Abstract
We conducted a phase I trial to examine the maximally tolerated dose (MTD) of the oral protease inhibitor nelfinavir (NFV) in combination with temozolomide and concurrent radiotherapy in patients with glioblastoma and to gather preliminary data for response. The study was conducted in patients with newly diagnosed glioblastoma after surgical resection. Patients were treated with standard radiotherapy (6,000 cGy to the gross tumor volume), temozolomide (75 mg/m2 daily) together with daily oral NFV starting 7–10 days prior to chemoradiotherapy continuing for the duration of chemoradiation for 6 weeks. Temozolomide (150–200 mg/m2) was resumed 4 weeks after completion of chemoradiotherapy. Two dose levels of NFV were investigated: 625 mg twice daily (bid) and 1,250 mg bid in a cohort escalation design. A total of 21 patients were enrolled. At the maximum tolerated dose, 18 subjects were enrolled to further evaluate toxicity and for preliminary estimate of efficacy for further phase II study. No dose-limiting toxicity was noted at 625 mg bid. At 1,250 mg bid, 3 dose-limiting episodes of hepatotoxicity were noted and one dose-limiting episode of diarrhea. The MTD for this study was 1,250 mg bid. NFV (1,250 mg bid) concurrent with temozolomide and radiotherapy is tolerated in most patients with glioblastoma. At the 1,250 mg bid dose level, patients should be monitored for hepatotoxicity and GI side effects.
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Acknowledgments
This work was supported by the Department of Radiation Oncology, University of Pennsylvania, ASCO Young Investigator Award, Burroughs Wellcome Career Award for Medical Scientists (1006792) and the National Institute of Health/National Institute of Neurologic Disorders and Stroke (K08 NS076548-01). We acknowledge the Department of Radiation Oncology Clinical Research Coordinators for their assistance with the study. The clinical trial protocol was formulated and written at the ASCO/AACR: Methods in Clinical Cancer Research (Vail) Workshop.
Conflict of interest
The University of Pennsylvania has a patent pending on the use of compounds of the type like NFV in combination with radiation. Under the policies of the University of Pennsylvania, the University may receive financial benefits based on the results of this study. There are no conflicts of interest to disclose for any of the authors.
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Michelle Alonso-Basanta and Penny Fang have contributed equally to this study.
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Alonso-Basanta, M., Fang, P., Maity, A. et al. A phase I study of nelfinavir concurrent with temozolomide and radiotherapy in patients with glioblastoma multiforme. J Neurooncol 116, 365–372 (2014). https://doi.org/10.1007/s11060-013-1303-3
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DOI: https://doi.org/10.1007/s11060-013-1303-3