Accepted Manuscript Title: Bavituximab Plus Paclitaxel and Carboplatin for the Treatment of Advanced Non–Small-Cell Lung Cancer Author: Raghunadharao Digumarti P.P. Bapsy Attili V. Suresh G.S. Bhattacharyya Lokanatha Dasappa Joseph Shan David E. Gerber PII: DOI: Reference:

S0169-5002(14)00355-9 http://dx.doi.org/doi:10.1016/j.lungcan.2014.08.010 LUNG 4673

To appear in:

Lung Cancer

Received date: Revised date: Accepted date:

12-3-2014 13-8-2014 14-8-2014

Please cite this article as: Digumarti R, Bapsy PP, Suresh AV, Bhattacharyya GS, Dasappa L, Shan J, Gerber DE, Bavituximab Plus Paclitaxel and Carboplatin for the Treatment of Advanced NonndashSmall-Cell Lung Cancer, Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungcan.2014.08.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Bavituximab Plus Paclitaxel and Carboplatin for the Treatment of

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Advanced Non–Small-Cell Lung Cancer

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Raghunadharao Digumarti, MD;1 P.P. Bapsy, MD;2 Attili V. Suresh, MD;3 G.S.

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Bhattacharyya, MD;4 Lokanatha Dasappa, MD;5 Joseph Shan, MPH;6 David E.

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Gerber, MD,7

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Bangalore, India; 3Yashoda Hospital, Hyderabad, India; 4Orchid Nursing Home,

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Kolkata, India; 5Kidwai Memorial Institute of Oncology, Bangalore, India; 6

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Nizam’s Institute of Medical Sciences, Hyderabad, India; 2Apollo Hospitals,

Peregrine Pharmaceuticals, Inc., Tustin, CA; 7UT Southwestern Medical

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Center, Dallas, TX;

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Address for Correspondence: Joseph Shan, MPH

Peregrine Pharmaceuticals, Inc. 14282 Franklin Avenue

Tustin, California 92780 Tel: (714) 508-6000

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Fax: (714) 734-1692

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[email protected]

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Abstract

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Objective:

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Bavituximab is a phosphatidylserine (PS)-targeting monoclonal antibody with

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immune-modulating and tumor-specific vascular targeting properties.

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Preclinical studies have shown activity against numerous solid tumors and at

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least an additive effect in combination with chemotherapy. This study

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evaluated bavituximab in combination with paclitaxel and carboplatin in

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patients with previously untreated, locally advanced or metastatic non–small-

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cell lung cancer (NSCLC).

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Patients and Methods:

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This phase II, open-label study (NCT00687817) was conducted in 49 patients

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Results:

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with stage IIIB/IV NSCLC utilizing a Simon two-stage design. Patients were treated with up to six cycles of carboplatin area under the concentration-time curve (AUC) 5 plus paclitaxel 175 mg/m2 every 21 days with weekly bavituximab 3 mg/kg followed by bavituximab monotherapy until progression or unacceptable toxicity.

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The primary efficacy endpoint of overall response rate (ORR) was 40.8%

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(complete response [CR] 2.0%, partial response [PR] was 38.8%). Median

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progression-free survival (PFS) and overall survival (OS) were 6.0 and 12.4

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months, respectively. Treatment-related adverse events (AEs) occurred in

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40.8% of patients. The most common treatment-related AEs were anemia

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(10.2%), asthenia, vomiting, paresthesia, anorexia, and fatigue (6.1% each).

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One patient with a central, cavitating squamous tumor developed fatal

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hemoptysis and aspiration.

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Conclusion:

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Bavituximab in combination with paclitaxel-carboplatin as first-line therapy

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demonstrated a tolerable safety profile and potential efficacy in this single-arm

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phase II trial in patients with advanced local or metastatic NSCLC.

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Randomized trials with this regimen are in progress.

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ClinicalTrials.gov Identifier: NCT00687817

Keywords

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bavituximab; non-small-cell lung cancer; immune modulation; monoclonal

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antibody; phosphatidylserine; paclitaxel, carboplatin

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Introduction

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To date, the addition of molecular targeted therapies to standard first-line

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chemotherapy for advanced non-small-cell lung cancer (NSCLC) has yielded

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only modest clinical benefit. Combining epidermal growth factor receptor

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(EGFR) or vascular endothelial growth factor receptor (VEGFR) tyrosine

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kinase inhibitors with platinum-doublet regimens does not improve survival [1,

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2, 3, 4, 5, 6]. The anti-EGFR monoclonal antibody cetuximab increases

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survival by approximately one month when added to cisplatin-vinorelbine, but

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does not enhance outcomes when combined with carboplatin-paclitaxel [7, 8].

