Decreasing hypoxia with mitochondrial inhibition in locally advanced rectal cancer: Phase 1 trial of papaverine in combination with radiation (DINOMITE).

TPS274 Background: Surgical resection of locally advanced rectal cancer (LARC) can be morbid with debilitating effects on quality of life, particularly in patients who require a permanent colostomy. Total neoadjuvant therapy (TNT), where all systemic and radiation therapy (RT) is delivered prior to surgery, achieves higher response rates than traditional standard of care (SOC) neoadjuvant treatment. However, even with TNT, nearly 50% of patients will have residual disease or develop local regrowth requiring resection. There is evidence of significant hypoxia in LARC, which can contribute to radiation resistance and an unfavorable host-tumor immune microenvironment (TIME). Our preclinical data has established that targeting mitochondrial oxygen consumption (MOC) with an FDA-approved and repurposed mitochondrial complex I inhibitor papaverine (PPV) can reduce hypoxia and sensitize model tumors to RT potentially facilitating an improved anti-tumor immune response. In this study, we test an innovative strategy of inhibiting MOC to radiosensitize LARC with the hypothesis that reversing tumor hypoxia not only improves tumor radiation sensitivity but also leads to beneficial changes in the TIME. Methods: DINOMITE is a randomized two-center phase I study for patients with histologically confirmed microsatellite stable LARC who want to pursue non-operative management. Patients are randomized in a 1:2 manner: Cohort 1- SOC short course RT (SCRT) delivered as 5 Gy x 5 fractions; Cohort 2 – SCRT plus daily PPV. Following a 3-week break, patients start consolidation chemotherapy (CC) with mFOLFOX6 or CAPOX for 3-4 months. Eight weeks following completion of CC, patients will undergo SOC response assessment with MRI and endoscopy. Patients with clinical complete response (cCR) will enter surveillance with serial endoscopy/pelvic MRI. For those with persistent disease or recurrence in the rectum during surveillance, salvage surgery will be recommended. For Cohort 2, a single dose of PPV will be administered for correlative analysis prior to the combination with RT (week 0). The dose limiting toxicity period will include acute (week 0 to start of CC) and late (start of CC until 12 months from week 0) phases. Cohort 2 will be conducted using the time-to-event Bayesian optimal interval design to find the maximum tolerated dose (MTD)/recommended phase 2 dose of PPV in combination with RT. Once the MTD is determined, additional patients will be enrolled in cohort 2 as an expansion cohort (total of 24 patients maximum in cohort 2). The maximum sample size is 36 patients. Correlative studies including functional MRI, tumor tissue, stool, and blood will be obtained prior to treatment start, prior to CC, and if salvage surgery is performed. The trial began in January 2025, and patient recruitment is ongoing. Support: R01CA297752 Clinicaltrials.gov identifier: NCT06834126. Clinical trial information: NCT06834126 .