PMID- 21590367
OWN - NLM
STAT- MEDLINE
DCOM- 20121029
LR  - 20220330
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 30
IP  - 4
DP  - 2012 Aug
TI  - Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, 
      olaparib (AZD2281) in combination with topotecan for the treatment of patients 
      with advanced solid tumors: a phase I study.
PG  - 1493-500
LID - 10.1007/s10637-011-9682-9 [doi]
AB  - BACKGROUND: The aim of this phase I study was to determine the safety and 
      tolerability and to establish the maximum tolerated dose (MTD) of orally 
      administered olaparib (AZD2281) in combination with topotecan in patients with 
      advanced solid tumors. PATIENTS AND METHODS: Patients aged >/= 18 years with 
      histologically or cytologically diagnosed advanced solid tumors for whom no 
      suitable effective therapy exists were included. Patients in four cohorts 
      received topotecan (0.5 mg/m(2)/day x 3 days or 1.0 mg/m(2)/day x 3 days) 
      intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six 
      cycles. The primary objectives were to determine the safety and tolerability and 
      to establish the MTD of olaparib in combination with topotecan. RESULTS: 
      Twenty-one patients were enrolled and 19 received treatment. Dose-limiting 
      toxicities were neutropenia and thrombocytopenia. The MTD was established as 
      topotecan 1.0 mg/m(2)/day x 3 days plus olaparib 100 mg bid. The most common 
      adverse events (AEs) included fatigue and gastrointestinal events. There was an 
      olaparib and topotecan dose-related increase in neutropenia which was dose 
      limiting. CONCLUSIONS: Further development of olaparib and topotecan in 
      combination was not explored due to dose-limiting hematological AEs and the 
      resulting sub-therapeutic MTD.
FAU - Samol, Jens
AU  - Samol J
AD  - St George's Hospital, Blackshaw Rd, London, UK.
FAU - Ranson, Malcolm
AU  - Ranson M
FAU - Scott, Edwina
AU  - Scott E
FAU - Macpherson, Euan
AU  - Macpherson E
FAU - Carmichael, James
AU  - Carmichael J
FAU - Thomas, Anne
AU  - Thomas A
FAU - Cassidy, James
AU  - Cassidy J
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20110518
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Phthalazines)
RN  - 0 (Piperazines)
RN  - 0 (Poly(ADP-ribose) Polymerase Inhibitors)
RN  - 7M7YKX2N15 (Topotecan)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - WOH1JD9AR8 (olaparib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/administration & dosage/adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Cohort Studies
MH  - Demography
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/administration & dosage/*adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/diagnostic imaging/*drug therapy
MH  - Phthalazines/administration & dosage/*adverse 
      effects/pharmacokinetics/therapeutic use
MH  - Piperazines/administration & dosage/*adverse effects/pharmacokinetics/therapeutic 
      use
MH  - *Poly(ADP-ribose) Polymerase Inhibitors
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Tomography, X-Ray Computed
MH  - Topotecan/administration & dosage/adverse effects/pharmacokinetics/*therapeutic 
      use
MH  - Treatment Outcome
EDAT- 2011/05/19 06:00
MHDA- 2012/10/30 06:00
CRDT- 2011/05/19 06:00
PHST- 2011/02/26 00:00 [received]
PHST- 2011/04/29 00:00 [accepted]
PHST- 2011/05/19 06:00 [entrez]
PHST- 2011/05/19 06:00 [pubmed]
PHST- 2012/10/30 06:00 [medline]
AID - 10.1007/s10637-011-9682-9 [doi]
PST - ppublish
SO  - Invest New Drugs. 2012 Aug;30(4):1493-500. doi: 10.1007/s10637-011-9682-9. Epub 
      2011 May 18.