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Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal

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antibody, increases survival by two months when added to carboplatin-

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paclitaxel but does not improve survival when added to cisplatin-gemcitabine

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[9,10]. Despite encouraging phase II trial results, the vascular disrupting agent

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ASA404 failed to enhance survival when added to carboplatin-paclitaxel in the phase III setting [11].

Immunotherapy has recently emerged as a promising treatment strategy for advanced NSCLC [12]. The ability of cancer cells to evade host immune

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responses results in tumor development and progression. Immune checkpoint

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inhibitors may counteract these immunosuppressive effects. Clinical trials with

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immunotherapies alone or in combination with chemotherapy in patients with 4

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advanced NSCLC have explored the effects of immune checkpoint inhibitors

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such as anti-cytotoxic T lymphocyte 4 (CTLA-4) antibodies, anti-programmed

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death-1 (PD-1) antibodies, and anti-PD-ligand 1 (PD-L1) antibodies have been

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conducted, yielding promising results [13,14,15].

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Bavituximab is a novel phosphatidylserine (PS)-targeting monoclonal antibody

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with immune and vascular modulating properties that represent a new approach

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to cancer therapy. Underlying the tumor specificity of bavituximab is the

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distribution of its molecular target, the anionic membrane phospholipid PS. In

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normal cells, PS is relegated to the inner membrane leaflet, where it is not

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available for binding by bavituximab [16]. In a solid tumor microenvironment,

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hypoxia and other physiologic stresses lead to PS “flipping” to the outer

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membrane leaflet of the tumor and tumor endothelial cells [17]. Bavituximab

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binds to exposed PS molecules via the serum protein, β2-glycoprotein 1

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(β2GP1) [18, 19].

Exposed PS exerts a potent immunosuppressive effect allowing tumors to evade immune detection. Specifically, exposed PS downregulates macrophage

secretion of tumor necrosis factor-α and interleukin-12, and upregulates

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production of transforming growth factor-β and interleukin-10. These effects

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suppress innate immunity, blocking the development of M1 macrophages,

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dendritic cell maturation, antigen presentation to T-cells, and cytotoxic T-cell 5

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responses. Bavituximab binding to PS counteracts these immunosuppressive

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processes and promotes proinflammatory pathways such as myeloid-derived

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suppressor cells (MDSC) differentiation, M2 to M1 polarization, recruitment of

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tumoricidal M1 macrophages, dendritic cell maturation, and antigen

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presentation [20]. Separately, bavituximab binding to PS induces antibody-

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dependent cellular cytotoxicity, resulting in tumor vessel destruction [19,21].

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In a phase I monotherapy study in patients with advanced solid tumors,

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bavituximab 3 mg/kg weekly was identified as the preferred dose based on

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effective target binding and dose response considerations [22]. There is strong

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biologic rationale to combine bavituximab with chemotherapy and other cancer

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treatments. In preclinical cancer models, cytotoxic agents such as taxanes

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increase the proportion of malignant vascular endothelial cells with exposed PS,

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thereby increasing bavituximab binding [19]. As a result, the addition of

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survival (OS) was 21.4 months [26].

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bavituximab to conventional therapies such as chemotherapy, radiation, and hormonal agents, appears to provide synergistic effects in multiple models [19,21,23,24,25]. In a phase II trial of docetaxel plus bavituximab in locally advanced or metastatic breast cancer, radiographic response rate was 61%, median progression-free survival (PFS) was 7.4 months, and median overall

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Based on unmet clinical need, biologic rationale, and encouraging safety and

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efficacy data in other disease contexts, we performed a single-arm phase II trial

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of bavituximab plus paclitaxel-carboplatin in patients with previously untreated,

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locally advanced or metastatic NSCLC.

