Abstract
Abstract
Background
AXL/GAS6 pathway has been implicated in disease progression and chemotherapy resistance in platinum-resistant ovarian cancer (PROC), where response to standard of care chemotherapy in patients is typically 10-15% [Gynecologic Oncology 133 (2014) 624–631]. AVB500’s safety profile allowed the initial clinical study to be conducted in healthy volunteers (NCT03401528) and a proprietary pharmacodynamic assay (serum GAS6) identified pharmacologically active doses. Rather than traditional cancer therapeutic dose selection using an MTD, PK/PD modeling was used to select a human dose targeting specific levels of GAS6 suppression in cancer patients. That AVB500 dose (10mg/kg) is now being investigated in a P1b/P2 PROC study (NCT03639246) in patients who received 1 to 3 prior lines of therapy. The safety, PK, PD and response rate via RECIST v1.1 from the initial cohort in the P1b Recurrent PROC trial are presented.
Methods
The phase 1b safety lead-in portion of the study enrolled patients into two cohorts to investigate the combination of AVB500 with pegylated liposomal doxorubicin (PLD) or paclitaxel (PAC). The primary objectives were to assess safety and tolerability of the combinations and to confirm the RP2D. Secondary endpoints included effects on serum GAS6 and preliminary anti-tumor efficacy measures.
Results
The data from the initial cohorts of patients (N = 12; 6 patients in each cohort) demonstrated full suppression of serum GAS6 confirming the RP2D. AVB500 was safe and well-tolerated in combination with PLD and PAC. There were no serious adverse events. Efficacy data show early proof of concept with overall best response rate (ORR)2 by Investigator determined RECIST v1.1 criteria: Partial responses (PR) in 5 out of 12 patients (41.7%; 95% CI [15.2, 72.3]) Three responders had at least 60% tumor regression Two responders had more than 80% regression Clinical benefit rate (PR+SD) of 58%
Conclusions
The current data provide early clinical proof of concept for anti-tumor activity of GAS6 inhibition in PROC (41.7%) when compared to historical data for SOC alone (10-15%). Given the safety profile and early evidence of anti-tumor activity, the AVB500 risk/benefit profile for this drug is compelling.
Clinical trial identification
NCT03639246.
Legal entity responsible for the study
Aravive Inc.
Funding
Aravive, Inc.
Disclosure
B.J. Monk: Advisory / Consultancy: Aravive. R.L. Coleman: Advisory / Consultancy: Aravive. K.N. Moore: Advisory / Consultancy: Aravive. K.C. Fuh: Advisory / Consultancy, Licensing / Royalties: Aravive. L. Bonifacio: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Aravive. G. McIntyre: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Aravive. D. Prohaska: Shareholder / Stockholder / Stock options, Full / Part-time employment: Aravive. A. Giaccia: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Aravive. M.J. Baker: Shareholder / Stockholder / Stock options, Full / Part-time employment: Aravive. R. Tabibiazar: Shareholder / Stockholder / Stock options, Officer / Board of Directors: Aravive. M.A. Bookman: Advisory / Consultancy: Aravive.