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Quadramet® (Samarium Sm-153 lexidronam, Cytogen) is a radiopharmaceutical used to manage pain in myeloma. The scientific name of the drug is 153Sm-EDTMP. It pairs the targeting ability of a chemical that attaches to bone (EDTMP) with the therapeutic potential of radiation (radioactive samarium). This combination has a short radioactive half-life and targets areas of rapid bone turnover, such as those that occur in cancers that metastasize to the bone (ie, prostate, breast, and others) and in myeloma. The radiation selectively concentrates in these areas of the bone, reducing the exposure of normal organs and soft tissues outside the bone.
Quadramet is currently approved in the US for relieving bone pain in patients who have confirmed metastatic bone lesions that are characterized by excessive bone formation and are visible on a bone scan, as is sometimes the case in myeloma.
Quadramet has been investigated at higher doses in combination with high-dose melphalan chemotherapy because it is thought that this combination may be more effective than standard conditioning regimens for myeloma prior to stem cell transplant. It is also being investigated in clinical studies in myeloma as a single agent at standard doses and in combination with potentially synergistic agents, such as Velcade® (bortezomib, Millennium), to cause disease regression or cure.
High dose, in combination with melphalan. A small Phase I study was conducted at the Mayo Clinic to investigate the use of higher-dose Quadramet in conjunction with melphalan as a conditioning regimen for stem cell transplant (Dispenzieri et al. Leukemia. 2005;19(1):118-125.) In this study, 12 patients were treated with escalating doses of Quadramet determined by body weight and a fixed dose of melphalan (200 mg/m2). No dose-limiting toxicity was seen. To better standardize the radiation dose to the bone marrow, an additional 6 patients received a targeted radiation dose to the red marrow of 40 Gy that was based on a trace labeled infusion administered beforehand. The addition of Quadramet to melphalan conditioning appeared to be safe and well tolerated and no kidney or bladder toxicity was observed. An overall response rate of 94% was achieved following transplant, including 7 very good partial responses (39%) and 5 complete responses (28%).
Based on these results, a Phase II study was initiated. Preliminary results of the study were reported at the American Society of Hematology (ASH) meeting in 2003. (Dispenzieri et al. Blood. 2003;102(11). Abstract 3656.) Addition of Quadramet (a bone marrow targeted dose of 40 Gy) to melphalan (200 mg/m2) resulted in complete responses in 13 of 45 (29%) of evaluable patients receiving a transplant following induction or at relapse. No dose-limiting toxicity or kidney problems were observed. It is still to early to determine the effect of this agent on survival.
In combination with Velcade. Previously, preclinical data from a mouse myeloma model have shown that Velcade appears to sensitize myeloma cells to the effects of Quadramet radiotherapy. (Goel A, et al. Blood. 2006;107(10):4063-70.) In December 2005, a phase I clinical trial evaluating this combination was initiated in patients with relapsed or refractory myeloma. Interim results presented at the 11th Congress of the European Hematology Association in June 2006 show that the combination, referred to as VELSAM, was well tolerated at doses studied to date and demonstrated antimyeloma activity. (Yeh HS. Et al. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. 2006;24(18S):7614.) Of the 12 patients treated at the time of the meeting with escalating doses of Quadramet (0.25 and 0.5 mCi/kg thus far) and Velcade (1.0 or 1.3 mg/m2), two experienced a response (1 CR, 1 PR) and four achieved stable disease. Toxicities were generally transient and manageable; no dose-limiting toxicity was noted to date.
A Phase II trial evaluating combination Quadramet and Velcade therapy in relapsed or refractory myeloma is being conducted at the Mayo Clinic. A total of 50 patients will be enrolled.
High dose, in combination with melphalan. A small Phase I study was conducted at the Mayo Clinic to investigate the use of higher-dose Quadramet in conjunction with melphalan as a conditioning regimen for stem cell transplant (Dispenzieri et al. Leukemia. 2005;19(1):118-125.) In this study, 12 patients were treated with escalating doses of Quadramet determined by body weight and a fixed dose of melphalan (200 mg/m2). No dose-limiting toxicity was seen. To better standardize the radiation dose to the bone marrow, an additional 6 patients received a targeted radiation dose to the red marrow of 40 Gy that was based on a trace labeled infusion administered beforehand. The addition of Quadramet to melphalan conditioning appeared to be safe and well tolerated and no kidney or bladder toxicity was observed. An overall response rate of 94% was achieved following transplant, including 7 very good partial responses (39%) and 5 complete responses (28%).
Based on these results, a Phase II study was initiated. Preliminary results of the study were reported at the American Society of Hematology (ASH) meeting in 2003. (Dispenzieri et al. Blood. 2003;102(11). Abstract 3656.) Addition of Quadramet (a bone marrow targeted dose of 40 Gy) to melphalan (200 mg/m2) resulted in complete responses in 13 of 45 (29%) of evaluable patients receiving a transplant following induction or at relapse. No dose-limiting toxicity or kidney problems were observed. It is still to early to determine the effect of this agent on survival.
In combination with Velcade. Previously, preclinical data from a mouse myeloma model have shown that Velcade appears to sensitize myeloma cells to the effects of Quadramet radiotherapy. (Goel A, et al. Blood. 2006;107(10):4063-70.) In December 2005, a phase I clinical trial evaluating this combination was initiated in patients with relapsed or refractory myeloma. Interim results presented at the 11th Congress of the European Hematology Association in June 2006 show that the combination, referred to as VELSAM, was well tolerated at doses studied to date and demonstrated antimyeloma activity. (Yeh HS. Et al. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. 2006;24(18S):7614.) Of the 12 patients treated at the time of the meeting with escalating doses of Quadramet (0.25 and 0.5 mCi/kg thus far) and Velcade (1.0 or 1.3 mg/m2), two experienced a response (1 CR, 1 PR) and four achieved stable disease. Toxicities were generally transient and manageable; no dose-limiting toxicity was noted to date.
A Phase II trial evaluating combination Quadramet and Velcade therapy in relapsed or refractory myeloma is being conducted at the Mayo Clinic. A total of 50 patients will be enrolled.
Reviewed by:
William I. Bensinger, MD
Member, Fred Hutchinson Cancer Research Center
Professor of Medicine, University of Washington
10/24/06
William I. Bensinger, MD
Member, Fred Hutchinson Cancer Research Center
Professor of Medicine, University of Washington
10/24/06