismatch repair (dMMR) protein status on biopsy will be considered for enrolment. Accrued patients will receive nivolumab 40 mg IV every 3 weekly for 6 months and then 6 weekly for next 6 months (maximum of 12 months or till disease progression, whichever is earlier). The study is planned in two stages. The null hypothesis is that the true progression free survival is 35% at 12 months with chemotherapy, which will be tested against a one-sided alternative. In the first stage, 20 patients will be accrued, and if there are 7 or fewer patients who are progression free at 12 months in these 20 patients, the study will be stopped. Otherwise, 27 additional patients will be accrued for a total of 47 patients. The null hypothesis will be rejected if 21 or more have progressed within 12 months in the entire cohort. This design yields a type I error rate of 0.1 and power of 90 when the progression free survival at 12 months is 55%. Assuming a loss to follow up or attrition rate of 10%, the total sample size of the study 52 patients.

Clinical trial identification

CTRI/2024/01/061681, Registered on: 22/01/2024.

Legal entity responsible for the study

Tata Memorial Hospital.

Funding

TMC Research Administration Council (TRAC), Tata Memorial Centre.

Disclosure

All authors have declared no conflicts of interest.