A phase I study of the human anti‐activin receptor‐like kinase 1 antibody PF‐03446962 in Asian patients with advanced solid tumors

Preclinical studies suggest that ALK‐1 signaling mediates a complementary angiogenesis pathway activated upon development of resistance to vascular endothelial growth factor (VEGF)‐targeted therapies. Inhibition of ALK‐1 signaling may lead to disruption of tumor angiogenesis and growth. We report findings from a multicenter, open‐label, phase I study of the fully human anti‐ALK‐1 mAb PF‐03446962 conducted in Japan and South Korea, in Asian patients with advanced solid tumors. The dose escalation Part 1 of the study was based on a standard 3 + 3 design (n = 16). In Part 2, patients were treated with PF‐03446962 at 7 and 10 mg/kg (10/cohort), including patients with disease progression following prior VEGF receptor (R)‐targeted therapy. Primary objectives were determination of the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity of PF‐03446962. No dose‐limiting toxicity (DLT) was noted in the 12 DLT‐evaluable patients. Treatment was well tolerated. The MTD for biweekly intravenous administration was estimated to be 10 mg/kg and the RP2D 7 mg/kg. Treatment‐related grades 1–3 thrombocytopenia was experienced by 27.8% patients. The most frequent nonhematologic treatment‐related AEs were grades 1–2 pyrexia and epistaxis. Four patients (3/4 with hepatocellular carcinoma) developed telangiectasia suggesting vascular targeting and in vivo ALK‐1 inhibition by PF‐03446962. Stable disease for 12 weeks or more was observed in 25.7% of patients and in 44.4% of those with hepatocellular carcinoma. ALK‐1 inhibition by PF‐03446962 may represent a novel antiangiogenic strategy for patients with advanced solid malignancies complementary to current treatment with VEGF(R)‐targeted inhibitors or chemotherapy.