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
Wainberg, Zev A. (David Geffen School of Medicina, UCLA (USA))
Alsina, Maria (Vall d'Hebron Institut d'Oncologia)
Soares, Heloisa P. (Moffitt Cancer Center (USA))
Braña, Irene (Princess Margaret Cancer Centre (Canada))
Britten, Carolyn D. (Medical University of South Carolina (USA))
Del Conte, Gianluca (IRCCS Ospedale San Raffaele(Italy))
Ezeh, Patrick (Pfizer Oncology (USA))
Houk, Brett (Pfizer Oncology (USA))
Kern, Kenneth A. (Pfizer Oncology (USA))
Leong, Stephen (University of Colorado (USA))
Pathan, Nuzhat (Pfizer Oncology, 10646 Science Center Drive, San Diego, CA 92121 USA)
Pierce, Kristen J. (Pfizer Oncology (USA))
Siu, Lillian L. (Princess Margaret Cancer Centre (Canada))
Vermette, Jennifer (Pfizer Oncology (USA))
Tabernero, Josep (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Data:	2017
Resum:	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/m 2 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. The online version of this article (10. 1007/s11523-017-0530-5) contains supplementary material, which is available to authorized users.
Nota:	Ajuts: This study was sponsored by Pfizer Inc.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Targeted Oncology, Vol. 12, Issue 6 (December 2017) , p. 775-785, ISSN 1776-260X

DOI: 10.1007/s11523-017-0530-5
PMID: 29067643

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