Abstract Objective Hypoxia is present in most solid tumors and acts as a driver of malignancy. Myo-inositol trispyrophosphate (ITPP) is a novel re-oxygenating compound without apparent toxicity. In preclinical models, it potentiates the efficacy of subsequent chemotherapy through vascular normalization. We sought to assess the safety, tolerability, and preliminary efficacy of ITPP. Methods In this monocentric, open-label, dose-escalation study following a 3+3 design, eligible patients with advanced primary and secondary hepatopancreatobiliary tumors received nine 8-h infusions of ITPP during 3 weeks across eight dose levels (1866–14,500 mg/m2/dose), followed by standard chemotherapy. Primary endpoints were safety and tolerability. Secondary endpoints were pharmacokinetics and estimation of efficacy based on radiological responses and angiogenic serum markers. Registration number: NCT02528526. Results From April 2015 to July 2018, a total of 28 enrolled patients were assessed for the primary endpoints. ITPP was safe up to single doses of 12,390 mg/m2, and 32 ITPP-related adverse events occurred: 19 (67.8%) hypercalcemia, 5 (17.8%) hyponatremia, and 4 (14.2%) hypomagnesemia. Following ITPP monotherapy, 52% of patients displayed morphological disease stabilization. Following subsequent chemotherapy, 10% showed a partial response, and 60% had stable disease. Angiogenic markers were decreased in 60% after ITPP and tended to correlate with responses and survival after chemotherapy. Conclusion Administration of ITPP is safe up to 12,390 mg/m2 with favorable pharmacokinetics. Preliminary translational efficacy data show decreased angiogenic markers, which might indicate an anti-hypoxic effect and enhancement of chemotherapy through ITPP.