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Phase I Study of Bendamustine and Fractionated Stereotactic Radiotherapy (FSRT) in Patients with One to Three Brain Metastases From Solid Malignancies

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr TPS146)

Author(s): J. C. Grecula, M. Ammirati, K. L. Kendra, M. Phelps, R. Cavaliere, B. McCracken-Bussa, J. Radawski, L. Wei, E. Mrozek, N. A. Mayr; The Ohio State University, Columbus, OH

Abstract:

Background: Bendamustine is a multifunctional alkylating agent with a purine-like ring system. It causes formation of intrastrand and interstand crosslinks between DNA bases, induces a concentration-dependent apoptosis as noted by changes in Bcl-2 and Bax expression profiles, downregulates inhibitors of apoptosis proteins, and induces nonapoptotic cell death, termed mitotic catastrophe. These mechanisms of action make it likely to also function as a radiosensitizer, and thus bendamustine is an attractive agent to study in combination with ionizing radiation.

Methods: This single-arm phase I study will determine the toxicity of combination therapy with bendamustine and FSRT for treatment of patients with KPS ≥ 70 and 1-3 untreated brain metastases. Metastases ≥ 5 cm or involving leptomeninges, thalamus, basal ganglia, or brainstem are excluded. The primary efficacy endpoint: the recommended phase II dose of bendamustine. Secondary endpoints: 1) bendamustine pharmacokinetics (PK), 2) drug quantitation utilizing high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) for plasma, brain metastases, brain margin, arachnoid, and cerebral spinal fluid, and 3) assessment of local control of brain metastases. Following consent, eligible patients will undergo treatment with bendamustine (40 mg/m2 IV) on days 1, 2, 3 and surgical resection of the brain metastases on day 3. In patients undergoing surgery, plasma for bendamustine PK will be obtained on day 1 or 2 prior to, during, and up to 2 hours after bendamustine infusion. FSRT will start within 4 weeks after surgery (day 1 if no surgery). Patients will receive 30 Gy in 5 daily fractions (Mon-Fri). Bendamustine IV will be administered over 30 minutes starting 1.5 hours prior to daily FSRT. Patients will be escalated utilizing a phase I design, starting at 40 mg/m2 IV x 5 days. With the standard method of 3 patients per dose level and with 6 at the MTD, we will study a minimum of 6 and a maximum of 18 patients. Two patients have been accrued. Approved and funded by National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc; supported in part by NCI P30 CA16058.

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