A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies

John W. Moroney, Matthew P. Schlumbrecht, Thorunn Helgason, Robert L. Coleman, Stacy Moulder, Aung Naing, Diane C. Bodurka, Filip Janku, David S. Hong, Razelle Kurzrock

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, toDand 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 immunhistochemistry 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.

Original languageEnglish (US)
Pages (from-to)6840-6846
Number of pages7
JournalClinical Cancer Research
Volume17
Issue number21
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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