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A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors

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Summary

Background Voxtalisib, a PI3K/mTOR inhibitor, has shown antitumor activity in capsule formulation in patients with solid tumors. This Phase I study assessed safety and pharmacokinetics of voxtalisib administered as immediate-release tablets in patients with solid tumors (NCT01596270). Methods A “3 + 3” dose escalation design was used. Adverse events (AEs), pharmacokinetics (PK), food effect and tumor response were evaluated. Results Thirty-two patients received voxtalisib doses ranging from 50 mg to 70 mg once daily (QD) and 17 patients received voxtalisib doses ranging from 30 mg to 50 mg twice daily (BID), for two 28-day cycles. Dose-limiting toxicities (DLTs) were Grade 3 fatigue (two patients at 70 mg QD, one patient at 40 mg BID) and Grade 3 rash (two patients at 50 mg BID). The maximum tolerated dose (MTD) was 60 mg for QD and 40 mg for BID regimens. Common treatment-emergent AEs were diarrhea (41%), nausea (37%) and fatigue (33%). Voxtalisib appeared to follow linear PK, with a general increase in plasma exposure with dose and no significant accumulation. Administration with food caused a slight decrease in exposure; however, given the high variability observed in the exposure parameters, this should be interpreted with caution. Best response was stable disease in 29% and 50% of patients (QD and BID regimens, respectively). Conclusions The safety profile of voxtalisib tablets at the MTD in patients with solid tumors was consistent with that observed with voxtalisib capsules. Given the limited activity observed across multiple clinical trials, no further trials of voxtalisib are planned.

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Acknowledgements

This study was funded by Sanofi. The authors received editorial support from Olga Ucar of MediTech Media, funded by Sanofi.

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Authors and Affiliations

  1. Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA

    Janice M. Mehnert, Mark Stein & Heather Camisa

  2. Medical and Surgical Clinic of Irving, Irving, TX, USA

    Gerald Edelman

  3. Sanofi, Cambridge, MA, USA

    Joanne Lager

  4. Sanofi, Chilly-Mazarin, France

    Jean-François Dedieu & Anne-Frédérique Ghuysen

  5. Sanofi, Bridgewater, NJ, USA

    Jyoti Sharma & Li Liu

  6. Yale University, New Haven, CT, USA

    Patricia M. LoRusso

Authors
  1. Janice M. Mehnert
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  2. Gerald Edelman
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  3. Mark Stein
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  4. Heather Camisa
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  5. Joanne Lager
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  6. Jean-François Dedieu
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  7. Anne-Frédérique Ghuysen
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  8. Jyoti Sharma
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  9. Li Liu
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  10. Patricia M. LoRusso
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Corresponding author

Correspondence to Janice M. Mehnert.

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Conflict of interest

JMM has participated in advisory boards for Merck, Genentech, EMD Serono, performed a consultancy role for Merck and Amgen, and received research funding from Polynone, Merck, Amgen, Sanofi, EMD Serono, Novartis, AstraZeneca, and Immunocore. GE, HC and PML have no conflict of interest to declare. MS reports research funding to his institution from Oncoceutics, Merck Sharp & Dohme, Abbvie, Janssen Oncology, Medivation/Astellas, Astellas Pharma, Bavarian Nordic and Advaxis. JL and JS are employees and shareholders of Sanofi. JFD, AFG and LL are remunerated employees and shareholders of Sanofi.

Funding

This study was funded by Sanofi. The authors received editorial support from Olga Ucar of MediTech Media, funded by Sanofi.

Ethical approval

All procedures involving human participants performed in this study 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.

Informed consent

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

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Mehnert, J.M., Edelman, G., Stein, M. et al. A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors. Invest New Drugs 36, 36–44 (2018). https://doi.org/10.1007/s10637-017-0467-7

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  • DOI: https://doi.org/10.1007/s10637-017-0467-7

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