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Patients and Methods

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Study Design

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This phase II, open-label, multicenter, non-randomized study (NCT00687817)

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used a Simon two-stage design. If ≥4 of the 21 patients in stage 1 achieved a

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radiographic response, 28 additional patients were to be enrolled in stage 2 for a

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total of 49 patients (p0 = 0.15, p1 = 0.3). The protocol was reviewed and

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approved by the institutional review boards of all participating sites, and written

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informed consent was obtained from patients before study initiation.

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Patients aged ≥18 years with measurable stage IIIb (with pleural effusion) or stage IV NSCLC confirmed by histology or cytology, a life expectancy of ≥3 months, and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 were eligible. Patients were also required to have adequate bone marrow, liver, and renal function, in addition to D-dimer ≤2 x ULN and New York Heart Association functional class I/II.

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Patients were excluded if they had a known history of bleeding diathesis or

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coagulopathy, current evidence of clinically significant bleeding, a history of

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thromboembolic events (not including central venous catheter-related

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thrombosis >12 months ago), grade 2 or higher peripheral neuropathy,

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symptomatic or clinically active central nervous system disease or metastatic

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lesions, major surgery within 4 weeks of initiation of study therapy, were

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pregnant or nursing, had uncontrolled intercurrent disease, a history of

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cardiovascular disease, cardiac arrhythmia requiring treatment, a serious non-

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healing wound, or a known chronic infection (eg, HIV or hepatitis).

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Additionally, patients requiring oral or parenteral anticoagulants (not including

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aspirin for cardiovascular prophylaxis), chronic daily treatment with

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nonsteroidal anti-inflammatory drugs, or steroids were ineligible. Eligibility

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related to thrombolic or hemorrhagic events reflected regulatory requirements

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arising from hypothetical concerns of a clinical antiphospholipid antibody syndrome and from generally observed vascular targeting agent-related toxicities. In bavituximab clinical trials conducted to date, rates of thromboembolic or hemorrhagic events do not appear to exceed the background rate expected for these populations [21,27,28].

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Treatment

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Enrolled patients received up to six cycles of chemotherapy with carboplatin

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area under the concentration-time curve (AUC) of 5 and paclitaxel 175 mg/m2

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every 21days combined with weekly intravenous (IV) infusions of bavituximab

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3 mg/kg until disease progression or unacceptable toxicities. The slightly lower

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dose compared to regimens routinely employed in North America and Western

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Europe (eg, carboplatin AUC 6 and paclitaxel 200 mg/m2) reflect standard

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practice in South Asia and other global regions [29]. No dose reductions of

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conventional therapies have been required with the addition of bavituximab

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across multiple trials, including combinations with docetaxel in NSCLC

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(NCT01138163, NCT01999673), sorafenib in hepatocellular carcinoma

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(NCT01264705), gemcitabine in pancreatic cancer (NCT01272791), and

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capecitabine-based chemoradiation in rectal cancer (NCT01634685). Prior to

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minutes after chemotherapy as IV infusion over 90 minutes.

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each bavituximab infusion, patients were premedicated with a steroid and antihistamine regimen according to institutional practice to decrease the risk of infusion reaction. Patients receiving premedication for paclitaxel did not require additional corticosteroids on days when both chemotherapy and bavituximab were administered. Bavituximab was administered at least 30

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In the event of chemotherapy-related adverse events (AEs), the start date of a

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new cycle was delayed up to 21 days from the completion of the prior cycle.

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Chemotherapy dose reductions followed instructions in the package insert.

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There were no bavituximab dose reductions.

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Patients who completed six cycles of combination therapy with ongoing disease

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control continued to receive weekly bavituximab monotherapy until disease

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progression or unacceptable toxicities. Clinical and laboratory assessments

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continued every 3 weeks, and tumor response was evaluated every 2 months

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until progressive disease (PD). Survival data were collected every 3 months.

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Study Endpoints

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The primary endpoint of this study was overall response rate (ORR), defined as

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complete response (CR) plus partial response (PR) using Response Evaluation

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Criteria in Solid Tumors (RECIST version 1.0). Secondary endpoints included

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PFS, duration of response (DR), OS, and safety. Safety was assessed by analyses of AEs and serious adverse events (SAEs), ECOG performance status, and laboratory evaluations (ie, hematology, coagulation assays, D-dimer, urinalysis, and serum chemistry). These data were recorded for all patients who

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received any study drug. AEs were graded for severity according to Common

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Terminology Criteria for Adverse Events (CTCAE) version 3.0 and coded

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using the Medical Dictionary for Regulatory Activities version 8.1, and the

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causal relationship of AEs to treatment was determined by the investigators.

