Purpose To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment, and to develop dosing guidelines for such a patient population. Patients and Methods Sixty-two adult cancer patients received intravenous bortezomib at 0.7–1.5 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73 m2 into five cohorts: normal renal function (≥60 mL/min/1.73 m2); mild dysfunction (40–59 mL/min/1.73 m2); moderate dysfunction (20–39 mL/min/1.73 m2); severe dysfunction (<20 mL/min/1.73 m2); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed. Results Bortezomib escalation to the standard 1.3 mg/m2 dose was well tolerated in all patients with CrCl ≥20 mL/min/1.73 m2; 0.7 mg/m2 was tolerated in three patients with severe renal dysfunction (<20 mL/min/1.73 m2). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3 mg/m2 in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function. Conclusion Bortezomib 1.3 mg/m2 is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.

Purpose We present the results of a randomized, multicenter clinical trial of adjuvant ZA in postmenopausal women with high-risk breast cancer. The primary objective was change in bone mineral density (BMD) at the lumbar spine and femoral neck at 1 year. Secondary objectives included change in calcaneal BMD, disease-free survival (DFS), overall survival (OS), and toxicity. Patients and Methods Postmenopausal women with stage II/III breast cancer diagnosed up to five years prior were eligible and randomized to either observation or ZA 4 mg IV every 3 months. BMD testing was performed at 0, 6 and 12 months. Results Sixty-eight women were enrolled: 36 (ZA) and 32 women (observation). The population was a median of 2 years from diagnosis and the majority received tamoxifen during study. There was a significant difference in the mean change from baseline to 1 year follow-up for lumbar spine (increased by 4.28±0.62%; p=0.01), total femur (increased by 1.9±0.4%; p=0.03), trochanter (increased by 2.97±0.69%; p=0.03) and calcaneal BMD (increased by 2±0.57%; p=0.01) in favor of the ZA arm. No significant difference in the mean change for the femoral neck was seen. No significant differences in DFS or OS were observed. Conclusion ZA significantly improved the BMD at multiple skeletal sites in postmenopausal women largely on tamoxifen. No new safety signals were noted. There were insufficient events to comment on DFS or OS.

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We report a case of bevacizumab (BEV)-induced thrombocytopenia in a 36-year-old woman treated with BEV as a single-agent for a recurrent high-grade glioma. The thrombocytopenia was both reversible and reproducible on multiple treatment cycles. The patient has improved clinically and by brain MR imaging with single-agent BEV for approximately 7 months to date. She did not have bleeding or thromboembolic complications. Treatment delays have been 1-2 weeks relative to a conventional plan of treatment, i.e., 10 mg/kg every 2 weeks. This is a rare complication that has not been previously reported.