A first patient has been dosed in a Phase III trial of AVB-500 (Aravive)  in platinum-resistant ovarian cancer (PROC). The trial is designed to evaluate the efficacy of AVB-500 in combination with paclitaxel (Taxol®; Bristol Meyers Squibb) and the primary endpoint is progression-free survival.

With the development of this novel treatment option, researchers at Aravive hope to address the high unmet medical needs for women with advanced ovarian cancer, a disease that ranks fifth in cancer deaths among women, and it is estimated that there will be approximately 21,410 new cases of ovarian cancer in the United States in 2021.

Due to the nonspecific nature of disease symptoms and lack of validated screening tools in the general population, most women present with advanced disease. Although aggressive cytoreductive surgery and platinum- and taxane-based combination chemotherapy can place most patients into remission, disease recurrence manifests in greater than 70% of patients. Ultimately, patients who relapse become platinum-resistant, and the identification of effective and tolerable treatment options is considered a high unmet clinical need.

Fusion protein
In addressing the specific unmet medical needs, researchers at Aravive have developed a therapeutic recombinant fusion protein (AVB-500) that has been shown to neutralize GAS6 activity by binding to GAS6 with very high affinity in preclinical models. In doing so, AVB-500 selectively inhibits the GAS6-AXL signaling pathway, which is upregulated in multiple cancer types including ovarian cancer.[1]

In preclinical studies, GAS6-AXL inhibition has shown anti-tumor activity in combination with a variety of anticancer therapies, including radiation therapy, immuno-oncology agents, and chemotherapeutic drugs that affect DNA replication and repair. Increased expression of AXL and GAS6 in tumors has been correlated with poor prognosis and decreased survival and has been implicated in therapeutic resistance to conventional chemotherapeutics and targeted therapies.

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Prior AXL antibodies have failed to achieve sufficient affinity to disrupt the interaction between AXL and GAS6. Small molecule multi-kinase inhibitors targeting AXL are often associated with significant off-target toxicity that limits their utility.

Hence researchers at Aravive found that affinity matters because the natural interaction between the ligand GAS6 and the AXL receptor is quite high (Kd~30 pM), thereby requiring a decoy receptor with a higher affinity that outcompetes the natural binding of GAS6.based on this discovery, the researchers targeting the GAS6/AXL signaling pathway using a Fc-fusion decoy receptor with ultra-high affinity for GAS6. This resulted in the development of AVB-500, an ultra-high affinity decoy protein that starves the GAS6/AXL signaling pathway, by capturing circulating and bound GAS6.

Clinical studies
AVB-500 is currently being evaluated in clinical trials and has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) in platinum-resistant recurrent ovarian cancer. Analysis of all safety data to date showed that AVB-500 has been generally well-tolerated with no dose-limiting toxicities or unexpected safety signals.

In the Phase 1b clinical trial, AVB-500 was well-tolerated with a favorable safety profile and had promising clinical responses in patients who achieved minimal efficacious concentration (MEC) in a subset analysis, which supported the Phase III trial design.

“AVB-500 provides a novel and differentiated approach to target the GAS6/AXL pathway, which we know is commonly overactive in ovarian cancer and responsible for some of the mechanisms of resistance that lead to poor outcomes for patients who have an urgent need for more effective therapies to halt the progression of the disease,” said Katherine Fuh, M.D., Ph.D., Associate Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Center for Reproductive Health Sciences, Washington University School of Medicine, St. Louis, MO.

“This Phase III trial will enable us to evaluate the impact of AVB-500 in improving responses to chemotherapy among women with platinum-resistant tumors with the goal of extending patient survival,” Fuh added.

The global, randomized, double-blind, placebo-controlled adaptive trial (GOG-3059/ENGOT OV-66) is designed to evaluate the efficacy and safety of AVB-500 at a dose of 15 mg/kg in combination with paclitaxel.

