Aravive Receives IND Clearance for AVB-500 Trial for Clear Cell Renal Cell Carcinoma

Aravive announced that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for investigation of the company’s lead candidate, AVB-500, for the treatment of clear cell renal cell carcinoma (ccRCC).

"The rapidly changing landscape of front line metastatic ccRCC has created a clinical need for studies in the second-line setting," said Brian Rini, M.D, Ingram Professor of Medicine, Vanderbilt-Ingram Cancer Center (VICC), Nashville, TN. "Investigation into the role of AXL in RCC to build on VEGF inhibition in this setting is an exciting new frontier in RCC research."

"Preclinical data demonstrate that inactivation of AXL/GAS6 pathway via treatment with AVB-500 in ccRCC cells plays a key role in both anti-tumor and anti-metastatic effects," said Gail Mcintyre, Ph.D., chief scientific officer of Aravive.

The study has a Phase 1b safety portion and a Phase 2 randomized, controlled portion. The Phase 1b portion will investigate the safety and tolerability of escalating doses of AVB-500 in combination with cabozantanib in patients with advanced clear cell renal cell carcinoma that have progressed with or were intolerant to front-line treatment. The primary endpoints for the Phase 1b portion of the clinical trial are safety, pharmacokinetic and pharmacodynamic measurements with secondary endpoints including preliminary activity measures. The Phase 2 portion of the study will investigate the recommended AVB-500 dose identified during the Phase 1b portion in combination with cabozantinib versus cabozantinib alone in patients with advanced clear cell renal cell carcinoma that have progressed with or were intolerant to front-line treatment. The primary endpoint will be progression free survival. The clinical trial will also explore AVB-500 effects on biomarkers (GAS6) in serum.

Kidney cancer is a leading cause of cancer-related deaths in the United States and is among the 10 most common cancers in both men and women. Metastasis to distant organs including the lung, bone, liver and brain is the primary cause of death in kidney cancer patients as only 12% of metastatic kidney cancer will survive past 5 years. According to the American Cancer Society, it is estimated that there will be approximately 73,750 new cases of kidney cancer in the U.S. and 14,830 people will die from this disease in 2020.

Preclinical studies have demonstrated there is a molecular link between the tumor suppressor gene VHL that is mutated in more than 80% of ccRCC tumors and AXL expression in RCC. The expression of the receptor tyrosine kinase AXL in tumors has been postulated as a biomarker and increased mRNA levels of AXL is associated with poor prognosis in renal cell cancer.

AVB-500 is a therapeutic recombinant fusion protein that has been shown to neutralize GAS6 activity by binding to GAS6 with very high affinity. In doing so, AVB-500 selectively inhibits the GAS6-AXL signaling pathway. In preclinical studies, GAS6-AXL inhibition has shown anti-tumor activity, both as a single agent and 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 is correlated to poor prognosis and survival, and has been implicated in therapeutic resistance to conventional chemotherapeutics and targeted therapies.

Aravive reported positive data from the expansion cohort in the Phase 1b portion of a Phase 1b/2 clinical trial of AVB-500 in platinum-resistant recurrent ovarian cancer. An investigator-sponsored Phase 1 study of AVB-500, in combination with durvalumab in patients with platinum-resistant recurrent epithelial ovarian cancer, is also ongoing. A Phase 2a trial in renal fibrosis initiated late 2019. Based on AVB-500’s safety profile and specifically targeted mechanism of action, this drug candidate has the potential to be used both in combination with existing therapies, as well as a maintenance drug. The U.S. Food and Drug Administration granted Fast Track Designation to AVB-500 in platinum-resistant recurrent ovarian cancer.

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