A Phase I Dose-Escalation Study Evaluating the Safety Tolerability and Pharmacokinetics of CUDC-427, a Potent, Oral, Monovalent IAP Antagonist, in Patients with Refractory Solid Tumors

作者：Tolcher Anthony W; Bendell Johanna C; Papadopoulos Kyriakos P; Burris Howard A; Patnaik Amita; Fairbrother Wayne J; Wong Harvey; Budha Nageshwar; Darbonne Walter C; Peale Franklin; Mamounas Michael; Royer Joo Stephanie; Yu Ron; Portera Chia C; Infante Jeffrey R

来源：Clinical Cancer Research, 2016, 22(18): 4567-4573.

DOI：10.1158/1078-0432.CCR-16-0308

<jats:title>Abstract</jats:title>
<jats:p>Purpose: To determine the dose-limiting toxicities (DLT), 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.</jats:p>
<jats:p>Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CUDC-427 orally on a daily 14-day on/7-day 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 (PBMC), and monocyte chemoattractant protein-1 (MCP-1) levels.</jats:p>
<jats:p>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 5 patients experienced AEs related to CUDC-427 that led to discontinuation and included grade 3 pruritus, and fatigue, and grade 2 drug hypersensitivity, pneumonitis, rash, and QT prolongation. The maximum planned dose of 600 mg orally daily for 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 in one patient with ovarian cancer and one patient with MALT lymphoma.</jats:p>
<jats:p>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. Clin Cancer Res; 22(18); 4567–73.

• 出版日期2016-9-15