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Statistical Analysis

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Unless otherwise noted, all statistical tests were two-sided and were performed

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at the 0.05 significance level and type 2 error at 0.20. The primary efficacy

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analysis was calculated using the treated population (the safety population; ie,

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all patients who received ≥1 dose of the study drug). The best overall response

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to treatment by category (CR, PR, stable disease, PD, or not evaluable) was

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used to classify patients. Two-sided 95% confidence intervals (CIs) were

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calculated along with CR and PR point estimates. The median time-to-event

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and 95% CIs were provided for OS, PFS, and DR. A Kaplan-Meier analysis

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was performed after 80% of patients had completed six cycles of therapy or had

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progressed. A post-hoc analysis was conducted to examine the ORR to

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treatment by different subgroups by age, sex, baseline tumor stage, and tumor histology.

Results

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Patient Disposition and Treatments

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A total of 49 patients were enrolled in the study from June 2008 to July 2010

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and received ≥ 1 dose of bavituximab. The mean age of the study population 11

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was 53.9 years. The majority of patients (73.5%) had stage IV disease at

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enrollment. All patients were of South Asian (Indian) ethnicity. Other baseline

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characteristics of the study population are listed in Table I. The mean number

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of weekly bavituximab infusions administered during the study was 18.2. The

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mean number of cycles of carboplatin-paclitaxel was 4.4 each (range 1 to 6).

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The most common reason for study exit/discontinuation was disease

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progression (55.1%). Other reasons for study exit/discontinuation were death

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(14.3%); consent withdrawn (12.2%); lost to follow-up (8.2%); AEs (4.1%);

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and non-compliance, investigator decision, and other (each occurring in 2.0%).

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Efficacy

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The ORR for all 49 treated patients was 40.8%, including one patient who

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achieved a CR and 19 patients who achieved a PR (Table II). The percentage

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reduction from baseline in target lesion size is shown in Figure 1. Median PFS

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was 6.0 months (95% CI, 4.3–7.7 months). Seventeen of the responders

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subsequently experienced PD or died during the study. The median DR was

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4.9 months (95% CI, 3.9-6.9), and median OS was 12.4 months (95% CI,

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9.518.7) Figure 2.

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The post-hoc analysis of ORR by subgroups is shown in Figure 3. Possibly

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due to small sample size, the ORR did not deviate significantly from that

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observed in the total study population for any subgroup analyzed.

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Safety

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reported AEs with grade 4 severity were hyponatremia (4.1%), infection,

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anemia, and neutropenia (2.0% each). SAEs were reported in 38.8% of

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patients. In seven patients (14.3%), the SAE was considered to be study drug-

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A total of 44 patients (89.8%) experienced ≥ 1 AE (Table 3). The most frequently occurring AEs were pyrexia (30.6%), diarrhea (28.6%), alopecia (26.5%), anemia (26.5%), and asthenia (22.4%). By severity, 22.4% of AEs were grade 3, and 6.1% were grade 4. The most common AEs with grade 3 severity were asthenia (10.2%), hypokalemia, and anemia (6.1% each). The

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related. Anemia, the most common treatment-related SAE, occurred in three

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patients (6.1%). Hematologic toxicities were within the expected range for a

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population of patients with advanced NSCLC receiving treatment with

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paclitaxel and carboplatin [30,31].

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Activated partial thromboplastin time (aPTT), prothrombin time (PT), and D-

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dimer were shifted from normal at baseline to high in 42.2%, 62.2%, and 20.0%

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of patients, respectively. The majority (95.6%) of transiently elevated aPTT

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values were grade 1 (ie, > ULN to 1.5 x ULN) severity with grade 2 (> 1.5 x

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ULN to 2.5 x ULN) and grade 3 (>2.5 ULN) elevations occurring in one patient

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each, without any bleeding. Prolongation of aPTT in human plasma with

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bavituximab has been attributed to in vitro assay interference with

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phospholipid-dependent activation of plasma coagulation, which was confirmed

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via extensive coagulation assessments in a phase I clinical trial of bavituximab

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in refractory advanced solid tumors [22]. Eight patients (16.3%) died during the study; five of these deaths were considered by the investigator to be unrelated to study treatment. Two of these patients died from a convulsion, one of a of snake bite, one of dyspnea, and one

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from an unknown cause.

