Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer.
OBJECTIVE
Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam.


METHODS
Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression.


RESULTS
Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption.


CONCLUSIONS
Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.
Morris
Michael J
MJ
Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. morrism@mskcc.org
Pandit-Taskar
Neeta
N
Carrasquillo
Jorge
J
Divgi
Chaitanya R
CR
Slovin
Susan
S
Kelly
William K
WK
Rathkopf
Dana
D
Gignac
Gretchen A
GA
Solit
David
D
Schwartz
Lawrence
L
Stephenson
Ryan D
RD
Hong
Christina
C
Delacruz
Anthony
A
Curley
Tracy
T
Heller
Glenn
G
Jia
Xiaoyu
X
O'Donoghue
Joseph
J
Larson
Steven
S
Scher
Howard I
HI
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000009:adverse effects; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000009:adverse effects; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects
D018712:Analgesics, Non-Narcotic; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D019275:Radiopharmaceuticals; D043823:Taxoids; D000077143:Docetaxel; C061972:samarium Sm-153 lexidronam; D017430:Prostate-Specific Antigen