A Phase I Trial of Liposomal Doxorubicin, Bevacizumab, and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies

Purpose: Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1 alpha). We, therefore, added temsirolimus (T), which inhibits HIF-1 alpha, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates. Patients and Methods: Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immun-histochemistry for PTEN loss were conducted. Results: This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27-79); prior regimens: 4 (1-11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) >= 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD >= 6 months (CR+PR+SD >= 6 months = 52%). Conclusions: DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations. Clin Cancer Res; 17(21); 6840-6. (C)2011 AACR.