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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

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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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Acknowledgements

This study received funding from Novartis Pharmaceuticals. Saiprasad Boddu, of Sai Life Sciences, performed the pharmacokinetic analyses. The authors of this study are supported by the Core Grant (P30 CA008748) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health, USA.

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Authors and Affiliations

  1. Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA

    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 & David M. Hyman

  2. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA

    Alexia Iasonos

  3. Department of Psychiatry, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA

    Philip Bialer

  4. Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA

    Mario E. Lacouture

  5. Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA

    Jerrold B. Teitcher & Joseph P. Erinjeri

  6. Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA

    Nora Katabi

  7. Oncology Clinical Sciences, Regeneron Pharmaceuticals, Tarrytown, NY, USA

    Matthew G. Fury

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  1. Lillian M. Smyth
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Corresponding author

Correspondence to Lillian M. Smyth.

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Conflict of interest

M.F., K.J., A.H., M.L, and M.V. have served on advisory boards and/or consulted for Novartis.

LMS: Advisory- Genentech, Research - AstraZeneca.

KJ: Consulting/Advisory - Novartis.

DH: Consulting - Chugai, CytomX, Atara, Research/Grants-AstraZeneca, PUMA, LOXO.

AH: Advisory/ Speaker- Novartis.

MV: Consulting- Novartis, Exelixis, Pfizer, Alexion, Research- BMS, Genentech.

No potential conflict of interest was disclosed by the other authors.

Funding

Funding was received from Novartis Pharmaceuticals. Saiprasad Boddu, of Sai Life Sciences, performed the pharmacokinetic analyses.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Smyth, L.M., Monson, K.R., Jhaveri, K. et al. 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. Invest New Drugs 35, 742–750 (2017). https://doi.org/10.1007/s10637-017-0445-0

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