An open-label phase 2 study of twice-weekly bortezomib and intermittent pegylated liposomal doxorubicin in patients with ovarian cancer failing platinum-containing regimens.
BACKGROUND
Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD.


METHODS
Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study.


RESULTS
Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease.


CONCLUSIONS
The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.
Division of Gynaecology, Istituto Europeo di Oncologia (IEO), Milan, Italy.
Gabriella
G
Parma
Rosanna
R
Mancari
Gianluca
G
Del Conte
Giovanni
G
Scambia
Angiolo
A
Gadducci
Dagmar
D
Hess
Dionyssios
D
Katsaros
Cristiana
C
Sessa
Andrea
A
Rinaldi
Francesco
F
Bertoni
Andrea
A
Vitali
Carlo Vittorio
CV
Catapano
Silvia
S
Marsoni
Helgi
H
van de Velde
Nicoletta
N
Colombo
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D018394:CA-125 Antigen / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011379:Prognosis; D011719:Pyrazines / Q000008:administration & dosage; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D055815:Young Adult
D001897:Boronic Acids; D018394:CA-125 Antigen; D011719:Pyrazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D010984:Platinum; D000069286:Bortezomib; D004317:Doxorubicin