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Thalidomide, Dexamethasone Combination Shows Greater Response Than Dexamethasone Alone in Multiple Myeloma Patients

NEW ORLEANS, June 7 /PRNewswire-FirstCall/ -- Celgene Corporation (NASDAQ:CELG) announced today that the Eastern Cooperative Oncology Group (ECOG) reported a clinical benefit in a Phase III study (E1A00) using thalidomide plus dexamethasone as therapy in multiple myeloma in comparison to dexamethasone monotherapy, a common conditioning regimen for this indication. The clinical data, which were presented at the American Society of Clinical Oncology (ASCO), the largest oncology meeting in the world, showed a statistically significant difference in response rates of 59% versus 41% (P=0.011) at four months with thalidomide plus dexamethasone compared to dexamethasone alone. Multiple myeloma is the second most common blood cancer in the United States affecting approximately 50,000 people. About 14,600 new cases of multiple myeloma are diagnosed each year and close to 11,000 Americans are expected to die of multiple myeloma in 2004.

"The results with these two oral regimens negate the need for complex intravenous chemotherapy like VAD (vincristine, adriamycin, and dexamethasone) as treatment for myeloma," said S.Vincent Rajkumar, M.D., Principal Investigator of the study and Associate Professor of Medicine at Mayo Clinic in Rochester, Minn.

"The ECOG E1A00 randomized Phase III trial has clinically shown that the oral regimen of thalidomide and dexamethasone can positively impact the lives of many newly diagnosed multiple myeloma patients," said Sol J. Barer, Ph.D., President and Chief Operating Officer of Celgene Corporation. "This trial may support thalidomide as an important treatment option for patients with these types of cancer. A regulatory submission of THALOMID in the treatment of multiple myeloma is presently pending FDA review, and we expect the ECOG E1A00 data to be utilized as support for future regulatory applications for thalidomide."

The randomized Phase III trial of THALOMID plus dexamethasone versus dexamethasone as first line therapy in newly diagnosed multiple myeloma (ElA00) was led by Dr. Rajkumar and coordinated by ECOG. The Phase III study enrolled 207 patients as planned with 103 patients randomized to thalidomide /dexamethasone and 104 patients randomized to dexamethasone alone. The median patient age was 65 years. The ECOG Data Monitoring Committee reviewed the planned interim analysis of the response and toxicity endpoints. The study was designed with stopping rules for both response (defined as best response within four months) and toxicity (defined as toxicity within four months). The interim analysis took place when response information was available on 109 patients and showed a statistically higher response rate with thalidomide and dexamethasone versus dexamethasone alone. At the ASCO meeting, response data were available on 196 of the 207 patients that confirmed the findings of the interim analysis, with responses occurring in 59% of patients treated with thalidomide plus dexamethasone compared to 41% of patients treated with dexamethasone alone, (p=0.01; one-sided Fisher's exact test). When the data were analyzed for "Best Response" in reduction in serum paraprotein concentrations, 68% responded to the thalidomide/dexamethasone arm and 46% to the dexamethasone only arm.

"The results of ECOG Phase III clinical study demonstrated that a treatment regimen with THALOMID/dexamethasone is a potential clinical therapy for newly diagnosed multiple myeloma patients," said Ken Anderson, M.D., Kraft Family Professor of Medicine from the Hematological Malignancies Disease Center at Dana Farber Cancer Institute.

As expected, the group that received thalidomide and dexamethasone had an increase in side effects as compared to dexamethasone alone. These side effects included deep vein thrombosis (DVT), rash, sinus bradycardia and neuropathy, and were clinically manageable. Dr. Rajkumar continued, "The study demonstrated a need to balance the higher response rate with thalidomide plus dexamethasone and the greater toxicity, with prophylactic measures that may be needed to prevent side-effects such as DVT."

