Phase I study (A8471004) in Asian patients of PF-03446962, a fully human mab against ALK-1 receptor involved in tumor angiogenesis: Safety, pharmacokinetics (PK), and pharmacodynamics (PD).

Abstract

11031 Background: Activin receptor like kinase 1 (ALK-1) is a member of the TGF-βRI family selectively expressed in proliferating endothelial cells, and plays an important role in regulating tumor initiation and metastasis. PF-03446962 is a fully human IgG2 mAb anti ALK-1 evaluated within two phase 1 studies in Western and Asian pts. Herein we report the preliminary safety, PK and PD data of the Phase I study. Methods: Primary objective is to identify the maximum tolerated dose (MTD) in Asian cancer pts; secondary objectives include the safety profile, PK, antitumor activity, and potential PD markers in blood and tumor samples. PF-03446962 is administered IV on Day 1, 29 and then q 2 weeks. Results: Study A8471004 consists of two parts: a 3+3 dose escalation (Part 1) and a dose expansion (Part 2) at 2 dose levels. In Part 1, 16 pts have been enrolled at 3 dose levels (4 pts at 4.5 mg/kg, 3 pts at 7.0 mg/kg, and 9 pts at 10 mg/kg). No DLTs occurred in Part 1 and 10 mg/kg was confirmed as MTD in the Asian population. The observed AUC0-28day for the 4.5, 7 and 10 mg/kg doses, were 12960, 22190 and 28030 μg·h/mL and Cmax were 97.1, 131.5 and 179.8 μg/mL, respectively. Drug exposure (mean Cmax and AUC) increased in a nearly dose proportional manner in Asians. In Part 2, expansion cohorts at doses of 7.0 mg/kg (10pts) and 10.0 mg/kg (8pts) of pts previously treated with VEGF inhibitors (VEGFi) have been enrolled, and the most common drug related adverse events observed (>10%) being thrombocytopenia, pyrexia, epistaxis, and telangiectasia (an anti-ALK-1 mediated toxicity) similarly in the 2 dose levels. Telangiectasia was observed in 1 CRC and 3 HCC patients. 4 patients who progressed after VEGFi treatment (RCC, sarcoma, 2 HCC patients) presented a SD lasting for 290, 248, 247 and 208 days, respectively, suggesting the ALK-1 could serve as mechanism of escape for VEGF. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 is well tolerated in the Asian pts and preliminary observation of clinical activity supports ALK-1 as a viable target. Update of study results and potential PD effects obtained on blood and tumor samples will be presented. Clinical trial information: NCT01337050.