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.

Autor:	Tolcher AW; South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas. atolcher@start.stoh.com., Bendell JC; Sarah Cannon Research Institute, Nashville, Tennessee., Papadopoulos KP; South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas., Burris HA; Sarah Cannon Research Institute, Nashville, Tennessee., Patnaik A; South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas., Fairbrother WJ; Genentech Inc., South San Francisco, California., Wong H; Genentech Inc., South San Francisco, California., Budha N; Genentech Inc., South San Francisco, California., Darbonne WC; Genentech Inc., South San Francisco, California., Peale F; Genentech Inc., South San Francisco, California., Mamounas M; Genentech Inc., South San Francisco, California., Royer-Joo S; Genentech Inc., South San Francisco, California., Yu R; Genentech Inc., South San Francisco, California., Portera CC; Genentech Inc., South San Francisco, California., Infante JR; Sarah Cannon Research Institute, Nashville, Tennessee.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Sep 15; Vol. 22 (18), pp. 4567-73. Date of Electronic Publication: 2016 Apr 13.
DOI:	10.1158/1078-0432.CCR-16-0308
Abstrakt:	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. 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. 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. 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. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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