About the Phase III Study
The Phase III trial enrolled 207 patients with previously untreated symptomatic multiple myeloma, with greater than 10% plasma cells in bone marrow, serum M protein greater than or equal to 1 g/dL, or urine M protein greater than or equal to 200 mg/d. Patients were randomized to thalidomide plus dexamethasone or dexamethasone alone for four cycles (28 days per cycle), followed by stem cell collection in patients eligible for high-dose chemotherapy. Patients in the thalidomide/dexamethasone arm (Arm A) received thalidomide at 200 mg/day with dexamethasone at 40 mg on days 1-4, 9-12, and 17-20. Patients in the dexamethasone arm (Arm B) received dexamethasone alone, at the same dose as Arm A. Therapy was repeated monthly.

The primary endpoint was best response at four months on intention to treat basis. At four months patients could go off study for stem cell transplant or elect to continue therapy. Response was defined as a decrease in serum and urine monoclonal M protein by 50% or higher. If the serum M protein was not measurable, a 90% or higher decrease in urine M protein was required. All patients received bisphosphonate therapy during study treatment. The primary end points of this trial were response and toxicity; the effect of thalidomide on bone marrow microvessel density and angiogenesis and the expression of vascular endothelial growth factor and basic fibroblast growth factor were also assessed.

Safety Notice
If thalidomide is taken during pregnancy, it can cause severe birth defects or death to an unborn baby. Thalidomide should never be used by women who are pregnant or who could become pregnant while taking the drug. Even a single dose, one capsule (50 mg, 100 mg and 200 mg), taken by a pregnant woman can cause severe birth defects. Because thalidomide is present in the semen of male patients, males receiving thalidomide must always use a latex condom during sexual contact with women of childbearing potential even if he has undergone a successful vasectomy. Thalidomide can only be marketed under a special restricted distribution program. This program is called the "System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.(R)). Under this program, only registered prescribers and pharmacists may dispense the drug. In addition, patients must be advised of, agree to and comply with the requirements of S.T.E.P.S.

Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Decreased white blood cell counts, including neutropenia, have been reported in the clinical use of thalidomide. In placebo controlled clinical trials of HIV-seropositive patient populations, there have been reports of increased plasma HIV RNA levels associated with thalidomide therapy. The most common adverse events observed in clinical use in ENL and HIV-seropositive patient populations are rash, maculo-papular rash, drowsiness/somnolence, peripheral neuropathy, dizziness/orthostatic hypotension, neutropenia, and increased HIV-viral load. Patients should be advised about these associated adverse events and routinely monitored by a physician during treatment with thalidomide.

THALOMID (thalidomide), manufactured by Celgene Corporation, received U.S. Food and Drug Administration (FDA) clearance on July 16, 1998 for the acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) and as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. THALOMID is not indicated as monotherapy for ENL treatment in the presence of moderate to severe neuritis. Thalidomide currently has a pending regulatory application (NDA) under review by the Food and Drug Administration (FDA) to confirm efficacy and safety for use in multiple myeloma, thalidomide is not presently indicated or approved by the FDA for use in the disease or any other related cancer.

About Multiple Myeloma
Multiple myeloma (also known as myeloma or plasma cell myeloma) is a cancer of the blood in which malignant plasma cells are overproduced in the bone marrow. Plasma cells are white blood cells that help produce antibodies called immunoglobulins that fight infection and disease. However, most patients with multiple myeloma have cells that produce a form of immunoglobulin called paraprotein (or M protein) that does not benefit the body. In addition, the malignant plasma cells replace normal plasma cells and other white blood cells important to the immune system. Multiple myeloma cells can also attach to other tissues of the body, such as bone, and produce tumors. The cause of the disease is unknown. Multiple myeloma is the second most common blood cancer in the United States affecting approximately 50,000 people. About 14,600 new cases of multiple myeloma are diagnosed each year and close to 11,000 Americans are expected to die of multiple myeloma in 2004.

About ECOG
The Eastern Cooperative Oncology Group (ECOG) was established in 1955 as one of the first cooperative groups launched to perform multi-center cancer clinical trials. A cooperative group is a large network of researchers, physicians, and health care professionals at public and private institutions across the country that is a member of the group. Funded primarily by the National Cancer Institute (NCI), ECOG has evolved from a five member consortium of institutions on the East Coast to one of the largest clinical cancer research organizations in the United States with almost 6000 physicians, nurses, pharmacists, statisticians, and clinical research associates (CRAs) from the United States, Canada, and South Africa.

Source: Celgene Corporation

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