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Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors

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Abstract

Purpose

To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer.

Methods

In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m2, day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50–110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR).

Results

Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m2. Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated.

Conclusions

Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting.

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Acknowledgements

The authors thank Peter Olson (Mirati Therapeutics Inc., San Diego, US) for analyzing the pharmacodynamic data reported in this study, Josée Morin (Excelsus Statistics Inc., Montreal, Canada) for her review of the manuscript, and Manal Tawashi (MethylGene, Inc.) for coordinating the conduct of the trial. Medical writing services were provided by Siân Marshall (SIANTIFIX, Cambridge, UK) and funded by Mirati Therapeutics, Inc.

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Correspondence to Richard Chao.

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Research involving human participants and/or animals

All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Funding

This study was sponsored by Mirati Therapeutics, Inc.

Conflict of interest

RC is an employee of Mirati Therapeutics, Inc. DP has received consultancy fees from Mirati Therapeutics, Inc. EC has received research support from Aduro Biotech, Bristol Myers Squibb, Halozyme Therapeutics, MethylGene (now known as Mirati Therpeutics, Inc.), Merrimack Pharmaceuticals, and support for Advisory Board attendance from Eli Lilly. EGC has received research support from Boehringer-Ingelheim and Celgene Pharmaceuticals, and support for Advisory Board attendance from Celgene Pharmaceuticals. TA has received consultancy fees from Shire and Sanofi. HH has received consultancy fees from Merck and Hoffman La-Roche/Genentech and research funding from Mirati Therapeutics, Inc./Methylgene, Novartis and Hoffman La-Roche/Genentech. NG and PO’D have no disclosures.

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Chan, E., Chiorean, E.G., O’Dwyer, P.J. et al. Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors. Cancer Chemother Pharmacol 81, 355–364 (2018). https://doi.org/10.1007/s00280-017-3494-3

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