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Target Oncol. 2017 Dec;12(6):775-785. doi: 10.1007/s11523-017-0530-5.

A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer.

Author information

1
David Geffen School of Medicine at UCLA, 2020 Santa Monica Blvd, Suite 600, Los Angeles, CA, 90404, USA. ZWainberg@mednet.ucla.edu.
2
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Vall d'Hebron 119-129, 08035, Barcelona, Spain.
3
Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
4
Princess Margaret Cancer Centre, 610 University Avenue, Toronto, M5G 2M9, Canada.
5
Medical University of South Carolina, 39 Sabin St., MSC 635, Charleston, SC, 29425, USA.
6
IRCCS Ospedale S. Raffaele, via Olgettina 60, 20132, Milan, Italy.
7
Pfizer Oncology, 300 Technology Square, Cambridge, MA, 02139, USA.
8
Pfizer Oncology, 10646 Science Center Drive, San Diego, CA, 92121, USA.
9
University of Colorado Denver School of Medicine, 13001 E 17th Place, Aurora, CO, 80045, USA.
10
Pfizer Oncology, 558 Eastern Point Road, Groton, CT, 06340, USA.

Abstract

BACKGROUND:

This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors.

OBJECTIVES:

Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.

PATIENTS AND METHODS:

Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D.

RESULTS:

The PF-04691502 combination arms were closed prematurely due to low tolerability, and the maximum tolerated doses (MTDs) were not determined for either arm. The MTD for the combination of gedatolisib with irinotecan 180 mg/m2 was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations.

CONCLUSIONS:

Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.

PMID:
29067643
PMCID:
PMC5700209
DOI:
10.1007/s11523-017-0530-5
[Indexed for MEDLINE]
Free PMC Article

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