An open label safety and efficacy phase 2a study of the N-cadherin (N-cad) antagonist ADH-1 in subjects with N-cadherin expressing solid tumors

3567 Background: Malignant transformation and invasive capacity is highly correlated with N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. ADH-1, a cyclic pentapeptide (CHAVC), is a functional inhibitor of N-cad, and produces apoptosis and tumor vascular disruption in preclinical models. We report results from a Phase 2a study of intravenous (IV) ADH-1 (q 3 W, modified to qW) in subjects with N-cad+ solid tumors. Methods: Subjects with the following N-cad+ refractory tumors with measurable disease were eligible: renal cell (RCC); hepatocellular (HCC); adrenocortical (ACC); gastroesophageal (GE); NSCLC; HNSCC; and breast (HSNCC and breast subjects were only eligible for q3W schedule). ADH-1 was administered at 500 mg/m2 q 3 W, or 600 mg/m2 in the qW schedule. Intra-subject dose escalation was permitted at cycle 3 to 600 mg/m2 (900 mg/m2 with the qW schedule) in the absence of significant toxicity, tumor response or progression. Results: Tumor samples from 159 subjects were tested for N-cad, and 90 were N-cad+ (N-cad+/number tested: GE 13/48, HCC 29/35; NSCLC 16/33; RCC 27/28; ACC 3/8; HNSCC 2/6; Breast 0/1). Forty subjects, 10 on the q3W and 30 on the qW schedule (19 HCC; 7 RCC; 6 NSCLC; 6 GE; 1 ACC; 1 HNSCC) received 121 cycles of ADH-1. The drug was well tolerated, with commonly reported adverse events being Grade 1 or 2 in severity. One subject with HCC had pre-existing renal insufficiency, developed Grade 2 nausea and vomiting 11 days after the 3rd cycle of ADH-1 administered q 3W, leading to non-oliguric renal failure. Following an initial period of recovery, she developed sepsis and died; these events were considered to not be related to study drug. A second subject with HCC developed a hemiparesis due to a Grade 3 intracranial hemorrhage from a previously unknown metastatic brain lesion, 5 days after the 1st dose of ADH-1. There were no complete or partial responses; 32 subjects had SD for =2 cycles, 8 had SD for =4 cycles (4 HCC, ACC, GE, RCC, HNSCC), 6 had SD for =6 cycles (3 HCC, GE, RCC, HNSCC). The longest duration on study was 12 cycles (RCC). Conclusions: ADH-1 was well tolerated and prolonged SD was noted in several subjects. No significant financial relationships to disclose.

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