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Three of these deaths were considered by the investigator to be possibly or

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probably related to study treatment. Two patients (4.1%) died due to 14

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myocardial infarction (MI). One of these patients had, however, discontinued

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the study treatment 69 days before the event. The third patient (2.0%), who had

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a large squamous cell NSCLC with cavitation, died due to hemoptysis and

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aspiration.

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Discussion

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Bavituximab is a PS-targeting monoclonal antibody with vascular targeting and

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immune modulating properties. It has a novel mechanism of action that

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capitalizes on the tumor-specific distribution of exposed PS. Preclinical studies

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have demonstrated at least additive effects when bavituximab is combined with

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various cytotoxic agents and radiation therapy. A phase 1 clinical trial

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established bavituximab 3 mg/kg weekly as the selected biologic dose.

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This study evaluated bavituximab in combination with carboplatin-paclitaxel as

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outcomes may be inferior to smaller phase II studies—carboplatin-paclitaxel

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first-line therapy for advanced NSCLC. In this single-arm trial, the ORR was 41%, with median PFS of 6.0 months and median OS of 12.4 months. From this experience alone, it is not possible to determine the degree to which the addition bavituximab to carboplatin-paclitaxel may improve clinical outcomes. In recent large phase III advanced NSCLC trials—a setting where clinical

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has demonstrated radiographic response rates ranging 15-27%, median PFS

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ranging 3.1-5.8 months, and median OS 8.1-11.2 months [5,9,29,32,33].

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This clinical trial was conducted entirely in India. The relatively young age of

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our study cohort (mean 54 years) is comparable to that of other recent lung

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cancer clinical trials conducted in India [29,34] and reflects the younger age at

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diagnosis in that region. This may reflect distinct smoking habits of the Indian

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population; for example smoking bidi (aged Indian tobacco wrapped in a

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temburni leaf) carries a higher risk of lung cancer than cigarette smoking

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[35,36]. Other characteristics of lung cancer in India are less clearly defined, 

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such as prevalence of specific oncogenic subtypes (eg, EGFR, ALK).  Despite 

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these regional differences, standard lung cancer treatments in India are similar 

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to those in other regions (for instance, platinum doublet therapy as first‐line 

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treatment for advanced NSCLC), and—in clinical trials—outcomes appear 

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carboplatin-paclitaxel therapy in this population [9]. The incidence of infusion

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reactions in this study (2%) is comparable to other studies of paclitaxel-

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containing regimens [32].

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comparable to those expected for such regimens [29]. In general, the combination of carboplatin-paclitaxel plus bavituximab appeared to be well tolerated. Gastrointestinal toxicities, fatigue, neuropathy, and hematologic toxicities were observed at rates and severities expected with

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Potential toxicities of vascular-targeting agents include bleeding, thrombosis,

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hypertension, proteinuria, wound healing complications, and visceral

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perforations [9]. In lung cancer trials of the anti-VEGF antibody bevacizumab,

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vascular-related AEs have been observed [9]. In contrast, in this study and

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other bavituximab oncology clinical trials, we have not observed hypertension,

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visceral perforations, or proteinuria [26,37]. Bleeding or thrombosis of any

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severity were observed in a small proportion of patients (8.2% and 6.1%,

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respectively) at levels which have been seen in patients with similar cancers

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[38,39,40]. It is difficult to determine whether the two observed myocardial

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infarctions were related to bavituximab, as these events could instead reflect

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common predisposing factors such as dyslipidemia and smoking.

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One patient developed fatal hemoptysis and aspiration. He was a 56-year-old

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male who completed three cycles of bavituximab plus paclitaxel-carboplatin

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factors could not be determined. In response to this event, future lung cancer

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clinical trials featuring bavituximab will concentrate on non-squamous NSCLC.

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followed by five cycles of bavituximab monotherapy. This patient had a large squamous cell tumor encasing the pulmonary artery, as well as progressive tumor cavitation over the course of study treatment, all of which may contribute to bleeding [9,41,42]. Whether the bleeding was driven by histology, the proximity of major vasculature, cavitary changes, or a combination of these

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On the basis of its proposed mechanism of action (binding the membrane

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phospholipid PS via complexing with β2GP1), it may be argued that

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bavituximab conveys a hypothetical risk of antiphospholipid syndrome (APS).

