First evidence of antitumor activity of ITPP, a novel hypoxia-modifier: Results of a phase Ib trial

Background: Tumor hypoxia promotes the Warburg effect, decreases anti-tumor immune responses and increases malignant behavior, thereby fostering disease progression. The novel anti-hypoxic molecule myo-inositoltrispyrophosphate (ITPP) acts as an allosteric effector of hemoglobin and efficiently counteracts hypoxia. In preclinical models, ITPP normalized tumor-associated vasculature, enhanced chemotherapy efficacy, decreased tumor burden and increased survival. Methods: The present study is a first in-human exploratory, prospective, open-labelled, mono-centric Phase IB study according to a classical 3 + 3 dose escalation scheme in patients with non-resectable hepatopancreatobiliary tumors. The study intervention consists of 9 infusions of ITPP over 3 weeks, followed by administration of conventional chemotherapy. Primary endpoints are the determination of safety and tolerability of ITPP, while secondary endpoints aim at assessing tumor responses via imaging. Results: 29 patients were included between 04/2015 and 07/2018, with 1 patient withdrawn from the study and 28 assessed for the primary endpoints. ITPP administration was safe and well tolerated. Dose limiting toxicity in the form of Hypercalcemia CTCAE grade 4 occured in the highest cohort tested (Cohort 8: 14’500mg/m2). 7 serious adverse events were recorded without relation to ITPP. 48 adverse events occurred, with 30 judged to be possibly or definitively related to ITPP. Hypercalcemia (19x), Hypomagnesemia (5x), Hypophosphatemia (4x) were the most freequently observed treatment emerged toxicities. Of the ITPP-treated patients, 10 had radiological disease stabilization, 4 experienced a decrease in tumor markers. 4 patients had stable disease with subsequent chemotherapy, while 5 benefited from a strong partial response. Conclusions: Administration of ITPP before chemotherapy is safe and well tolerated with acceptable side-effects. Further exploration of ITPP's potential in phase II/III trials is warranted. Clinical trial identification: NCT02528526. Legal entity responsible for the study: Pierre-Alain Clavien. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.