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Ref Type Journal Article
PMID (29067643)
Authors Wainberg ZA, Alsina M, Soares HP, Braña I, Britten CD, Del Conte G, Ezeh P, Houk B, Kern KA, Leong S, Pathan N, Pierce KJ, Siu LL, Vermette J, Tabernero J
Title 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.
Journal Targeted oncology
Vol 12
Issue 6
Date 2017 Dec
Abstract Text 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.Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D.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.Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable Gedatolisib + Irinotecan Case Reports/Case Series Actionable In a Phase I trial, treatment with the combination of Gedatolisib (PF-05212384) and Camptosar (irinotecan) resulted in an overall response rate of 4.7%, with 2 colorectal cancer patients achieving a partial response, and clinical benefit rate of 16.3% in an advanced solid tumor patient cohort comprising 93% colorectal cancer patients (PMID: 29067643; NCT01347866)). 29067643