Results from this study demonstrated that the combination was tolerable and of 32 evaluable patients, 15 participants, or more than 46% achieved a response or stabilization of their disease. Of these, six patients responded to the combination regimen, with three achieving a complete response (CR) and three achieving a minor response (MR). Of the 15 patients who achieved either a response to treatment or stabilization of their disease, nine had previously failed treatment with bortezomib.
"For years we have known that radiopharmaceuticals, such as QUADRAMET, are an effective palliative treatment for patients with metastatic bone disease," said Michael D. Becker, president and chief executive officer of Cytogen. "The data from this Phase 1 study suggest that administration of QUADRAMET is safe and may also have anticancer activity when used in combination with bortezomib and should be studied further in this setting. Cytogen is committed to developing and commercializing innovative products, like QUADRAMET, for cancer patients, and these results support our ongoing development plan investigating additional synergistic combinations and patient populations that may benefit from this important therapy."
Previously published preclinical studies demonstrated that the proteasome inhibitor bortezomib selectively sensitizes myeloma cells to the lethal effects of radiation from QUADRAMET, resulting in prolonged survival, reduced clonogenicity of bone marrow-resident 5TGM1 cells, reduced serum myeloma-associated paraprotein levels, and better preservation of bone mineral density. Multiple myeloma is also a highly radiosensitive skeletal malignancy, yet bone-seeking radiopharmaceuticals such as QUADRAMET have not yet found their place in either pain palliation or disease management. Accordingly, the primary objective of the Phase 1 dose escalation study was to determine safety and tolerability of the combination regimen for patients with relapsed or refractory multiple myeloma. As a secondary objective, the study is also assessing response rates.
A complete treatment cycle is eight weeks in duration and consists of injections of bortezomib on days one, four, eight and eleven with a single dose of QUADRAMET administered on day three. By way of comparison, bortezomib monotherapy is typically administered on days one, four, eight and eleven of a treatment cycle that is repeated every three weeks, typically for six to eight cycles. Patients were permitted to receive up to four treatment cycles providing their disease was stabile or responsive without undue toxicity and they continued to meet baseline eligibility criteria.
There were two parallel arms to the study. The first arm administered bortezomib at 1.0 mg/m(2) and the second arm administered bortezomib at 1.3 mg/m(2). Both arms used escalating doses of QUADRAMET (0.25 mCi/kg, 0.5 mCi/kg, and 1.0 mCi/kg). The standard approved dose of QUADRAMET for palliation of bone pain is 1.0 mCi/kg. Patients were enrolled alternately into parallel cohorts.
A summary of the poster is as follows:
-- The study enrolled 33 patients with relapsed or refractory multiple myeloma and measurable disease who overall received 60 cycles of treatment. At the time of the presentation, 32 patients were evaluable for response. Previous treatment with bortezomib was permissible.
-- Patients enrolled in the study had progressive disease despite receiving an average of 3.4 prior treatment regimens (median 3, range 1-8) and 21 of the 33 had relapsed following prior treatment with bortezomib.
-- Of the 32 evaluable patients, 14 received more than one treatment cycle. Response or stabilization of disease along with recovery from hematologic toxicity was required for administration of subsequent treatment cycles.
-- Six patients responded to the combination regimen, three of whom achieved a complete response (CR) and three a minor response (MR). Two of the patients achieving a CR received the protocol maximum four cycles (32 weeks) of treatment while the third has received two cycles (16 weeks) to date and remains on study. Similarly, one of the patients achieving a MR received the maximum four cycles (32 weeks) of treatment, one has received three cycles (24 weeks) to date and remains on study and the third has received two cycles (16 weeks) to date and remains on study.
-- Nine patients had stabilization of their disease, one has received one treatment cycle (8 weeks) to date and remains on study, four received two treatment cycles (16 weeks) with two still remaining on study, three received three treatment cycles (24 weeks) with two still remaining on study, and one received all four permitted treatment cycles (32 weeks).
-- Of the 15 patients who achieved a response or stablization of their disease, nine had previously failed treatment with bortezomib.
-- Toxicities were generally transient and manageable. Dose-limiting toxicity was observed in cohort six (1.0 mCi/kg of QUADRAMET and 1.3 mg/m(2) of bortezomib) thus, additional patients were enrolled in an extension of cohort three (1.0 mCi/kg of QUADRAMET and 1.0 mg/m(2) of bortezomib), which was not found to be dose-limiting, to confirm the tolerability of this dose.
