North Central Cancer Treatment Group Phase I Trial N057K of Everolimus (RAD001) and Temozolomide in Combination With Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme

doi:10.1016/j.ijrobp.2010.05.064

International Journal of Radiation OncologyBiologyPhysics

Volume 81, Issue 2, 1 October 2011, Pages 468-475

https://doi.org/10.1016/j.ijrobp.2010.05.064 Get rights and content

Background

The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. On the basis of promising preclinical data, the safety and tolerability of therapy with the mTOR inhibitor RAD001 in combination with radiation (RT) and temozolomide (TMZ) was evaluated in this Phase I study.

Methods and Materials

All patients received weekly oral RAD001 in combination with standard chemoradiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide. RAD001 was dose escalated in cohorts of 6 patients. Dose-limiting toxicities were defined during RAD001 combination therapy with TMZ/RT.

Results

Eighteen patients were enrolled, with a median follow-up of 8.4 months. Combined therapy was well tolerated at all dose levels, with 1 patient on each dose level experiencing a dose-limiting toxicity: Grade 3 fatigue, Grade 4 hematologic toxicity, and Grade 4 liver dysfunction. Throughout therapy, there were no Grade 5 events, 3 patients experienced Grade 4 toxicities, and 6 patients had Grade 3 toxicities attributable to treatment. On the basis of these results, the recommended Phase II dosage currently being tested is RAD001 70 mg/week in combination with standard chemoradiotherapy. Fluorodeoxyglucose (FDG) positron emission tomography scans also were obtained at baseline and after the second RAD001 dose before the initiation of TMZ/RT; the change in FDG uptake between scans was calculated for each patient. Fourteen patients had stable metabolic disease, and 4 patients had a partial metabolic response.

Conclusions

RAD001 in combination with RT/TMZ and adjuvant TMZ was reasonably well tolerated. Changes in tumor metabolism can be detected by FDG positron emission tomography in a subset of patients within days of initiating RAD001 therapy.

Introduction

Sirolimus and everolimus (RAD001) are structurally related drugs that selectively inhibit the signaling activity of the mammalian target of rapamycin (mTOR). mTOR functions within 2 distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, and the sirolimus family of drugs selectively suppresses signaling through mTORC1. This complex functions downstream from multiple receptor tyrosine kinases in a PI3K/Akt-dependent pathway to promote cell growth and proliferation 1, 2. mTORC1 signaling also modulates expression of vascular endothelial growth factor during hypoxia, and mTOR inhibitors are antiangiogenic in multiple tumor types (3). Hyperactivation of PI3K/Akt/mTOR signaling is common and is associated with increased dependence on mTOR signaling in a subset of glioblastoma multiforme (GBM) 4, 5, 6. Whereas monotherapy with mTOR inhibitors in recurrent GBM has limited activity 7, 8, preclinical studies in GBM and melanoma models suggest that the combination of mTOR inhibitors with either radiation therapy (RT) or temozolomide (TMZ) provides additive to synergistic enhancement of cell killing 9, 10, 11. Based on these data, the North Central Cancer Treatment Group (NCCTG) N057K clinical trial was initiated to evaluate the acute tolerability of RAD001 therapy integrated with standard TMZ and radiotherapy (RT) in patients with newly diagnosed GBM.

Section snippets

Eligibility criteria

Patients with a new diagnosis of a World Health Organization Grade IV astrocytoma, confirmed by central review, were enrolled between 1 and 6 weeks after surgical resection or biopsy. Additional enrollment criteria were as follows: age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, absolute neutrophil count ≥1500/μL, hemoglobin ≥9.0 g/dL, platelets ≥100,000/μL, total bilirubin ≤2.5 ×upper limit of normal (ULN), serum total cholesterol <350 mg/dL, serum

Patient characteristics

Between May 30, 2008, and May 29, 2009, 18 patients were enrolled on this clinical study. All 18 patients received the study treatment and were evaluable for toxicity. The patient characteristics are shown in Table 1.

Toxicities

Dose-limiting toxicities were defined during concomitant treatment with RAD001, RT, and TMZ. One of 6 patients had a DLT at each of the three dose levels: Grade 3 fatigue (30 mg/week RAD001); Grade 4 neutropenia, lymphopenia, and thrombocytopenia (50 mg/week RAD001); and Grade 4

Discussion

Concurrent suppression of mTOR signaling during RT and/or chemotherapy has the potential to enhance the efficacy of treatment. In this Phase I study, weekly oral RAD001 combined with RT/TMZ and adjuvant TMZ was well tolerated, with an acceptable rate of toxicity. The spectrum of toxicities observed are encompassed by the known risks of TMZ-based chemoradiotherapy or RAD001 therapy with the most common adverse events, including fatigue, thrombosis, thrombocytopenia, and elevated lipids.

Conclusions

The integration of weekly RAD001 therapy with standard chemoradiotherapy in newly diagnosed GBM patients was reasonably well tolerated. Early FDG PET imaging after 1 week of RAD001 monotherapy demonstrated partial metabolic response in a subset of patients.

Acknowledgments

The authors thank Sue Steinmetz and Debra Sprau for clinical support, Sara Braun for protocol development, and Sara Felton and Keith Anderson for biostatistical analysis.

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: This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.

: Supported in part by Public Health Service grants: CA-25224, CA-37404, CA-35103, CA 114740, and Brain SPORE CA-108961 from the National Cancer Institute, Department of Health and Human Services. Funding also was provided by Novartis.

: The content is solely the responsibility of the authors and does not necessarily represent the views of the National Cancer Institute, the National Institute of Health, or Novartis.

: Conflict of interest: none.

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Clinical InvestigationNorth Central Cancer Treatment Group Phase I Trial N057K of Everolimus (RAD001) and Temozolomide in Combination With Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme

Background

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Eligibility criteria

Patient characteristics

Toxicities

Discussion

Conclusions

Acknowledgments

Neoplasia

J Invest Dermatol

Int J Radiat Oncol Biol Phys

Eur J Cancer

J Thorac Oncol

Transplant Proc

Radiother Oncol

Transplant Proc

J Biol Chem

Mammalian target of rapamycin: Master regulator of cell growth in the nervous system

Histol Histopathol

Current development of TOR inhibitors as anticancer agents

Nat Rev Drug Discov

Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents

Curr Cancer Drug Targets

Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR

Proc Natl Acad Sci U S A

Analysis of the phosphatidylinositol 3'-kinase signaling pathway in glioblastoma patients in vivo

Cancer Res

Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A North Central Cancer Treatment Group study

J Clin Oncol

Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme

Invest New Drugs

Enhanced radiation damage of tumor vasculature by mTOR inhibitors

Oncogene

Clinical Investigation
North Central Cancer Treatment Group Phase I Trial N057K of Everolimus (RAD001) and Temozolomide in Combination With Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme