Clinical Trials

Date: 2017-04-04

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting

Company: Peregrine Pharmaceuticals (USA - CA)

Product: bavituximab

Action mechanism:

• monoclonal antibody. Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab blocks PS to alter this immunosuppressive signal and send an immune activating signal. Targeting PS with bavituximab has been shown to shift the functions of immune cells in tumors, resulting in anti-tumor immune responses.

Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. PS-targeting antibodies have demonstrated an ability to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. Bavituximab is believed to override PS immunosuppressive signaling by blocking the engagement of PS with its receptors and sending an alternate immune activating signal. Peregrine's clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations. These trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination. Additionally, Peregrine continues to advance its pre-clinical collaboration with MSK with the goal of evaluating combinations of bavituximab with checkpoint inhibitors and other immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab's combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.

Disease: non-small-cell lung cancer (NSCLC)

Therapeutic area: Cancer - Oncology

Country: Australia, Belgium, France, Germany, Greece, Hungary, Italy, Republic of Korea, Romania, Russian Federation, Spain, Taiwan, Ukraine, USA

Trial details:

• SUNRISE is a phase III, randomized, double-blind, placebo-controlled multicenter trial of bavituximab plus docetaxel versus docetaxel alone in patients with previously treated stage IIIb/IV non-squamous non small-cell lung cancer. The primary purpose of this research study is to see whether adding bavituximab (an investigational drug) to the standard chemotherapy drug docetaxel, will improve the results of the treatment for non-small-cell lung cancer. (NCT01999673 )

Latest news:

• • On April 4, 2017, Peregrine Pharmaceuticals announced the presentation of results of a new analysis of the Phase III SUNRISE trial of bavituximab in patients with previously treated locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Data demonstrated that for patients in the study's bavituximab plus docetaxel treatment arm who received subsequent immunotherapy, the median overall survival (mOS) was not reached, while mOS was 13.0 months for patients in the study's placebo plus docetaxel arm who received subsequent immunotherapy [HR = 0.43; p=0.005]. These are the first clinical results reported supporting the hypothesis that bavituximab may modulate the tumor microenvironment to enhance the anti-tumor activity of immunotherapy agents. Data were presented by Peregrine scientists at the 2017 Annual Meeting of the American Association for Cancer Research (AACR).
• The presentation highlighted an analysis in which the company evaluated the impact of subsequent immunotherapy treatment, as well as patients' pre-treatment interferon gamma (IFN-?) levels on overall survival. Overall, low peripheral IFN-? correlated with more favorable OS in the patients receiving bavituximab + docetaxel and is a biomarker of interest. Data were also analyzed by low versus high IFN-? levels. For patients with low pre-treatment IFN-? levels who received subsequent immunotherapy, those in the bavituximab plus docetaxel arm did not reach mOS compared to mOS of 12.1 months for the placebo plus docetaxel arm [HR = 0.24; p < 0.001].
• • On October 10, 2016, Peregrine Pharmaceuticals reported that top-line data from the Phase III SUNRISE trial of bavituximab in patients with previously treated locally advanced or metastatic non-squamous non-small cell lung cancer were presented in an oral presentation at the European Society for Medical Oncology (ESMO) 2016 Congress. The presentation included interim efficacy and safety outcomes, as well as initial findings from the company's ongoing biomarker analysis of samples collected during the study. The SUNRISE Phase III trial was discontinued earlier this year based on a pre-specified interim analysis although patient treatment and follow-up in the study were allowed to continue. The pre-planned biomarker analysis has been taking place as patient follow-up has continued and available results were evaluated as part of the recent top-line data analysis.
• The study protocol pre-specified the collection of thousands of patient samples for exploratory analyses over a wide range of possible biomarkers, including pre-treatment levels of beta-2 glycoprotein-1 (?2GP1). Data presented at ESMO demonstrated that patients with pre-treatment ?2GP1 levels between 200 and 240 (representing approximately 30% of randomized patients) achieved a statistically significant, 5.5-month improvement (13.2 months vs. 7.7 months) in median overall survival (OS) as compared to patients in the control group with the same range of ?2GP1 levels [p = 0.049; hazard ratio (HR) = 0.67]. A similar trend was observed with pre-treatment ?2GP1 levels ? 200 µg/mL (representing approximately 50% of randomized patients) with 11.9 months vs. 10.1 months median OS in favor of the bavituximab-containing group (p = 0.155; HR = 0.81). Taken together, this strongly suggests ?2GP1 levels may be useful for identifying patients who are more likely to benefit from a bavituximab containing therapeutic regimen. Numerous additional biomarkers are currently being analyzed with the goal of developing a multi-marker signature that can potentially identify patients that are likely to receive significant clinical benefit from a bavituximab-containing therapeutic regimen.
• Top-line results reported at ESMO  were based on a data cut-off after 70% (330/473) of the targeted OS events had been reached and demonstrated the addition of bavituximab to docetaxel did not result in improvement of the study's primary endpoint of OS in the intent-to-treat population. Median OS for the bavituximab plus docetaxel group was 10.7 months as compared to 10.8 months for the placebo plus docetaxel control group (HR = 1.110; p = 0.382). Median progression free survival (PFS) for the bavituximab-containing group was 4.1 months compared to 3.9 months for the control group (HR = 0.97; p = 0.803). Objective response rates based on independent central review are currently 13% and 11% (p = 0.53) for the bavituximab-containing and control groups, respectively. Additionally, the safety profile of the combination of bavituximab with docetaxel was similar to placebo plus docetaxel. Peregrine intends to further evaluate the role of ?2GP1 levels in response to bavituximab therapy in future clinical trials. The company has filed a new patent application directed to the use of this initial biomarker discovery. Additional patient sample testing and analysis is ongoing and may result in other biomarkers of importance.
• • On February 25, 2016, Peregrine Pharmaceuticals announced that it is discontinuing the company's Phase III SUNRISE trial of bavituximab in patients with previously treated locally advanced or metastatic non-squamous non-small cell lung cancer. The decision to stop the trial was based on the recommendation of the study's Independent Data Monitoring Committee (IDMC) following a pre-specified interim analysis performed after 33% of targeted overall events (patient deaths) in the study were reached.
• Results of the analysis demonstrated that the bavituximab plus docetaxel group did not show a sufficient improvement in overall survival as compared to the docetaxel group to warrant continuation of the study. The interim analysis showed that the bavituximab combination group is performing as expected according to the original trial assumptions in terms of overall survival, while the docetaxel group is dramatically outperforming overall survival expectations based on the original trial assumptions and as compared to recently published studies.

Is general: Yes