The trial is expected to enroll approximately 300-400 patients with high-grade serous ovarian cancer who have received one to four prior lines of therapy at approximately 165 sites in the U.S. and Europe. The primary endpoint for the trial is progression-free survival and the secondary endpoint is overall survival.

Exploratory endpoints include objective response rate, duration of response, quality of life, clinical benefit rate, pharmacokinetic and pharmacodynamic profile, and sAXL/GAS6 ratio.

A prospectively defined interim analysis will determine whether randomization will continue with all patients, regardless of prior bevacizumab (Avastin®; Genentech/Roche) treatment, or only with patients medically ineligible to receive bevacizumab or who chose not to receive bevacizumab.

The study is being conducted in partnership with The GOG Foundation, a not-for-profit organization with the purpose of promoting clinical and translational scientific research in gynecologic malignancies, through the GOG Partners program in the USA and in partnership with the European Network for Gynaecological Oncological Trial (ENGOT) groups in Europe.

Simplified statistical analysis
Aravive has simplified the Phase III trial’s statistical analysis plan to include a single prospectively defined interim analysis to determine whether randomization will continue with all patients, regardless of prior bevacizumab treatment, or only with patients medically ineligible to receive bevacizumab or who chose not to receive bevacizumab. The final analysis of the primary endpoint preserves the opportunity to evaluate the efficacy in patients who received bevacizumab prior to study entry, as well as those patients who never received bevacizumab. This provides an additional opportunity to be successful in both patient populations, regardless of the results of the interim analysis.

Analysis of pretreatment serum sAXL/GAS6 will be conducted to determine whether it can identify patients who benefit from AVB-500 plus paclitaxel.  However, the data will not be used in an interim analysis to select patients, because, the Aravive’ scientists believe that the trial is well-powered for the anticipated treatment effect without the need for biomarker enrichment.

The primary endpoint of the trial remains progression-free survival by RECIST 1.1, a standard method of assessing clinical activity in this patient population and the accepted regulatory endpoint for full approval. The secondary endpoint is overall survival.

Biologics License Application
“The registrational AVB-500 Phase III trial, if successful, should be sufficient to submit a Biologics License Application for PROC. We remain on track to conduct the interim analysis in the first quarter of next year,” said Reshma Rangwala, M.D., Ph.D., Chief Medical Officer of Aravive.

“We are pleased to announce the first patient dosing of AVB-500, and we are excited about the meaningful difference AVB-500 may provide for patients with advanced-stage difficult-to-treat ovarian cancer. This is an important milestone for the Aravive, and we remain steadfast in our commitment to bringing safe and differentiated treatment options to the oncology community. We are enthusiastic about our AVB-500 development program, which we believe has significant potential in multiple therapeutic combinations across a broad range of diseases,” Rangwala concluded.

Clinical trial
Efficacy and Safety Study of AVB-S6-500 in Patients With Platinum-Resistant Recurrent Ovarian Cancer – NCT03639246
Study of AVB-S6-500 in Combination With Paclitaxel vs Paclitaxel in Patients With Platinum-Resistant Recurrent Ovarian Cancer – NCT04729608
Safety and Efficacy Study of AVB-S6-500 in Patients With Advanced Clear Cell Renal Cell Carcinoma – NCT04300140.

Highlights of prescribing information 
Paclitaxel (Taxol®; Bristol Meyers Squibb) [Prescribing information]
Bevacizumab (Avastin®; Genentech/Roche) [Prescribing Information]

[1] Fuh KC, Bookman MA, Coleman RL, Herzog TJ, Thaker PH, Liu JF, Lane MW, Rangwala RA, McIntyre GF, et al. Phase 1B Study of GAS6/AXL Inhibitor (AVB-500) in Recurrent, Platinum-resistant Ovarian Carcinoma. Presented at: SGOAACR Annual Meeting 2021; March 19-25; Virtual. [Presentation]

Featured image: Women suffering from ovarian cancer. Photo courtesy: © 2019. – 2021 Fotolia/Adobe. Used with permission.

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