Faculty Collaboration Database

Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity. Clin Cancer Res 2012 Oct 15;18(20):5796-805

Date

08/29/2012

Pubmed ID

22927482

DOI

10.1158/1078-0432.CCR-12-1158

Scopus ID

2-s2.0-84867551535 (requires institutional sign-in at Scopus site)   73 Citations

Abstract

PURPOSE: Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines.

EXPERIMENTAL DESIGN: We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types.

RESULTS: The most common cancers were breast (n = 29), epithelial ovarian (n = 23), and colorectal cancer (n = 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n = 28) stable disease (SD) ≥ 6 months and 21% (n = 29) rate of partial or complete remission [PR/CR; (total SD ≥ 6 months/PR/CR = 42% (n = 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m(2) and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly.

CONCLUSIONS: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted.

Author List

Moroney J, Fu S, Moulder S, Falchook G, Helgason T, Levenback C, Hong D, Naing A, Wheler J, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Angiogenesis Inhibitors
Antibiotics, Antineoplastic
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Breast Neoplasms
Colorectal Neoplasms
Disease-Free Survival
Doxorubicin
Drug-Related Side Effects and Adverse Reactions
Female
Humans
Maximum Tolerated Dose
Middle Aged
Neoplasms, Glandular and Epithelial
Ovarian Neoplasms
Protein Kinase Inhibitors
Sirolimus