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BMP9 as a potential biomarker for dalantercept efficacy against ALK1-mediated angiogensis in head and neck cancer.

30 Background: Activin receptor-like kinase 1 (ALK1) is a type 1 receptor in the TGF-β superfamily. The ALK1 pathway plays a role in vascular development and pathological angiogenesis. Mutations affecting this pathway result in hereditary hemorrhagic telangiectasia, a disease characterized by failed vascular development and arteriovenous malformations. Therefore, disruption of this pathway in adults may help in conditions with pathological angiogenesis. Bone morphogenetic protein 9 (BMP9) is a ligand that binds with high affinity to ALK1 and stimulates endothelial cell sprouting during vessel maturation. BMP9 is upregulated in the RIP1-Tag2 murine model of vascular invasive carcinoma; treatment with a murine version of dalantercept (RAP-041) can inhibit tumor growth.


METHODS
Dalantercept (ACE-041) is a soluble receptor protein comprising the extracellular domain of ALK1 linked to an IgG1 Fc region, which functions as a ligand trap to inhibit endogenous BMP9 signaling.


RESULTS
In a phase I study of dalantercept in advanced solid tumors, three patients with squamous cell carcinoma of the head and neck (SCCHN) were enrolled. One SCCHN patient received 10 cycles (30 weeks) at 0.4 mg/kg and had a partial response (32.5% decrease in target lesion size). A second SCCHN patient received 11 cycles (33 weeks) at 1.6 mg/kg and had a 28.9% decrease in lesion size. A third SCCHN patient had progressive disease after 1 cycle at 0.8 mg/kg. Dalantercept was generally well-tolerated. Common AEs included fatigue, peripheral edema, nausea, anemia, headache, anorexia, and dyspnea. Analysis of archived tumor samples from SCCHN patients demonstrated that 25% had high BMP9 expression and 44% had medium levels of expression.


CONCLUSIONS
A phase II study to evaluate the efficacy, safety and pharmacodynamics (PD) of dalantercept in SCCHN is ongoing. The primary objective is ORR. Secondary objectives include PFS, OS, safety, tolerability and pharmacokinetics. Exploratory analyses in this study will examine BMP9 expression in archived and fresh tumor biopsies as well as serum levels of BMP9 and other markers; association of biomarkers with response to therapy will be examined as potential companion diagnostics.