Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies

Abstract

14087 Background: Bortezomib, a potent proteasome and NF-kB inhibitor, potentiates the activity of chemotherapy in a variety of tumors in vitro and in mouse models, and preclinical data suggest that the combination of bortezomib, gemcitabine, and liposomal doxorubicin is synergistic. Because tolerance to combination therapy may be attenuated in elderly patients, we performed a phase I age- stratified trial to determine the maximum tolerated dose (MTD), toxicity, and antitumor activity of this combination. Methods: Starting doses were bortezomib 0.7 mg/m2 (days 1 and 8), gemcitabine 500 mg/m2 (days 1 and 8), and liposomal doxorubicin 20 mg/m2 (day 1). Two parallel age-stratified arms (< 65 and = 65 years old) were accrued, with at least three patients per dose level per arm. Each treatment cycle was 21 days. Results: 47 patients have enrolled, and the MTD has not yet been reached. For patients < 65 years old, accrual continues at the ninth dose level with bortezomib 1.3 mg/m2 (days 1, 4, 8, 11), gemcitabine 800 mg/m2 (days 1 and 8), and liposomal doxorubicin 40 mg/m2 (day 1). For patients = 65 years old, accrual continues at the fourth dose level with bortezomib 1.0 mg/m2 (days 1, 4, 8, 11), gemcitabine 800 mg/m2 (days 1 and 8) and liposomal doxorubicin 20 mg/m2 (day 1). The most common side effects have been thrombocytopenia and neutropenia, with thrombocytopenia necessitating dose delays and withholding of doses. In the arm with patients = 65 years old, a dose-limiting toxicity of grade 3 fatigue was observed at dose level 4, and that cohort is currently undergoing dose expansion. Seven patients have achieved a partial response, including one patient with small cell lung carcinoma (6 months; 3 prior therapies) and all of six evaluable patients with cutaneous T cell lymphoma (1, 3, 4, 6, 7, and 8 months; median 4 prior therapies). Stable disease = 6 months was observed in 5 patients with various solid tumors (7, 7, 8, 9, and 9 months; median 4 prior therapies). Conclusions: This combination regimen is well tolerated. Dose-limiting toxicity has developed earlier in the elderly cohort, as predicted. Antitumor activity in heavily pretreated patients with advanced malignancies has been observed. No significant financial relationships to disclose.