A phase 1b dose-escalation study of TRC105 (endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC)

Background

Resistance to VEGF-targeted therapy is a major challenge in contemporary treatment of mRCC, and endoglin (CD105) activation may be an important mechanism leading to resistance. Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and mRCC cancer stem cells, and is upregulated following VEGF inhibition. TRC105 is an endoglin monoclonal antibody that potentiates the anti-tumor activity of bevacizumab and VEGF receptor tyrosine kinase inhibitors in preclinical models.

Methods

Heavily pretreated mRCC pts with ECOG PS 0-1 and acceptable organ function were treated with TRC105 weekly (8mg/kg and then 10mg/kg) in combination with axitinib (initially at 5 mg BID and then escalated per patient tolerance to a maximum of 10 mg BID).

Results

Eighteen mRCC pts (median age = 61.5; M:F 16:2; median number of prior therapies = 3, including > 1 VEGFR TKI, clear cell = 13, prior axitinib = 1) were treated. TRC105 dose escalation proceeded from 8 mg/kg (n = 3) to 10 mg/kg (n = 15) without dose limiting toxicity. Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, headache, fatigue, diarrhea, and gingival bleeding. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses in 29% of patients by RECIST 1.1, and longer PFS than expected with axitinib as a single agent. The overall disease control rate (CR/PR/SD > 2 months) was 88% (15 of 17). Median PFS overall was 8.4 months, and was 9.6 months among patients with clear cell RCC. Tumor response will be correlated with baseline protein biomarkers. TRC105 pharmacokinetic parameters will be reported.

Conclusions

TRC105 at 8 and 10 mg/kg was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter randomized Phase 2 trial of axitinib +/- TRC105 is actively enrolling at this time (NCT01806064).

Clinical trial identification

Protocol # 105RC101 (NCT01806064)

Legal entity responsible for the study

Sponsor: TRACON Pharmaceuticals, Inc. Lead PI: Toni Choueiri

Funding

Sponsor: TRACON Pharmaceuticals, Inc.

Disclosure

T. Choueiri: Consulting or Advisory Role: Pfizer, GSK, Bayer, Novartis Research Funding (institution): Pfizer. M.D. Michaelson: Consulting or Advisory Role: Mellenium, Astellas, Novartis, Medivation Research Funding (Institution): Pfizer, Eisas, Argos, Mellenium, Novartis, Tracon. E. Posadas: Consulting or Advisory Role: Medivation, Bavarian Nordic Immunotherapeutics Research Funding (Institution): Janssen, Bavarian Nordic Immunotherapeutics, Tracon. D. McDermott: Consulting or Advisory Role: Genentech, Merck, BMS, Pfizer Research Funding: Promethus Labs. B. Seon: Patents - Roswell Park Cancer Institute. M. Jivani: Employee of TRACON Pharmaceuticals, Inc. Stock ownership of TRACON Pharmaceuticals, Inc. R. Shazer: Employee of TRACON Pharmaceuticals, Inc. Stock ownership of BMS B. Adams, C. Theuer: Employee of TRACON Pharmaceuticals, Inc. Stock ownership of TRACON Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.