PMID- 23892959
OWN - NLM
STAT- MEDLINE
DCOM- 20131023
LR  - 20221207
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 72
IP  - 3
DP  - 2013 Sep
TI  - Phase I, dose-escalation study of AZD7762 alone and in combination with 
      gemcitabine in Japanese patients with advanced solid tumours.
PG  - 619-27
LID - 10.1007/s00280-013-2234-6 [doi]
AB  - PURPOSE: AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing 
      activity with gemcitabine in xenograft models. METHODS: This open-label, Phase I, 
      dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary 
      efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in 
      Japanese patients with advanced solid tumours (NCT00937664). Patients received 
      intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed 
      by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in 
      ascending AZD7762 dose cohorts. RESULTS: Twenty patients received AZD7762 at 
      doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). 
      Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: 
      one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, 
      neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and 
      alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was 
      therefore regarded as non-tolerable. The most common adverse events (AEs) in 
      cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and 
      fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia 
      (45 %) and hypertension, fatigue and rash (30 % each). Grade >/=3 AEs were reported 
      in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). 
      AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to 
      affect AZD7762 PK. There were no objective responses; five patients (all lung 
      cancer) had stable disease. CONCLUSIONS: The maximum tolerated dose of AZD7762 in 
      combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese 
      patients.
FAU - Seto, Takashi
AU  - Seto T
AD  - Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan. 
      tseto@nk-cc.go.jp
FAU - Esaki, Taito
AU  - Esaki T
FAU - Hirai, Fumihiko
AU  - Hirai F
FAU - Arita, Shuji
AU  - Arita S
FAU - Nosaki, Kaname
AU  - Nosaki K
FAU - Makiyama, Akitaka
AU  - Makiyama A
FAU - Kometani, Takuro
AU  - Kometani T
FAU - Fujimoto, Chinatsu
AU  - Fujimoto C
FAU - Hamatake, Motoharu
AU  - Hamatake M
FAU - Takeoka, Hiroaki
AU  - Takeoka H
FAU - Agbo, Felix
AU  - Agbo F
FAU - Shi, Xiaojin
AU  - Shi X
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130728
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 (Thiophenes)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 8W8T17847W (Urea)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.11 (Checkpoint Kinase 2)
RN  - EC 2.7.11.1 (CHEK1 protein, human)
RN  - EC 2.7.11.1 (CHEK2 protein, human)
RN  - EC 2.7.11.1 (Checkpoint Kinase 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse 
      effects/*therapeutic use
MH  - Checkpoint Kinase 1
MH  - Checkpoint Kinase 2
MH  - Deoxycytidine/administration & dosage/analogs & derivatives
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Japan
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/pathology
MH  - Protein Kinases/*drug effects
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Thiophenes/administration & dosage
MH  - Urea/administration & dosage/analogs & derivatives
MH  - Gemcitabine
EDAT- 2013/07/31 06:00
MHDA- 2013/10/24 06:00
CRDT- 2013/07/30 06:00
PHST- 2012/11/06 00:00 [received]
PHST- 2013/07/10 00:00 [accepted]
PHST- 2013/07/30 06:00 [entrez]
PHST- 2013/07/31 06:00 [pubmed]
PHST- 2013/10/24 06:00 [medline]
AID - 10.1007/s00280-013-2234-6 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2013 Sep;72(3):619-27. doi: 
      10.1007/s00280-013-2234-6. Epub 2013 Jul 28.