Phase II randomized study of dalantercept in combination with axitinib compared to axitinib alone as second-line treatment in patients with metastatic renal cell carcinoma.

Abstract

TPS4595 Background: The treatment of metastatic renal cell cancer (mRCC) with therapies targeting the vascular endothelial growth factor (VEGF) pathway delays disease progression; however, overcoming tumor resistance to these agents remains a therapeutic challenge. Activin receptor-like kinase 1(ALK1) is a type 1 receptor in the TGF-ß superfamily and is selectively expressed on activated endothelial cells. While VEGF drives the proliferative stage of angiogenesis, ALK1 is primarily involved in the maturation phase. Dalantercept is a human ALK1-Fc receptor fusion protein that binds to bone morphogenetic proteins (BMP) 9 and 10 (ligands for ALK1) and acts as a ligand trap. Preclinically, dalantercept showed delayed tumor growth in solid tumor models, including RCC models alone and in combination with sunitinib. In RCC models, the addition of dalantercept to sunitinib enhanced the reduction in tumor blood flow compared to sunitinib alone. Dalantercept showed anti-tumor activity in a completed phase 1 study in 37 pts. with advanced solid tumors. Based on this promising data, we hypothesize that ALK1 inhibition may be synergistic with axitinib, a VEGFR tyrosine kinase inhibitor (TKI), in pts. with mRCC. Methods: A two-part, multi-center, open label phase 2 study to evaluate safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of dalantercept plus axitinib as second line therapy is ongoing. In Part 1, dose escalation using a 3+3 design will assess the safety and PK of dalantercept SC every 3 weeks plus axitinib 5 mg PO BID until disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) has been determined, up to 20 pts. may be enrolled in an expansion cohort to establish safety for the recommended dose for Part 2. Part 2 will include 112 pts. randomized 1:1 to dalantercept plus axitinib vs. axitinib alone. Key eligibility criteria are one prior TKI in the first-line setting, ECOG </= 1, and measurable disease. The primary efficacy endpoint is PFS. Secondary endpoints are OS, TTP, ORR, DOR, DCR, and PD biomarkers on archived tumor and serum specimens including BMP9/10 and ALK1 expression. Clinical trial information: NCT01727336.