Phase I Study of CUDC-427

Purpose:To determine the dose-limiting toxicities, adverse events (AE), pharmacokinetics, and preliminary evidence of antitumor activity of CUDC-427 (formerly GDC-0917), a selective antagonist of inhibitor of apoptosis (IAP) proteins. Experimental Design:Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily14-days on/7 days-off schedule in 21-day cycles using a modified continuous reassessment method design. Blood samples were assayed to determine the pharmacokinetic properties, pharmacodynamic alterations of cellular IAP levels in peripheral blood mononuclear cells (PBMCs), and monocyte chemoattractant protein-1 (MCP-1) levels. Results:Forty-two patients received 119 cycles of CUDC-427. Overall, the most common treatment-related toxicities were fatigue, nausea, vomiting, and rash. One DLT (Grade 3 fatigue) occurred in a patient at 450 mg dose level during cycle 1; and five patients experienced AEs related to CUDC-427 that led to discontinuation and included Grade 3 pruritis, and fatigue, and Grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg po daily x 2 weeks was reached, which allometrically scaled to exceed the IC90 in preclinical xenograft studies. Significant decreases in cIAP-1 levels in PBMCs were observed in all patients 6 hours after initial dosing. Responses included durable complete responses (CR) in one patient with ovarian cancer and one patient with MALT lymphoma. Conclusions:CUDC-427 can be administered safely at doses up to 600 mg daily for 14 days every 3 weeks. The absence of severe toxicities, inhibition of cIAP-1 in PBMC, and antitumor activity warrant further studies.

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