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 Journal Article


Authors: Smyth, L. M.; Monson, K. R.; Jhaveri, K.; Drilon, A.; Li, B. T.; Abida, W.; Iyer, G.; Gerecitano, J. F.; Gounder, M.; Harding, J. J.; Voss, M. H.; Makker, V.; Ho, A. L.; Razavi, P.; Iasonos, A.; Bialer, P.; Lacouture, M. E.; Teitcher, J. B.; Erinjeri, J. P.; Katabi, N.; Fury, M. G.; Hyman, D. M.
Article 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
Abstract: 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. © 2017, Springer Science+Business Media New York.
Keywords: adult; clinical article; controlled study; aged; mutation; constipation; drug tolerability; fatigue; neutropenia; cancer combination chemotherapy; diarrhea; drug dose reduction; drug efficacy; drug safety; hypertension; side effect; paclitaxel; anorexia; carboplatin; controlled clinical trial; multiple cycle treatment; sensory neuropathy; anemia; leukopenia; nausea; thrombocytopenia; myalgia; cohort analysis; continuous infusion; abdominal pain; coughing; dizziness; drug dose escalation; hyperglycemia; hypomagnesemia; lymphocytopenia; pruritus; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; hypoalbuminemia; hypokalemia; hyponatremia; maculopapular rash; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; homozygote; open study; headache; phase 1 clinical trial; hypercholesterolemia; pten; alopecia; dysgeusia; drug dose intensification; buparlisib; human; male; female; priority journal; article; phase ib; solid malignant neoplasm
Journal Title: Investigational New Drugs
Volume: 35
Issue: 6
ISSN: 0167-6997
Publisher: Springer  
Date Published: 2017-12-01
Start Page: 742
End Page: 750
Language: English
DOI: 10.1007/s10637-017-0445-0
PROVIDER: scopus
PMCID: PMC5591764
PUBMED: 28281183
DOI/URL:
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Vicky Makker
    105 Makker
  2. Philip A Bialer
    38 Bialer
  3. Mario E Lacouture
    319 Lacouture
  4. James Joseph Harding
    106 Harding
  5. Alexia Elia Iasonos
    208 Iasonos
  6. Nora Katabi
    209 Katabi
  7. Martin Henner Voss
    163 Voss
  8. Gopakumar Vasudeva Iyer
    165 Iyer
  9. Matthew G Fury
    101 Fury
  10. Mrinal M Gounder
    109 Gounder
  11. David Hyman
    299 Hyman
  12. Komal Lachhman Jhaveri
    66 Jhaveri
  13. Joseph Patrick Erinjeri
    110 Erinjeri
  14. Alan Loh Ho
    118 Ho
  15. Alexander Edward Drilon
    248 Drilon
  16. Wassim Abida
    67 Abida
  17. Kelsey Renee Monson
    2 Monson
  18. Pedram Razavi
    59 Razavi
  19. Bob Tingkan Li
    97 Li
  20. Lillian   Smyth
    31 Smyth