There are roughly 250,000 new cases of metastatic cancer to the skeleton in the U.S. each year. "Bone-seeking" radiopharmaceuticals are used for bone pain palliation and have shown promise for treating bone metastases. They typically combine a radioactive metal such as samarium-153 with a chelant. The chelant part of the molecule is taken up by growing bone and carries the radioactive "payload" along with it. Approximately 50% of the radioactivity in the radiopharmaceutical concentrates in bone and irradiates the adjacent tumor. This radiation absorbed dose produces the therapeutic effect. Two rare earth metal-based bone-seeking radiopharmaceuticals (Sm-153-EDTMP and Ho-166- DOTMP) have been investigated for treating bone tumors and have shown promising clinical results. However, one has an inefficient chelant that limits how much radioactivity can be delivered to the bone. The other has a radionuclide that is too strong and causes intolerable side effects. We are developing the bone-seeking radiopharmaceutical CycloSam(R) (Sm-153-DOTMP) for the treatment of bone metastases. Compared to the two compounds that have already been tried, CycloSam combines the better radionuclide, samarium-153, with the better phosphonic acid chelant, DOTMP. We anticipate that CycloSam will be able to deliver the prescribed radiation absorbed dose to bone tumors while avoiding intolerable radiation damage to normal, non-target tissues. Phase II of this project will: 1. manufacture clinical grade CycloSam;2. verify that the clinical grade CycloSam has the same biodistribution and dose delivery properties that we measured in Phase I;and 3. treat bone tumors using increasing quantities of clinical grade CycloSam to determine the maximum amounts that may be safely given with no clinically significant suppression of the bone marrow and with marrow suppression that is mild enough for spontaneous recovery. Phase II will make clinical grade material under good laboratory practices (GLP) and current good manufacturing practices (cGMP) conditions. The pharmacological toxicity of the clinical grade material will be tested in rats and dogs. The biodistribution of the clinical grade material will be tested in rats. The dose escalation study wil be performed in dogs that present to a veterinary clinic with osteosarcomas in order to estimate the maximum dosage at which concurrent chemotherapy might be given and the maximum dosage at which the expected myelosuppression would not require a bone marrow transplant. These dosage thresholds, combined with the dosimetry data, will be used in the design of the protocols to be presented along with the manufacturing and toxicology data in an IND application to the FDA for the first human trials.
Bone metastases have been treated by radioactive drugs, or radiopharmaceuticals. Thus far, their effects have been primarily palliative. We are developing the radiopharmaceutical, CycloSam(R), to act directly upon and resolve metastatic lesions in addition to providing pain palliation.