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A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study

  • Sarah Lapointe
  • Warren Mason
  • Mary MacNeil
  • Craig Harlos
  • Roger Tsang
  • Joana Sederias
  • H. Artee Luchman
  • Samuel Weiss
  • John P. Rossiter
  • Dongsheng Tu
  • Lesley Seymour
  • Martin SmoragiewiczEmail author
PHASE I STUDIES

Summary

The PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100 mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5 days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51–77), females 8). Vistusertib 125 mg BID in combination with TMZ 150 mg/m2 daily for 5 days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1–2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median duration 9.6 months, range 3.7-not yet reached). Six-month progression-free survival (PFS) rate was 26.6%. Combination of vistusertib with TMZ in GBM patients at first recurrence demonstrated a favorable safety profile at the tested dose levels.

Keywords

Clinical trial Glioblastoma Temozolomide mTOR inhibitor mTORC2 AZD2014 

Notes

Acknowledgments

The authors acknowledge support from the Canadian Cancer Society and Terry Fox Research Institute. The authors acknowledge Dr. Gregory Cairncross for his leadership heading the TFRI GBM Consortium and support in this collaboration.

Funding

Financial support was provided by grants from the Canadian Cancer Society (grant # 704970) and Terry Fox Research Institute (grant # 2009–20). This research was conducted with the support from AstraZeneca Canada Inc., which provided study drug.

Compliance with ethical standards

Conflict of interest

Dr. Seymour received funding from AstraZeneca on behalf of CCTG, and holds shares in AstraZeneca. No other authors declared any conflicts of interest.

Ethical approval

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.

Informed consent

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

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sarah Lapointe
    • 1
    • 2
  • Warren Mason
    • 2
  • Mary MacNeil
    • 3
  • Craig Harlos
    • 4
  • Roger Tsang
    • 5
  • Joana Sederias
    • 6
  • H. Artee Luchman
    • 7
  • Samuel Weiss
    • 7
  • John P. Rossiter
    • 8
  • Dongsheng Tu
    • 6
  • Lesley Seymour
    • 6
  • Martin Smoragiewicz
    • 6
    Email author
  1. 1.Division of NeurologyCentre Hospitalier de l’Université de MontréalMontréalCanada
  2. 2.Division of Neuro-Oncology, Pencer Brain Tumor CenterUniversity Health Network-Princess Margaret HospitalTorontoCanada
  3. 3.QEII Health Sciences CentreHalifaxCanada
  4. 4.CancerCare ManitobaWinnipegCanada
  5. 5.Tom Baker Cancer CenterCalgaryCanada
  6. 6.Canadian Cancer Trials GroupQueen’s UniversityKingstonCanada
  7. 7.Arnie Charbonneau Cancer Institute & Hotchkiss Brain Institute, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
  8. 8.Department of Pathology and Molecular MedicineQueen’s UniversityKingstonCanada

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