Phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy: a study of the department of defense prostate cancer clinical trials consortium.
OBJECTIVE
Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed.


METHODS
Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or > or = grade 3 nonhematologic toxicity.


RESULTS
Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced > or = 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone > or = 30 mg/m2, nine (43%) experienced > or = 50% PSA declines (95% CI, 22% to 66%).


CONCLUSIONS
These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.
Department of Medicine, University of California San Franscisco, Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St, Box 1711, San Francisco, CA 94115, USA. jonathan_rosenberg@dfci.harvard.edu
Jonathan E
JE
Rosenberg
Charles J
CJ
Ryan
Vivian K
VK
Weinberg
David C
DC
Smith
Maha
M
Hussain
Tomasz M
TM
Beer
Christopher W
CW
Ryan
Paul
P
Mathew
Lance C
LC
Pagliaro
Andrea L
AL
Harzstark
Jeremy
J
Sharib
Eric J
EJ
Small
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002369:Castration / Q000009:adverse effects*; D000077143:Docetaxel; D034261:Epothilones / Q000627:therapeutic use; D006801:Humans; D055104:Infusions, Subcutaneous; D008297:Male; D008875:Middle Aged; D008889:Military Personnel; D008942:Mitoxantrone / Q000627:therapeutic use; D011241:Prednisone / Q000627:therapeutic use; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D043823:Taxoids / Q000627:therapeutic use*
D034261:Epothilones; D043823:Taxoids; D000077143:Docetaxel; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; C430592:ixabepilone; D011241:Prednisone