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A phase I study of temozolomide and everolimus (RAD001) in patients with newly diagnosed and progressive glioblastoma either receiving or not receiving enzyme-inducing anticonvulsants: an NCIC CTG study

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Summary

Purpose This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Patients and Methods Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150 mg/m2/day for 5 days every 28 days, and everolimus was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles. Results Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10 mg daily plus TMZ 150 mg/m2/day for 5 days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease. Conclusion A dosage of 10 mg everolimus daily with TMZ 150 mg/m2/day for five consecutive days every 28 days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen.

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Funding

Financial support was provided by Novartis, Inc. to NCIC CTG for the conduct of this trial

Conflicts of Interest

Dr. Urva is an employee of Novartis, Inc. and owns stock in the company. On behalf of the NCIC CTG Dr. Eisenhauer received funding from Novartis, Inc. for the conduct of this trial

Author information

Authors and Affiliations

  1. University Health Network-Princess Margaret Hospital, 610 University Avenue, Suite 18-717, Toronto, ON, M5G 2M9, Canada

    Warren P. Mason & Zarnie Lwin

  2. QEII Health Sciences Centre, Halifax, Canada

    Mary MacNeil

  3. Department of Oncology, McGill University, Montréal, Canada

    Petr Kavan

  4. Tom Baker Cancer Centre, Calgary, Canada

    Jacob Easaw

  5. London Regional Cancer Centre, London, Canada

    David Macdonald

  6. BCCA–Vancouver Cancer Centre, Victoria, Canada

    Brian Thiessen

  7. Novartis Pharmaceuticals Corporation- Oncology Business Unit, Florham Park, USA

    Shweta Urva

  8. NCIC Clinical Trials Group, Kingston, Canada

    Lynn McIntosh & Elizabeth Eisenhauer

Authors
  1. Warren P. Mason
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  2. Mary MacNeil
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  3. Petr Kavan
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  4. Jacob Easaw
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  5. David Macdonald
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  6. Brian Thiessen
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  7. Shweta Urva
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  8. Zarnie Lwin
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  9. Lynn McIntosh
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  10. Elizabeth Eisenhauer
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Corresponding author

Correspondence to Warren P. Mason.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Pharmacokinetic Variables of Temozolomide in NEIAED and EIAED Patients (DOC 48 kb)

Supplementary Table 2

Pharmacokinetic Variables of Everolimus in NEIAED and EIAED Patients (DOC 42 kb)

Supplementary Figure 1

Mean TMZ AUCinf in plasma at Day 1 in EIAED and NEIAED cohorts by dose level. (JPEG 2056 kb)

High resolution image (EPS 297 kb)

Supplementary Figure 2

Mean TMZ AUCinf in plasma at Day 5 in EIAED and NEIAED cohorts by dose level. (JPEG 2056 kb)

High resolution image (EPS 294 kb)

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Mason, W.P., MacNeil, M., Kavan, P. et al. A phase I study of temozolomide and everolimus (RAD001) in patients with newly diagnosed and progressive glioblastoma either receiving or not receiving enzyme-inducing anticonvulsants: an NCIC CTG study. Invest New Drugs 30, 2344–2351 (2012). https://doi.org/10.1007/s10637-011-9775-5

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  • DOI: https://doi.org/10.1007/s10637-011-9775-5

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