Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors.
BACKGROUND
To establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors.


METHODS
Patients aged ≥ 18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50-200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1-5 or 1-10) in combination with cisplatin (60-75 mg/m(2) intravenously) on day 1 of each cycle.


RESULTS
Dose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m(2) with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m(2) with olaparib 100 mg bid days 1-10 or 50 mg bid days 1-5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1-5 and 60 mg/m(2), respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade ≥ 3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colony-stimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively.


CONCLUSIONS
Olaparib in combination with cisplatin 75 mg/m(2) was not considered tolerable; intermittent olaparib (50 mg bid, days 1-5) with cisplatin 60 mg/m(2) improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation.
University Hospital Vall d'Hebron and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain jbalmana@vhio.net.
J
J
Balmaña
Beth Israel Deaconess Medical Center, Boston.
N M
NM
Tung
Massachusetts General Hospital, Boston.
S J
SJ
Isakoff
University Hospital Vall d'Hebron and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
B
B
Graña
Massachusetts General Hospital, Boston.
P D
PD
Ryan
University Hospital Vall d'Hebron and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
C
C
Saura
AstraZeneca, Wilmington, USA.
E S
ES
Lowe
AstraZeneca, Macclesfield, UK.
P
P
Frewer
Dana-Farber Cancer Institute, Boston.
E
E
Winer
Memorial Sloan-Kettering Cancer Center, New York, USA.
J
J
Baselga
Dana-Farber Cancer Institute, Boston.
J E
JE
Garber
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D010793:Phthalazines; D010879:Piperazines; D002945:Cisplatin; C531550:olaparib
BRCA1; BRCA2; breast cancer; cisplatin; olaparib