PMID- 24448638
OWN - NLM
STAT- MEDLINE
DCOM- 20140710
LR  - 20221207
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 73
IP  - 3
DP  - 2014 Mar
TI  - Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in 
      combination with gemcitabine in US patients with advanced solid tumors.
PG  - 539-49
LID - 10.1007/s00280-014-2380-5 [doi]
AB  - PURPOSE: AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to 
      DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 
      monotherapy and with gemcitabine in advanced solid tumor patients. EXPERIMENTAL 
      DESIGN: In this Phase I study, patients received intravenous AZD7762 on days 1 
      and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by 
      AZD7762 plus gemcitabine 750-1,000 mg/m(2) on days 1 and 8, every 21 days, in 
      ascending AZD7762 doses (cycle 1; combination therapy). RESULTS: Forty-two 
      patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 
      3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with 
      gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], 
      neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) 
      patients] and nausea, pyrexia and alanine aminotransferase/aspartate 
      aminotransferase increase [26 % (11/42) patients each]. Grade >/=3 AEs occurred in 
      19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting 
      toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin 
      I increase (32 mg) and grade 3 myocardial ischemia with chest pain, 
      electrocardiogram changes, decreased left ventricular ejection fraction, and 
      increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine 
      did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients 
      achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m(2) and 
      AZD7762 9 mg cohort). CONCLUSIONS: The maximum-tolerated dose of AZD7762 in 
      combination with gemcitabine 1,000 mg/m(2) was 30 mg. Although development of 
      AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 
      remains an important therapeutic target.
FAU - Sausville, Edward
AU  - Sausville E
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland, 22 S. 
      Greene Street, Baltimore, MD, 21201, USA, esausville@umm.edu.
FAU - Lorusso, Patricia
AU  - Lorusso P
FAU - Carducci, Michael
AU  - Carducci M
FAU - Carter, Judith
AU  - Carter J
FAU - Quinn, Mary F
AU  - Quinn MF
FAU - Malburg, Lisa
AU  - Malburg L
FAU - Azad, Nilofer
AU  - Azad N
FAU - Cosgrove, David
AU  - Cosgrove D
FAU - Knight, Richard
AU  - Knight R
FAU - Barker, Peter
AU  - Barker P
FAU - Zabludoff, Sonya
AU  - Zabludoff S
FAU - Agbo, Felix
AU  - Agbo F
FAU - Oakes, Patricia
AU  - Oakes P
FAU - Senderowicz, Adrian
AU  - Senderowicz A
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20140122
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide)
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Thiophenes)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 8W8T17847W (Urea)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (CHEK1 protein, human)
RN  - EC 2.7.11.1 (Checkpoint Kinase 1)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antimetabolites, Antineoplastic/administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/*adverse 
      effects/pharmacokinetics
MH  - Checkpoint Kinase 1
MH  - Deoxycytidine/administration & dosage/adverse effects/analogs & 
      derivatives/pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/enzymology/metabolism/pathology
MH  - Protein Kinases/metabolism
MH  - Thiophenes/administration & dosage/adverse effects
MH  - Urea/administration & dosage/adverse effects/analogs & derivatives
MH  - Gemcitabine
PMC - PMC4486055
MID - NIHMS700711
EDAT- 2014/01/23 06:00
MHDA- 2014/07/11 06:00
PMCR- 2015/06/30
CRDT- 2014/01/23 06:00
PHST- 2013/10/21 00:00 [received]
PHST- 2014/01/08 00:00 [accepted]
PHST- 2014/01/23 06:00 [entrez]
PHST- 2014/01/23 06:00 [pubmed]
PHST- 2014/07/11 06:00 [medline]
PHST- 2015/06/30 00:00 [pmc-release]
AID - 10.1007/s00280-014-2380-5 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2014 Mar;73(3):539-49. doi: 
      10.1007/s00280-014-2380-5. Epub 2014 Jan 22.