title: A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer.
abstract: Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid-derived suppressor cells, as well as trigger antitumor effects by inducing an antibody-dependent cellular cytotoxicity on tumor-associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2-negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m(2) for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression-free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion-related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS-expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte-derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion-related reactions with no evidence for increased thrombogenicity. Recent preclinical data suggest that bavituximab can also promote antitumor immune activity that should be explored in future clinical trials.
authors.affiliation: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, Arizona, 85724.
authors.forename: Pavani
authors.initials: P
authors.lastname: Chalasani
authors.affiliation: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, Arizona, 85724.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Marron
authors.affiliation: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, Arizona, 85724.
authors.forename: Denise
authors.initials: D
authors.lastname: Roe
authors.affiliation: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, Arizona, 85724.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Clarke
authors.affiliation: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, Arizona, 85724.
authors.forename: Maria
authors.initials: M
authors.lastname: Iannone
authors.affiliation: University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, Arizona, 85724.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.affiliation: Peregrine Pharmaceuticals, Inc., 14282 Franklin Avenue, Tustin, California, 92780.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Shan
authors.affiliation: Stonybrook Medicine University, PO Box 1554, Stonybrook, New York, 11790.
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; C547825:bavituximab
keywords: Bavituximab; circulating tumor cells; metastatic breast cancer; microparticles; paclitaxel
references.citation: Cancer Res. 2002 Nov 1;62(21):6132-40
references.pmid: 12414638
references.citation: Clin Cancer Res. 2010 Nov 1;16(21):5233-43
references.pmid: 20978147
references.citation: J Lipid Res. 2003 Feb;44(2):233-42
references.pmid: 12576505
references.citation: J Clin Oncol. 2003 Feb 15;21(4):588-92
references.pmid: 12586793
references.citation: Thromb Haemost. 2004 Apr;91(4):667-73
references.pmid: 15045126
references.citation: Cancer Res. 2005 May 15;65(10):4408-16
references.pmid: 15899833
references.citation: Int J Cancer. 2006 May 15;118(10):2639-43
references.pmid: 16353142
references.citation: J Thromb Haemost. 2007 Mar;5(3):520-7
references.pmid: 17166244
references.citation: Clin Cancer Res. 2007 Sep 1;13(17):5211-8
references.pmid: 17785577
references.citation: Nature. 2007 Nov 15;450(7168):430-4
references.pmid: 17960134
references.citation: Cell Death Differ. 2008 Jan;15(1):192-201
references.pmid: 17962816
references.citation: Semin Thromb Hemost. 2010 Nov;36(8):888-906
references.pmid: 21049390
references.citation: J Clin Oncol. 2011 Apr 1;29(10):1252-60
references.pmid: 21383283
references.citation: EMBO Rep. 2011 Apr;12(4):358-64
references.pmid: 21399623
references.citation: Immunotherapy. 2011 Aug;3(8):933-44
references.pmid: 21843081
references.citation: Clin Cancer Res. 2011 Nov 1;17(21):6888-96
references.pmid: 21989064
references.citation: Hamostaseologie. 2012;32(2):127-31
references.pmid: 21792463
references.citation: Br J Cancer. 2012 Oct 9;107(8):1286-94
references.pmid: 22955853
references.citation: J Pharm Pharm Sci. 2013;16(2):238-53
references.pmid: 23958193
references.citation: CA Cancer J Clin. 2014 Jan-Feb;64(1):52-62
references.pmid: 24114568
references.citation: Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1479-84
references.pmid: 12459374
references.citation: N Engl J Med. 2007 Dec 27;357(26):2666-76
references.pmid: 18160686
references.citation: Clin Cancer Res. 2008 Mar 1;14(5):1377-85
references.pmid: 18316558
references.citation: Semin Thromb Hemost. 2008 Mar;34(2):199-203
references.pmid: 18645926
references.citation: N Engl J Med. 2008 Aug 28;359(9):938-49
references.pmid: 18753650
references.citation: Best Pract Res Clin Haematol. 2009 Mar;22(1):61-9
references.pmid: 19285273
references.citation: Leuk Lymphoma. 2009 May;50(5):728-35
references.pmid: 19373598
references.citation: Clin Cancer Res. 2009 Nov 15;15(22):6871-80
references.pmid: 19887482
references.citation: Thromb Res. 2010 Jun;125(6):511-2
references.pmid: 19854471
references.citation: Immunol Rev. 2010 May;235(1):172-89
references.pmid: 20536563
references.citation: J Clin Oncol. 2010 Jul 10;28(20):3239-47
references.pmid: 20498403
references.citation: Ann Oncol. 2010 Sep;21(9):1851-7
references.pmid: 20147742
references.citation: Cancer Immunol Res. 2013 Oct;1(4):256-68
references.pmid: 24777853