-- Overall, there were 15 patients in this expanded cohort who had received a mean 3.4 prior treatment regimens and 10 of the 15 had relapsed following prior treatment with bortezomib. For the entire cohort, the mean neutophil nadir was 1,410/mm(3) and the mean platelet nadir was 108,000/mm(3)
-- The incidence of treatment emergent neuropathy (a side effect commonly observed following bortezomib administration) was low (9%). Two patients with Grade 1 neuropathy at baseline progressed to Grade 2 with one case resolving while on study and a single additional patient experienced Grade 3 neuropathy.
-- Preparations are underway for a follow-up Phase 2 study to further evaluate the efficacy and safety of 1.0 mCi/kg of QUADRAMET and 1.0 mg/m(2) of bortezomib for patients refractory or recently relapsed from bortezomib-containing regimens.
Responses were assessed using Blade criteria, a rigorous assessment standard used to describe changes in disease status, including a confirmation six weeks later. A "complete response" required 100 percent disappearance of M-protein (a marker of tumor burden); negative immunofixation testing; no increase in size or number of lytic bone lesions; and disappearance of soft tissue tumors (plasmacytomas). "Partial" remissions and "minimal" responses represented lesser degrees of response based on the same criteria. Worsening of these indicators constituted "progressive disease".
QUADRAMET is indicated for the relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan. This press release references clinical applications that differ from that reported in the QUADRAMET package insert.
QUADRAMET 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, multip le 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 tumor.
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 Safety Profile
QUADRAMET causes bone marrow suppression. In clinical trials, white blood cell counts and platelet counts decreased to a nadir of approximately 40% to 50% of baseline in 123 (95%) 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% or more of patients and greater than placebo were plain flare (7%), diarrhea (6%), infection (7%), spinal cord compression (6.5%), arrhythmias (5%), and hematuria (5%). Patients who receive QUADRAMET should be advised that for several hours following administration, radi oactivity will be present in excreted urine. To help protect themselves and others in their environment, precautions need to be taken for 12 hours following administration.
About Multiple Myeloma
Multiple myeloma is a cancer of the bone marrow in which white blood cells called plasma cells, normally responsible for the production of antibodies (proteins that fight infection and disease), are overproduced. The proliferation of these abnormal plasma cells, known as myeloma cells, causes decreased production of normal red and white blood cells, and of normal disease-fighting antibodies, as well as the growth of tumors that spread to multiple sites - hence the term multiple myeloma. The decreased white blood cell production damages the immune system while the myeloma tumors cause bone destruction that manifests as pain and fractures.
The American Cancer Society estimates there will be about 19,900 new cases of multiple myeloma in the United States in 2007. Of these, about 10,960 will be in men and about 8,940 in women. About 10,970 Americans are expected to die of multiple myeloma in 2007.
Multiple myeloma is highly radiosensitive and is locally radiocurable. Novel systemic radionuclide-based therapies may therefore provide a significant advance in clinical therapy of myeloma.
Cytogen is a specialty pharmaceutical company dedicated to advancing the treatment and care of patients by building, developing, and commercializing a portfolio of oncology products. The Company's specialized sales force currently markets three therapeutic products and one diagnostic product to the U.S. oncology market. CAPHOSOL(R) is an advanced electrolyte solution for the treatment of oral mucositis and dry mouth that is approved in the U.S. as a prescription medical device. QUADRAMET(R) (samarium Sm-153 lexidronam injection) is approved for the treatment of pain in patients whose cancer has spread to the bone. PROSTASCINT(R) (capromab pen detide) is a PSMA-targeting monoclonal antibody-based agent to image the extent and spread of prostate cancer and SOLTAMOX(TM) (tamoxifen citrate) is the first liquid hormonal therapy approved in the U.S. for the treatment of breast cancer in adjuvant and metastatic settings. The Company is also developing CYT-500, a third-generation radiolabeled antibody to treat prostate cancer. Cytogen's product-focused strategy centers on attaining sustainable growth through clinical, commercial, and strategic initiatives.
A copy of the full prescribing information for CAPHOSOL, QUADRAMET, PROSTASCINT, and SOLTAMOX, including box warnings, may be obtained in the U.S. from Cytogen Corporation by calling toll free 800-833-3533 or by visiting Cytogen's web site at www.cytogen.com. The Company's website is not part of this press release.
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Susan M. Mesco, 609-750-8213