Phase 1 trial of gemcitabine with bortezomib in elderly patients with advanced solid tumors

Bortezomib, a proteasome inhibitor, has synergistic antitumor activity with gemcitabine, an antimetabolite, in preclinical and clinical studies. The safety of this combination has not yet been established in elderly patients; therefore, this dose-escalation study was designed to assess the maximum-tolerated dose of bortezomib and gemcitabine in patients aged 70 years or older with advanced-stage solid tumors. Patients and Methods: Gemcitabine was administered intravenously (800 to 1000 mg/m ²) over 30 minutes on days 1 and 8, followed 60 minutes later by bortezomib administered as an intravenous push over 3 to 5 seconds (1.0 to 1.8 mg/m ²) on a 21-day cycle. This study used a standard phase 1 dose-escalation design with 3 or 6 patients per dose level. Results: Seventeen patients with stage IV solid tumors were treated. Median age was 73 years (range: 70 to 87 y). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status less than 2. Median number of earlier chemotherapy regimens was 2 (range: 0 to 6). Dose-limiting toxicities were seen in 2 of 8 patients enrolled at the second dose level of gemcitabine (1000 mg/m ²) and bortezomib (1.0 mg/m ²), which consisted of grade ≥3 lower extremity edema, thrombocytopenia, fatigue, and dehydration. The most common grade ≥3 toxicities included thrombocytopenia (n=9), neutropenia (n=6), and anemia (n=5). Partial response (n=3) or disease stabilization (n=3) was seen in 6 of 14 evaluable patients. Conclusions: Concurrent weekly gemcitabine (800 mg/m ²) and bortezomib (1 mg/m ²) is the recommended schedule for future phase 2 trials in elderly patients with stage IV solid tumors.