A phase I study of bortezomib (BTZ) and temozolomide (TMZ) in patients with advanced solid tumors.

Abstract

2563 Background: BTZ is a proteasome inhibitor with activity against a wide array of solid tumors in preclinical studies. TMZ is an alkylating agent with activity primarily against gliomas. The rationale for combining these 2 agents is based on their nonoverlapping mechanisms of action and potential for synergy. Methods: A standard 3+3 dose escalation schema was used, with a cycle length of 28 days. BTZ was administered on days 2, 5, 9, and 12, starting dose 1.0 mg/m2; TMZ on days 1-5, starting dose 100 mg/m2. Patients (pts) with primary or metastatic brain tumors were eligible. Pts were stratified based on whether they were taking enzyme-inducing anticonvulsants [EIAC] (group A) or not (group B). The same dose escalation schema was used for both groups; however, the drugs were escalated separately in each group. Pharmacokinetics (PK) of BTZ were determined on Days 2 and 9 of cycle 1. Results: 25 pts were enrolled; 3 in grp A and 22 in grp B. For both groups, the maximum tolerated dose (MTD) of BTZ was 1.3 mg/m2 and for TMZ 200 mg/m2. Dose-limiting toxicities were grade 3 constipation and hyponatremia, grade 4 neutropenia and thrombocytopenia. The median number of treatment cycles/pt was 2 (1-6). Stable disease (>8 weeks) was observed in 5 patients. PK data were available in 23 pts on Day 2 (grp A=3; grp B=20) and 21 pts on Day 9 (grp A=2; grp B=19). Clearance (CLsys) of BTZ on Day 9 was, on average, 49% (range 21%-101%) of the CLsys on Day 2 (p<0.001, paired T-test). The mean CLsys of BTZ on Day 2 was significantly higher in grp A than grp B (1527 vs 810 ml/min, p<0.02 Wilcoxon test), and the CLsys on Day 9 was higher in grp A than grp B (950 vs 373 ml/min, p<0.04 Wilcoxon test). Conclusions: BTZ dosed at 1.3 mg/m2 can be safely combined with TMZ at 200 mg/m2, and these are the recommended doses for future phase II studies of this combination in pts not taking EIAC. Although sample size was small, the rate of BTZ elimination in pts taking EIAC was increased 2-fold. Additional dose-seeking trials are needed to better define the optimal dosing in such patients. Supported by K12 CA01727 and P30 CA33572. No significant financial relationships to disclose.