PMID- 27076626
OWN - NLM
STAT- MEDLINE
DCOM- 20180112
LR  - 20180112
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 22
IP  - 18
DP  - 2016 Sep 15
TI  - 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.
PG  - 4567-73
LID - 10.1158/1078-0432.CCR-16-0308 [doi]
AB  - 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. (c)2016 AACR.
CI  - (c)2016 American Association for Cancer Research.
FAU - Tolcher, Anthony W
AU  - Tolcher AW
AD  - South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San 
      Antonio, Texas. atolcher@start.stoh.com.
FAU - Bendell, Johanna C
AU  - Bendell JC
AD  - Sarah Cannon Research Institute, Nashville, Tennessee.
FAU - Papadopoulos, Kyriakos P
AU  - Papadopoulos KP
AD  - South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San 
      Antonio, Texas.
FAU - Burris, Howard A
AU  - Burris HA
AD  - Sarah Cannon Research Institute, Nashville, Tennessee.
FAU - Patnaik, Amita
AU  - Patnaik A
AD  - South Texas Accelerated Research Therapeutics, START Center for Cancer Care, San 
      Antonio, Texas.
FAU - Fairbrother, Wayne J
AU  - Fairbrother WJ
AD  - Genentech Inc., South San Francisco, California.
FAU - Wong, Harvey
AU  - Wong H
AD  - Genentech Inc., South San Francisco, California.
FAU - Budha, Nageshwar
AU  - Budha N
AD  - Genentech Inc., South San Francisco, California.
FAU - Darbonne, Walter C
AU  - Darbonne WC
AD  - Genentech Inc., South San Francisco, California.
FAU - Peale, Franklin
AU  - Peale F
AD  - Genentech Inc., South San Francisco, California.
FAU - Mamounas, Michael
AU  - Mamounas M
AD  - Genentech Inc., South San Francisco, California.
FAU - Royer-Joo, Stephanie
AU  - Royer-Joo S
AD  - Genentech Inc., South San Francisco, California.
FAU - Yu, Ron
AU  - Yu R
AD  - Genentech Inc., South San Francisco, California.
FAU - Portera, Chia C
AU  - Portera CC
AD  - Genentech Inc., South San Francisco, California.
FAU - Infante, Jeffrey R
AU  - Infante JR
AD  - Sarah Cannon Research Institute, Nashville, Tennessee.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20160413
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Inhibitor of Apoptosis Proteins)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Biomarkers
MH  - Cytokines/blood/metabolism
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins/*antagonists & inhibitors
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/diagnosis/*drug therapy/metabolism
MH  - Retreatment
MH  - Treatment Outcome
EDAT- 2016/04/15 06:00
MHDA- 2018/01/13 06:00
CRDT- 2016/04/15 06:00
PHST- 2016/02/12 00:00 [received]
PHST- 2016/03/28 00:00 [accepted]
PHST- 2016/04/15 06:00 [entrez]
PHST- 2016/04/15 06:00 [pubmed]
PHST- 2018/01/13 06:00 [medline]
AID - 1078-0432.CCR-16-0308 [pii]
AID - 10.1158/1078-0432.CCR-16-0308 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2016 Sep 15;22(18):4567-73. doi: 10.1158/1078-0432.CCR-16-0308. 
      Epub 2016 Apr 13.