Phase I evaluation of CycloSam® (Sm-153-DOTMP) bone seeking radiopharmaceutical in dogs with spontaneous appendicular osteosarcoma.

153 Sm-DOTMP (CycloSam® ) is a newly-patented radiopharmaceutical for bone tumor treatment. DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate) is a macrocyclic chelating agent with superior binding properties to 153 Sm when compared with EDTMP (Quadramet™, used for palliative treatment of bone cancer). CycloSam® was administered at 1 mCi/kg (37 MBq/kg) in a prospective pilot study to seven dogs with bone cancer resulting in no myelosuppression. Then, 13 dogs were enrolled in a prospective clinical trial study using traditional 3+3 dose escalation and starting at 1.5 mCi/kg. Baseline evaluation included hematologic and biochemical testing, diagnosis confirmation, thoracic and limb radiographs, technetium-99 m-HDP bone scintigraphy, and 18 F-FDG PET scan (SUVmax). Toxicity (primary endpoint) was assessed through weekly blood counts and adverse events. Dogs received 1.5 mCi/kg (n = 4), 1.75 mCi/kg (n = 6), and 2 mCi/kg (n = 3) of 153 Sm-DOTMP. Dose-limiting neutropenia and thrombocytopenia were seen at 2 mCi/kg. No dose-limiting nonhematologic toxicities occurred. Efficacy (secondary endpoint) was assessed by objective lameness measurement (body-mounted inertial sensors), owner quality-of-life (QoL) questionnaire, and repeat PET scan. Objective lameness measurement improved in four dogs (53%-60% decrease) was equivocal in three dogs, and worsened in four dogs (66%-115% increase); two dogs were not evaluable. Repeat 18 F-FDG PET scan results varied and change in lameness did not consistently correlate with SUVmax changes. QoL score worsened (n = 5) or was improved/stable (n = 7). Carboplatin chemotherapy (300 mg/m2 IV every 3 weeks ×4) started 4 weeks after 153 Sm-DOTMP injection. No dog died of chemotherapy-related complications. All dogs completed study monitoring. The recommended dose for CycloSam® in dogs is 1.75 mCi/kg, which resulted in some pain control with minimal toxicity and was safely combined with chemotherapy.

Osteochondrodysplasia in a Scottish Fold Cat Treated with Radiation Therapy and Samarium-153-1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetramethylene-Phosphonic Acid.

Osteochondrodysplasia is a painful, progressive clinical syndrome unique to Scottish fold cats because of a heritable missense mutation in the TRPV4 gene. An 8 yr old male neutered Scottish fold cat was presented for a mass on his hind paw. The mass caused decreased mobility in the metatarsal region and digits and resulted in significant discomfort. Because of extensive skeletal abnormalities attributed to breed-related osteochondrodysplasia, the owner was reluctant to pursue amputation. Radiation therapy was pursued for palliation of pain. After coarsely fractionated external beam radiotherapy resulted in stabilization of the mass with eventual progression after 14 mo, samarium-153-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid was administered systemically, and the cat showed immediate, whole-body improvement in mobility. Concurrent intestinal and respiratory disease was evaluated and managed. Samarium-153-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid administration was repeated approximately every 6 mo for three treatments until the cat succumbed to thromboembolic disease attributed to previously diagnosed cardiac disease. Radiation therapy administered using either external beam or bone-seeking radioisotopes can be effective at palliating clinical signs associated with the skeletal abnormalities that accompany this disease.