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NeoRx Corp., Seattle, has announced it is actively enrolling patients on a Phase II study evaluating its Skeletal Targeted Radiotherapy (STR) compound, 166Ho-DOTMP in patients with multiple myeloma.

What is Skeletal Targeted Radiotherapy?

Multiple myeloma is a radiosensitive malignancy, but current methods of delivering large-field radiation, such as total body irradiation (TBI), can result in high exposure to non-target organs that may limit the ability to deliver an effective dose. 166Ho-DOTMP is a bone-seeking tetraphosphonate agent chelated to a beta-emitting radioisotope that demonstrates general skeletal uptake, enhanced uptake in areas of active bone turnover, and no uptake in non-skeletal tissues. 166Ho-DOTMP thus has the potential to deliver large doses of radiation to the bone surfaces and marrow, and be an effective component of conditioning regimens for transplant for multiple myeloma.

166Ho-DOTMP has been evaluated in preliminary clinical studies in 83 patients with multiple myeloma. These Phase 1-2 studies were designed to test the safety and efficacy of a single therapy dose of 166Ho-DOTMP (calculated to deliver 20, 30 or 40 Gy to the bone marrow) in combination with high-dose melphalan, with or without TBI, followed by peripheral blood stem cell transplantation. The time to engraftment after treatment was similar to that reported with high-dose melphalan alone, suggesting that marrow toxicity is not dose-limiting with 166Ho-DOTMP. Thirty-five percent of the patients achieved a complete response (CR) defined as two consecutive negative immunofixation electrophoreses. The overall response rate (CR + PR) was 69%. With a median follow-up of 29 months (minimum 21 months), the median survival time has not been reached and the median even-free survival is 22 months. Thirty percent of patients treated with <30 Gy to the marrow from 166Ho (n = 37) achieved a CR. All patients treated with <30 Gy were alive at 1 year.

There were no early treatment-related toxicities. Late toxicities were seen in these study and usually occurred 6 to 12 months after transplant. These toxicities included hemorrhagic cystitis (HC), observed in 22 of 83 patients (27%). This complication occurred predominately in patients who did not receive continuous bladder irrigation (21 of 51 patients; 41%) and in only one patient who did receive continuous bladder irrigation (1 of 32 patients; 3%). To reduce the incidence of HC, all patients in current and future trials will be required by protocol to receive continuous bladder irrigation during and for 6 hours following 166Ho-DOTMP treatment. Seven patients (8%) exhibited a syndrome compatible with thrombocytic thrombocytopenic purpura or hemolytic uremic syndrome (TTP/HUS) after STR. Six of these 7 patients were treated with a marrow dose of > 40 Gy and no cases occurred at doses < 30 Gy. Additionally, renal toxicity was more common at doses > 40 Gy. The incidence of NCI Grades 3 and 4 renal toxicities was 33% in patients treated with > 40 Gy and 11% in patients treated with < 30 Gy. This toxicity was likely due to the rapid elimination of non-bound 166Ho-DOTMP through the kidneys. Future trials will use a target marrow dose of < 30 Gy as the therapeutic dose because of the lower risk of renal toxicity and TTP/HUS-like symptoms, no apparent loss of efficacy, and better long-term survival.

A second Phase II study is currently ongoing at 5 transplant centers in the U.S. (Seattle, Houston, Nashville, Birmingham, and Sacramento). This study is designed to further characterize the efficacy, distribution, dosimetry, and safety of 166Ho-DOTMP in preparation for a multicenter, randomized, Phase III trial planned to begin in early 2003. This study is open to enrollment of patients with multiple myeloma at any stage of disease. Patients will be treated with 166Ho-DOTMP at a target marrow dose of 25 Gy plus melphalan 200 mg/m2 followed by stem cell transplant.