Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors

Marcel A. Schneider, Michael Linecker, Ralph Fritsch, Urs J. Muehlematter, Daniel Stocker, Bernhard Pestalozzi, Panagiotis Samaras, Alexander Jetter, Philipp Kron, Henrik Petrowsky, Claude Nicolau, Jean-Marie Lehn, Bostjan Humar, Rolf Graf, Pierre-Alain Clavien () and Perparim Limani ()
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Marcel A. Schneider: University Hospital Zurich
Michael Linecker: University Hospital Zurich
Ralph Fritsch: University Hospital Zurich
Urs J. Muehlematter: University Hospital Zurich
Daniel Stocker: University Hospital Zurich
Bernhard Pestalozzi: University Hospital Zurich
Panagiotis Samaras: Oncology Center, Hirslanden Hospital Zurich
Alexander Jetter: University Hospital Zurich
Philipp Kron: University Hospital Zurich
Henrik Petrowsky: University Hospital Zurich
Claude Nicolau: Tufts University
Jean-Marie Lehn: Université de Strasbourg, 8 allée Gaspard Monge
Bostjan Humar: University Hospital Zurich
Rolf Graf: University Hospital Zurich
Pierre-Alain Clavien: University Hospital Zurich
Perparim Limani: University Hospital Zurich

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Hypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

Date: 2021
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DOI: 10.1038/s41467-021-24069-w

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