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Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors

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Purpose The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy. Methods Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor samples with PIK3CA and/or PTEN alterations. Results The most common cancers were colorectal (n = 31) and breast cancer (n = 21). Median number of prior antineoplastic regimens was four (range: 1–12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers (18F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit. Conclusion Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.

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Acknowledgments

The following members of the Vall d’Hebron study team are thanked for their contributions to the study: Dr Begoña Graña, Dr Cristina Cruz, Dr Javier Cortes, Dr Cristina Saura, Dr Rodrigo Dienstmann, and Adelaida Piera. From SCRI: Dr Howard Burris, Dr Jeffrey Infante, and Dr Suzanne Jones. Diane van der Biessen and Leni van Doorn of the Erasmus MC Cancer Institute are also thanked for their contributions. Karyn McKeever, Lindsay Carlsson, and Monika Wizemann of the Princess Margaret Cancer Centre are also thanked for their contributions. Douglas Robinson of the Novartis Institute for Biomedical Research is thanked for his statistical expertise. Lea Dutta, previously of Novartis Pharmaceuticals, is thanked for her contributions. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Ben Holtom for medical editorial assistance with this manuscript.

Conflict of interest

Jordi Rodon: Advisory board participation: Novartis (remunerated), Irene Braña, No conflicts of interest, Lillian L Siu: Research funding: Novartis, Maja J De Jonge: No conflicts of interest, Natasha Homji: Employed by Novartis Pharmaceuticals, David Mills: Employee of Novartis, Emmanuelle Di Tomaso: Employee of Novartis, Celine Sarr: Employee of Novartis, Lucia Trandafir: Employee of Novartis, Cristian Massacesi: Employee of Novartis, Ferry Eskens: No conflicts of interes, Johanna C Bendell: No conflicts of interest

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Authors and Affiliations

  1. Vall d’Hebron University Hospital, Barcelona, Spain

    Jordi Rodon & Irene Braña

  2. Universitat Autònoma de Barcelona, Barcelona, Spain

    Jordi Rodon & Irene Braña

  3. Princess Margaret Cancer Centre, Toronto, Canada

    Lillian L Siu

  4. Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Maja J De Jonge & Ferry Eskens

  5. Novartis Pharmaceuticals, Florham Park, NJ, USA

    Natasha Homji

  6. Novartis Pharma AG, Basel, Switzerland

    David Mills

  7. Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, USA

    Emmanuelle Di Tomaso

  8. Novartis Pharmaceuticals, East Hanover, NJ, USA

    Celine Sarr

  9. Novartis Oncology, Paris, France

    Lucia Trandafir & Cristian Massacesi

  10. Sarah Cannon Research Institute, Nashville, TN, USA

    Johanna C Bendell

  11. Medical Oncology Department, Vall d’Hebrón University Hospital, Barcelona, Spain

    Jordi Rodon

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Rodon, J., Braña, I., Siu, L.L. et al. Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. Invest New Drugs 32, 670–681 (2014). https://doi.org/10.1007/s10637-014-0082-9

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