title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas. atolcher@start.stoh.com.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas.
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San Antonio, Texas.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Nageshwar
authors.initials: N
authors.lastname: Budha
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Darbonne
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Franklin
authors.initials: F
authors.lastname: Peale
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Mamounas
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Royer-Joo
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Ron
authors.initials: R
authors.lastname: Yu
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Chia C
authors.initials: CC
authors.lastname: Portera
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015415:Biomarkers; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins