Dose-finding study of 153Sm-EDTMP in patients with poor prognosis osteosarcoma

Abstract

10539 Background: Osteosarcoma is a radioresistant tumor, requiring ≥70 Gy for disease control. 153Samarium ethylenediaminetetramethlenephosphonate (153Sm-EDTMP) is a bone-seeking radiopharmaceutical that targets osteoblastic skeletal metastases. Our primary goal was to identify a dose of 153Sm-EDTMP that would allow hematopoietic recovery within 6 weeks. Secondary goals included evaluation of efficacy and quantification of the radiation delivered to target lesions. Methods: Patients aged ≤ 40 years with high-risk osteosarcoma detectable on 99mTc bone scan were treated with intravenous 153Sm- EDTMP. Beginning with the FDA-approved dose of 1.0 mCi/kg, the first increase was by 40%. Thereafter dosing was determined by the continuous reassessment method (CRM), using a target frequency of dose limiting toxicity (DLT) of 30%. The CRM algorithm was applied after evaluation of every 2 patients. DLT was defined as failure of hematopoietic recovery (ANC < 750/mm3 or platelet count < 75,000/mm3) after 6 weeks. 153Sm-EDTMP scans were performed 4 hours and 24–48 hours after. Medical internal radiation dosimetry (MIRD) formalism was employed to calculate the actual doses of radiation adsorbed by the target lesions and normal bone. Radiographic response assessment was performed. Results: The MTD in the 13 enrolled patients was 1.21 mCi/kg, 20% higher than the FDA-approved dose. The 90% confidence interval for the DLT rate at the dose of 1.21 mCi/kg is 15% - 54%. The only DLT was hematologic, particularly delayed platelet recovery. Two subjects with significant pulmonary involvement experienced Grade 2–3 pulmonary toxicities at 1.2 and 1.4 mCi/kg that were likely tumor-mediated, not related to study drug. No other significant non-hematologic toxicities were observed. MIRD formalism determined that 3.4 - 39.3 Gy were delivered to target lesions. Tumor adsorbed dose showed no interpatient correlation with administered dose. Tumor avidity for 153Sm-EDTMP appeared variable and unrelated to tumor volume. Stable disease was achieved in 6/13 patients. Conclusions: 153Sm-EDTMP can be safely administered to patients with osteosarcoma. The development of chemoradiotherapy regimens for osteosarcoma patients with bone metastases is feasible. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytogen