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

Warren P. Mason; Mary MacNeil; Petr Kavan; Jacob Easaw; David MacDonald; Brian Thiessen; Shweta Urva; Zarnie Lwin; Lynn McIntosh; Elizabeth Eisenhauer

doi:10.1007/s10637-011-9775-5

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

Warren P. Mason, Mary MacNeil, Petr Kavan, Jacob Easaw, David MacDonald, Brian Thiessen, Shweta Urva, Zarnie Lwin, Lynn McIntosh, Elizabeth Eisenhauer

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	2344-2351
Number of pages	8
Journal	Investigational New Drugs
Volume	30
Issue number	6
DOIs	https://doi.org/10.1007/s10637-011-9775-5
Publication status	Published - Dec 2012
Externally published	Yes

Bibliographical note

Funding Information:
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

ASJC Scopus Subject Areas

Oncology
Pharmacology
Pharmacology (medical)

PubMed: MeSH publication types

Clinical Trial, Phase I
Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

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10.1007/s10637-011-9775-5

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Mason, W. P., MacNeil, M., Kavan, P., Easaw, J., MacDonald, D., Thiessen, B., Urva, S., Lwin, Z., McIntosh, L., & Eisenhauer, E. (2012). 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. Investigational New Drugs, 30(6), 2344-2351. https://doi.org/10.1007/s10637-011-9775-5

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. / Mason, Warren P.; MacNeil, Mary; Kavan, Petr et al.
In: Investigational New Drugs, Vol. 30, No. 6, 12.2012, p. 2344-2351.

Research output: Contribution to journal › Article › peer-review

Mason, WP, MacNeil, M, Kavan, P, Easaw, J, MacDonald, D, Thiessen, B, Urva, S, Lwin, Z, McIntosh, L & Eisenhauer, E 2012, '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', Investigational New Drugs, vol. 30, no. 6, pp. 2344-2351. https://doi.org/10.1007/s10637-011-9775-5

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title = "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",

abstract = "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.",

author = "Mason, {Warren P.} and Mary MacNeil and Petr Kavan and Jacob Easaw and David MacDonald and Brian Thiessen and Shweta Urva and Zarnie Lwin and Lynn McIntosh and Elizabeth Eisenhauer",

note = "Funding Information: 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",

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T1 - 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

T2 - An NCIC CTG study

AU - Mason, Warren P.

AU - MacNeil, Mary

AU - Kavan, Petr

AU - Easaw, Jacob

AU - MacDonald, David

AU - Thiessen, Brian

AU - Urva, Shweta

AU - Lwin, Zarnie

AU - McIntosh, Lynn

AU - Eisenhauer, Elizabeth

N1 - Funding Information: 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

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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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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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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