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This autoimmune disorder is characterized by antiphospholipid antibody

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production which prolongs aPTT without an increase in bleeding propensity.

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However, the aPTT prolongation is a dose-dependent in vitro artifact caused by

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binding of the antiphospholipid antibodies to the phospholipid activator

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required for clotting.

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While bavituximab targets exposed PS, its specific mode of action makes a

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clinical antiphospholipid antibody syndrome highly unlikely. When

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complexing with β2GP1, bavituximab recognizes domain II in contrast to

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domain I, in the circular plasma (“non-activated”) conformation of β2GP1 and

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to a class of anti-β2GP1 antibodies that do not cause thrombosis [43].

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population as a whole (29% versus 41%). However, no conclusions can be

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drawn due to the small number of patients with a squamous or mixed

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Furthermore, monitoring of D-dimer revealed that 9 (20%) of the patients had a shift from normal at baseline to abnormal high post-baseline without being correlated with any clinical symptoms. In a post-hoc analysis, tumors of squamous or mixed adenosquamous

histology were associated with a decreased ORR compared with the study

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adenosquamous tumor type (n = 7). A second, phase II study in NSCLC

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(NCT01160601) was completed that excluded patients with this type of tumor

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to provide a more homogeneous patient population.

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It is not possible to compare this single-arm trial with other studies employing

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vascular targeting agents in combination with chemotherapy for advanced

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NSCLC. Numerous and vascular targeting agents have been studied for this

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indication. To date, the anti-VEGF monoclonal antibody bevacizumab, the

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anti-VEGF receptor monoclonal antibody ramucirumab, and the multitargeted

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angiokinase inhibitor nintedanib have demonstrated improvements in OS when

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added to chemotherapy [9,44,45]. However, several other agents targeting the

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VEGF pathway, including sorafenib, axitinib, cediranib, and others, have failed

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to achieve this endpoint [46,47,48,49]. It remains to be seen whether the

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specificity for tumor vasculature and the added mechanism of activating anti-

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tumor immunity of bavituximab will result in more favorable therapeutic and toxicity profiles than these other agents. Thus far, bavituximab does not appear to induce immune-related side effects (eg, colitis, dermatitis, hepatitis, hypophysitis, pneumonitis), as have been seen with antibodies targeting cytotoxic t-lymphocyte antigen 4 (CLTA-4), PD-1, and PD-L1 [12, 13, 14, 15]. In conclusion, the addition of bavituximab to carboplatin-paclitaxel for previously untreated advanced NSCLC demonstrated potential efficacy. The

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regimen did not appear to enhance chemotherapy-associated toxicities. Nor

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was bavituximab associated with hypertension, proteinuria, or autoimmune

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events. The low rate of possible vascular events is not clearly related to

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bavituximab and warrants follow-up in future studies.

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Acknowledgements

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Conflict of Interest Statement:

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Raghunadharao Digumarti, MD, P.P. Bapsy, MD, AVS Suresh, MD, G.S.

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Bhattacharyya, MD, and Lokanatha Dasappa, MD have no financial interests or

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relationships requiring disclosure. David E. Gerber, MD, has received research

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funding from Peregrine Pharmaceuticals. Joseph Shan, MPH, is employed by

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and owns stock in Peregrine Pharmaceuticals.

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submit for publication.

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Editorial and Medical Writer Assistance:

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Funding source:

This study was supported by Peregrine Pharmaceuticals, Inc. Role of sponsors:

Peregrine Pharmaceuticals, Inc. participated in the study design; collection, analysis, and interpretation of the data; writing of the report; and the decision to

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Medical writing and editorial services were provided by Deshawnt Jelani,

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PharmD of Peregrine Pharmaceuticals, Inc.

