Cytogen Corporation has announced results from a phase 1 clinical trial of Quadramet (samarium Sm-153 lexidronam injection) in combination with hormonal therapy and external beam radiation therapy in high-risk, clinically non-metastatic prostate cancer patients.

Data from the study indicate that the combination regimen was well tolerated with preliminary anti-tumour activity observed as evidenced by prostate specific antigen or PSA responses. Results were presented at the 48th annual meeting of the American Society for Radiology and Oncology (ASTRO) held November 5-9, 2006, in Philadelphia, PA.

Richard Valicenti, M.D., associate professor of radiation oncology at Jefferson Medical College of Thomas Jefferson University and Jefferson's Kimmel Cancer Center in Philadelphia, has been investigating the neoadjuvant use of Quadramet in high risk prostate cancer patients being treated with a combination of hormonal and external beam radiation therapies. The patients are at high risk for having disease, which has spread to their bones, but none exhibited any clinical or radiographic signs of bone metastases at the time of treatment.

"The strategy is to use Quadramet, a bone-targeted agent, upfront and in combination with standard treatment regimens consisting of a combination of hormones and external beam radiation for high-risk prostate cancer," said Dr. Valicenti. "We're hypothesizing that the combination of hormones and radiation could be used to treat microscopic bony metastasis, which could help reduce death rates due to prostate cancer."

Twenty patients with newly diagnosed high risk (PSA>20 mg/mL) and Gleason score greater than or equal to 7; or greater than or equal to T2 and Gleason score greater than or equal to 8) clinically non-metastatic (known as M0) prostate cancer were treated with a regimen consisting of one month of hormonal therapy followed by a single administration of Quadramet followed by four more months of hormonal therapy in combination with external beam radiation therapy (RT). RT was administered as 46.8 Gy to the pelvic region and 23.4 Gy to the prostate (total dose of 70.2 Gy). Quadramet was administered in escalation doses of 0.25 mCi/kg (4 patients), 0.5 mCi/kg (4 patients), 0.75 mCi/kg (6 patients) and 1.0 mCi/kg (6 patients). The primary endpoint of the study was assessment of the incidence of Grade 3 (or higher) toxicity following all therapy.

Nineteen patients received all planned therapy without any delays and one patient required surgery before the start of RT. Median follow-up time for the entire group was 19 months. Two patients experienced Grade 3 hematologic toxicity and there were no other Grade 3 or 4 side effects. Nadir levels of platelets were significantly lower in the twelve patients receiving Quadramet doses greater than 0.5 mCi/kg than in the eight patients receiving less than or equal to 0.5 mCi/kg. At last follow-up, 15 patients had exhibited recovery of testosterone to non-castrate levels following completion of hormonal therapy. Nine of these 15 patients (60 per cent) had not had a rise in PSA above 0.2 mg/mL. The authors concluded that administration of Quadramet in combination with hormonal therapy and RT was safe and feasible in patients with high risk M0 prostate cancer and that additional follow-up was necessary to determine of the unexpected PSA response rate was durable in nature.

"The results reported by Dr. Valicenti from this investigator initiated study are certainly very encouraging, particularly with regard to the tolerability of Quadramet when administered with external beam radiation," said William Goeckeler, Ph.D., senior vice president of operations at Cytogen. "Based on these results, we are continuing to support the ongoing phase 1 study and are working with Dr. Valicenti to expand on this proof of concept for early intervention in larger follow-on studies and to do so in a clinical setting where efficacy findings can be obtained in a time- and cost-effective manner."




Quadramet is indicated for the relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan.

Quadramet is an oncology product indicated for pain relief that pairs the targeting ability of a small molecule, bone-seeking phosphonate (EDTMP) with the therapeutic potential of radiation (samarium Sm-153). Skeletal invasion by prostate, breast, multiple myeloma, and other cancers often creates an imbalance between the normal process of bone destruction and formation. Quadramet selectively targets such sites of imbalance, thereby delivering radioactivity to areas of the skeleton that have been invaded by metastatic tumour.

Quadramet has demonstrated a range of characteristics that may be advantageous for the treatment of pain arising from metastatic bone disease, including early onset of pain relief (patients may experience pain relief within the first week with maximal relief generally occurring at three to four weeks after injection), length of pain relief, lasting a median of four months in responding patients, and predictable and reversible bone marrow toxicity or myelosuppression that tends to return to pretreatment levels after eight weeks. Quadramet is administered as a single intravenous injection, usually on an outpatient basis, and exhibits selective uptake in areas of bone formation with little or no detectable accumulation in soft tissue.

Quadramet causes bone marrow suppression. In clinical trials, white blood cell counts and platelet counts decreased to a nadir of approximately 40 per cent to 50 per cent of baseline in 123 (95 per cent) of patients within 3 to 5 weeks after Quadramet, and tended to return to pretreatment levels by 8 weeks. Because of the unknown potential for additive effects on bone marrow, Quadramet should not be given concurrently with chemotherapy or external beam radiation therapy unless the clinical benefits outweigh the risks. Blood counts should be monitored weekly for at least 8 weeks, or until recovery of adequate bone marrow function. Non-hematologic adverse events that occurred in 5 per cent or more of patients and greater than placebo were pain flare (7 per cent), diarrhoea (6 per cent), infection (7 per cent), spinal cord compression (6.5 per cent), arrhythmias (5 per cent), and hematuria (5 per cent). Patients who receive Quadramet should be advised that for several hours following administration, radioactivity would be present in excreted urine. To help protect themselves and others in their environment, precautions need to be taken for 12 hours following administration.