Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Fig 1.

(A, B) Treatment schedule. ¹⁵³Sm, samarium-153.

Fig 2.

(A, B) Post-treatment changes in platelets (PLT) for patients in cohorts 2 and 5. Both show a decline in platelet counts. A clear relationship between the severity or duration of thrombocytopenia and either the dose of docetaxel or the dose of samarium-153 (¹⁵³Sm) ethylenediaminetetramethylenephosphonate is not seen.

Fig 3.

Waterfall graphs of prostate-specific antigen (PSA) response by cohort. (A) All patients; (B) patients with taxane-naïve disease; (C) taxane pretreated patients; (D) patients with taxane-refractory disease.