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Investigational New Drugs
Published in: Investigational New Drugs 6/2017

01-12-2017 | PHASE I STUDIES

A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel

Authors: Lillian M. Smyth, Kelsey R. Monson, Komal Jhaveri, Alexander Drilon, Bob T. Li, Wassim Abida, Gopa Iyer, John F. Gerecitano, Mrinal Gounder, James J. Harding, Martin H. Voss, Vicky Makker, Alan L. Ho, Pedram Razavi, Alexia Iasonos, Philip Bialer, Mario E. Lacouture, Jerrold B. Teitcher, Joseph P. Erinjeri, Nora Katabi, Matthew G. Fury, David M. Hyman

Published in: Investigational New Drugs | Issue 6/2017

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Summary

Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors,
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Metadata
Title
A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel
Authors
Lillian M. Smyth
Kelsey R. Monson
Komal Jhaveri
Alexander Drilon
Bob T. Li
Wassim Abida
Gopa Iyer
John F. Gerecitano
Mrinal Gounder
James J. Harding
Martin H. Voss
Vicky Makker
Alan L. Ho
Pedram Razavi
Alexia Iasonos
Philip Bialer
Mario E. Lacouture
Jerrold B. Teitcher
Joseph P. Erinjeri
Nora Katabi
Matthew G. Fury
David M. Hyman
Publication date
01-12-2017
Publisher
Springer US
Published in
Investigational New Drugs / Issue 6/2017
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-017-0445-0

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