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Cancer Chemother Pharmacol. 2018 Feb;81(2):355-364. doi: 10.1007/s00280-017-3494-3. Epub 2017 Dec 13.

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

Author information

1
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
2
Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
3
Indiana University Cancer Center, Indianapolis, IN, USA.
4
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
5
Gabrail Cancer Center, Canton, OH, USA.
6
McGill University Health Centre, Montreal, QC, Canada.
7
Mirati Therapeutics Inc., 9393 Towne Centre Drive, Suite 200, San Diego, CA, 92121, USA.
8
Mirati Therapeutics Inc., 9393 Towne Centre Drive, Suite 200, San Diego, CA, 92121, USA. chaor@MIRATI.COM.
9
Duke University Medical Center, Durham, NC, USA.

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.

KEYWORDS:

Gemcitabine; Histone deacetyltransferase; Mocetinostat; Pancreatic cancer; Pharmacodynamics; Phase 2

PMID:
29238851
DOI:
10.1007/s00280-017-3494-3
[Indexed for MEDLINE]

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