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.
Rosenberg
Jonathan E
JE
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
Ryan
Charles J
CJ
Weinberg
Vivian K
VK
Smith
David C
DC
Hussain
Maha
M
Beer
Tomasz M
TM
Ryan
Christopher W
CW
Mathew
Paul
P
Pagliaro
Lance C
LC
Harzstark
Andrea L
AL
Sharib
Jeremy
J
Small
Eric J
EJ
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