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16. Balasubramanian K, Schroit AJ. Aminophospholipid asymmetry: A matter of life and death. Annu Rev Physiol. 2003;65:701-34. 17. Ran S, Downes A, Thorpe PE. Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res. 2002;62:6132-40. 18. Luster TA, He J, Huang X, et al. Plasma protein beta-2-glycoprotein 1 mediates interaction between the anti-tumor monoclonal antibody 3G4 and anionic phospholipids on endothelial cells. J Biol Chem. 2006;281:29863-71. 19. Ran S, He J, Huang X, Soares M, et al. Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin Cancer Res. 2005;11:1551-62. 20. Yin Y, Huang X, Lynn KD, Thorpe PE. Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation. Cancer Immunol Res. 2013;1:256-68. 21. Beck AW, Luster TA, Miller AF, et al. Combination of a monoclonal antiphosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice. Int J Cancer. 2006 May 15;118(10):2639-43. 22. Gerber DE, Stopeck AT, Wong L, et al. Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2011;17:6888-96. 23. He J, Luster TA, Thorpe PE. Radiation-enhanced vascular targeting of human lung cancers in mice with a monoclonal antibody that binds anionic phospholipids. Clin Cancer Res. 2007 Sep 1;13(17):5211-8. 24 He J, Yin Y, Luster TA, et al. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res. 2009 Nov 15;15(22):6871-80. 25. Yin Y, Thorpe PE. Targeting phosphatidylserine to improve androgen deprivation therapy of prostate cancer. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract 621. 26. Tabagari J, Nemsadze G, Janjalia M, et al. Phase II study of bavituximab plus docetaxel in locally advanced or metastatic breast cancer. J Clin Oncol 2010; 28 suppl 15:1042. 27. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000 Mar 27;160(6):809-15. 28. Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005 Feb 9;293(6):715-22. 29. Digumarti R, Wang Y, Raman G, et al. A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer. J Thorac Oncol. 2011 Jun;6(6):1098-103. 30. Bristol-Myers Squibb: Paraplatin (carboplatin) for injection, prescribing information, 2010. 31. Bristol-Myers Squibb: Taxol (paclitaxel) injection, prescribing information, 2011. 23

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32. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92-8. 33. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-celllung cancer: final results of a phase III trial. J Clin Oncol. 2012 Jun 10;30(17):2055-62. 34. Parikh PM, Vaid A, Advani SH, et al. Randomized, double-blind, placebo-controlled phase II study of single-agent oral talactoferrin in patients with locally advanced or metastatic non-small-cell lung cancer that progressed after chemotherapy. J Clin Oncol. 2011 Nov 1;29(31):4129-36. 35. Parikh P, Chang AY, Nag S, et al. Clinical experience with gefitinib in Indian patients. J Thorac Oncol. 2008 Apr;3(4):380-5. 36. Jindal SK, Behera D. Clinical Spectrum Of Primary Lung Cancer-Review Of Chandigarh Experience Of 10 Years. Lung India. 1990;8(2):94-98. 37. Jain M, Raizada N, Kuttan R, et al. Phase II study of bavituximab plus paclitaxel and carboplatin in locally advanced or metastatic breast cancer: interim results. J Clin Oncol 2010; 25 suppl 15;1062. 38. Wall JG, Weiss RB, Norton L, et al. Arterial thrombosis associated with adjuvant chemotherapy for breast carcinoma: a Cancer and Leukemia Group B Study. Am J Med. 1989;87:501-4. 39. Sack GH Jr, Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine (Baltimore). 1977;56(1):1-37. 40. Pereira J, Phan T. Management of bleeding in patients with advanced cancer. Oncologist. 2004;9:561-70. 41. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:218491. 42. Ito M, Niho S, Nihei K, et al. Risk factors associated with fatal pulmonary hemorrhage in locally advanced non-small cell lung cancer treated with chemoradiotherapy. BMC Cancer. 2012;12:27. 43. Agar C, van Os GM, Mörgelin M, et al. Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome. Blood. 2010;116:1336-43. 44. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Jun 2. pii: S0140-6736(14)60845-X. 45. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.

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46. Heymach JV, Paz-Ares L, De Braud F, et al. Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2008;26:5407-15. 47. Laurie SA, Arnold A, Shepherd FA. Randomized, double-blind Phase II trial of carboplatin plus paclitaxel (C+P) with either daily oral cediranib, an inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, or placebo, in advanced non-small cell lung cancer (NSCLC): a study of the national cancer institute of canada clinical trials group. Ann Oncol 2008;19:abstr 231 PD. 48. Scagliotti G, von Pawel J, Reck M, et al. Sorafenib plus carboplatin/paclitaxel in chemonaive patients with stage IIIB-IV non-small cell lung cancer (NSCLC): interim analysis (IA) results from the phase III, randomized, double-blind, placebo-controlled, ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy in NSCLC) trial. J Thor Oncol. 2008;3:S97. 49. Garon EB, Kabbinavar F, Neidhart JA. Randomized phase II trial of a tumor vascular disrupting agent fosbretabulin tromethamine (CA4P) with carboplatin (C), paclitaxel (P), and bevacizumab (B) in stage IIIb/IV nonsquamous non-small cell lung cancer (NSCLC): the FALCON trial. J Clin Oncol 2010;28:abstr 7587.

