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

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.

Conflict of interest statement

C.N. is co-founder, director, and member of the scientific advisory board of NormOxys ®, Inc. and J.-M.L. is co-founder and chairman of scientific advisory board of NormOxys ®, Inc, this being the company that holds the patent on ITPP. M.A.S., P.L., R.G., B.H. and P.-A.C. had access to raw data. The study drug was provided by NormOxys ®, Inc, free of charge. Neither NormOxys ®, Inc nor any other funding source were involved in study design, patient recruitment/care, data collection, analysis/interpretation, or manuscript writing. The remaining authors declare no competing interests.

Figures

Fig. 1. Study setup and pharmacokinetics.

a Schema of study flow with timepoints of ITPP administration and assessments. b Dose-escalation schema with single, weekly, and total doses for different cohorts. c Boxplots displaying median plasma concentrations at start of infusion (hour 0), 3 and 6 h as wells as 30 min, 1 and 2 h after end of intravenous ITPP administration (hour 8) of increasing doses in cohorts on treatment days. Upper and lower ends of boxplots represent 25th and 75th quartiles. Whiskers extend to values within 1.5 * IQR from the boxplot, with data beyond plotted separately as outliers (n = 3–4 patients per cohort with 1 measurement performed in technical duplicates per timepoint for each treatment day (normally 9) per patient).

Fig. 2. Radiological responses post ITPP and chemotherapy.

Displayed as waterfall plots of percental changes of either diameter in millimeters for RECIST1.1 criteria or SUV uptake for EORTC criteria. Morphological changes according to RECIST1.1 criteria (a) and metabolic changes according to EORTC criteria (b) in target lesions after ITPP monotherapy. Morphological changes according to RECIST1.1 criteria (c) and metabolic changes according to EORTC criteria (d) in target lesions after subsequent chemotherapy. *Indicates the appearance of new (FDG avid) lesions.

Fig. 3. Changes in serum angiogenic markers post ITPP and correlation with chemotherapy responses and survival.

Changes in circulating levels of VEGFA (a), ANG1 (b), ANG2 (c), EGF (d), and PECAM1/CD31 (e). Percental changes of pre- versus post-ITPP monotherapy markers levels are depicted (from left to right) by patient as waterfall plots. Association of morphological and metabolic response post chemotherapy with changes in serum angiogenesis markers under ITPP treatment are shown as boxplots displaying median values with the upper and lower ends representing the 25th and 75th quartiles, respectively. Whiskers extend to values within 1.5 * IQR from the boxplot, with all individual data points shown overlaid and colored according to tumor type. Survival stratified by decreased or increased marker levels displayed as Kaplan–Meier curves. n = 27 individual patients, marker measurements performed as technical duplicates.

Fig. 4. Tissue-based hypoxia response markers of one exemplary patient.

a Histological images taken at 20x magnification of the sample taken before ITPP treatment (left hemi-hepatectomy) compared to the sample obtained after ITPP (microwave ablation). Note the decreased expression of hypoxia-mediated genes such as CA9 and SLC2A1 after ITPP treatment and signs of increased vessel maturity by increased EGR expression. Scale bare: 200 μm. N = 1 patient. Histological quantifications are shown as boxplots displaying mean values ± standard deviation and overlaid single measurements. Statistical differences derived from two-sided students t-test with no adjustment for multiple comparisons. **p < 0.01, ***p ≤ 0.001, NS. = No significant difference.