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Figure Legends Figure 1. Percent reduction in sum of the longest diameters (SLD) of target lesions from baseline (all treated patients). Dashed line represents the 30% threshold for a Response

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Evaluation Criteria in Solid Tumors (RECIST) clinical response. Figure 2. Kaplan-Meier (KM) curve for overall survival (all treated patients).

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Figure 3. Forest plot of response rates for subgroups of interest. Dashed line represents the

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observed response rate of the study population as a whole. The plots for subgroups represent the mean relative risk (RR) ± 1 standard error (SE); Resp, partial and complete responders; BSLD,

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sum of largest diameters at baseline, cm

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Highlights •  Bavituximab with paclitaxel/carboplatin is well-tolerated with clinical activity •  Encouraging 41% response rate, 6.0 month PFS and 12.4 month OS in advanced NSCLC

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We intend to deliver the remaining highlights offline.

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Figure 1

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Figure 1. Tumor Response

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Figure 2

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Figure 2. Overall Survival

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Figure 3

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Figure 3. Subgroup Analysis

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Characteristic Age, years, mean (SD)

Asian (Indian)

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Weight, kg, mean (SD)

All Treated Patients

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Race, n (%)

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Table I. Demographics and Baseline Characteristics

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Table 1

(N = 49) 53.9 (10.8)

49 (100.0)

55.0 (10.9) 1.5 (0.2)

ECOG Performance Status (0/1/2)

2/47/0

Gender (male/female)

35/14

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Body surface area, m2, mean (SD)

Tumor stage at entry, n (%) Stage III

13 (26.5)

Stage IV

36 (73.5)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; SD, standard deviation.

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Table II. Best Overall Tumor Response by RECIST

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Table 2

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Complete response

Stable disease

Response, N (%, 95% CI) 20 (40.8, 27.0-55.8)

Overall response rate

Partial response

All Treated Patients (N = 49)

1 (2.0, 0.1-10.9) 19 (38.8, 25.2-53.8) 16 (32.7, 19.9-47.5) 4 (8.2, 2.3-19.6)

Not evaluable or missing

9 (18.4, 8.8-32.0)

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Progressive disease

Abbreviations: CI, confidence interval; RECIST, Response Evaluation Criteria in Solid Tumors. Note: The overall response rate is defined as complete response plus partial response.

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Table 3

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Table III. Summary of Adverse Events

All Treated Patients (N = 49) Grade 3 AEs (%)

Grade 4 AEs (%)

11 (22.4)

3 (6.1)

0 (0.0)

0 (0.0)

2 (4.1)

0 (0.0)

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Parameter

13 (26.5)

0 (0.0)

0 (0.0)

10 (20.4)

1 (2.0)

0 (0.0)

7 (14.3)

1 (2.0)

0 (0.0)

5 (10.2)

0 (0.0)

0 (0.0)

5 (10.2)

1 (2.0)

0 (0.0)

5 (10.2)

0 (0.0)

0 (0.0)

11 (22.4)

5 (10.2)

0 (0.0)

3 (6.1)

3 (6.1)

0 (0.0)

13 (26.5)

3 (6.1)

1 (2.0)

4 (8.2)

2 (4.1)

1 (2.0)

3 (6.1)

1 (2.0)

2 (4.1)

1 (2.0)

0 (0.0)

1 (2.0)

Total, N (%) Patients with ≥1 AE

44 (89.8) 15 (30.6)

Pyrexia

14 (28.6)

Diarrhea Alopecia Neuropathy

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Vomiting Paresthesia Anorexia

Asthenia

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Fatigue

Hypokalaemia Anaemia Neutropenia

Hyponatraemia Infection

Abbreviations: AE, adverse event Page 33 of 33

Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer.

Bavituximab is a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating and tumor-specific vascular targeting properties. Precli...
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