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Thalomid Plus Temozolomide Promising As Oral Regimen For Treating Patients With Advanced-Stage Metastatic Melanoma

WARREN, NJ -- September 8, 2003 -- Celgene Corporation (Nasdaq: CELG) today announced the results of a clinical study using Thalomid® in combination with temozolomide as an oral regimen for metastatic melanoma, published in the September 1, 2003 issue of the Journal of Clinical Oncology (JCO). This clinical study investigated the combination of a low-dose daily schedule of temozolomide with Thalomid (200 mg - 400 mg) in patients with advanced-stage metastatic melanoma. One (3%) patient had clinical complete response and five (13%) patients had surgical complete response made possible by the > 90% tumor regression of soft tissue, lymph node, and lung metastases that was achieved with treatment. Moreover, the study achieved an overall objective response rate of 32% and a median survival, in this advanced-stage patient population, of 9.5 months.

"This data enhances our knowledge of Thalomid in combination with temozolomide for the treatment of metastatic melanoma," said Dr. Sol J. Barer, Ph.D., President and Chief Operating Officer of Celgene Corporation. "It is still too early to be sure of any long-term clinical outcomes, but from the preliminary results we have seen in this Memorial Sloan-Kettering Cancer Center study, there is reason for further investigation of this oral combination regimen."

The study's daily regimen of concomitant temozolomide plus Thalomid was administered to a total of 38 patients carried over from the phase I study who were treated at the same dose level used in the phase II study. Median age was 62 years (range, 21 to 83 years) and median Karnofsky performance status was 90%. Eleven patients were > or equal to 70 years of age. Twenty-seven patients had cutaneous melanoma, 9 patients had unknown primaries, and 1 patient each had melanoma of the vulva and of the rectum. One patient had stage IIIc disease with multiple in-transit metastases and the remaining patients all had stage IV disease. Hematologic toxicity associated with temozolomide led to dose delay in only 1 patient and discontinuation in only 2 patients. Thalomid-associated neurotoxicity and rash led to discontinuation in several patients.

Hematologic toxicity consisted primarily of lymphopenia and leukopenia. Grade 3 lymphopenia developed in 14 (37%) patients. One patient had transient grade 4 leukopenia and neutropenia plus persistent grade 4 thrombocytopenia, which led to discontinuation. A second patient developed transient grade 4 neutropenia and discontinued because of a gastrointestinal bleed. The most frequent non-hematologic adverse events > or equal to grade 2 occurring in > or equal to 5% of patients included rash, constipation, vomiting, dizziness, dyspnea, fatigue, nausea, headache, and infection. Most non-hematologic adverse events were grade 2 and manageable. Furthermore, after a median follow-up of more than 24 months, brain metastases developed in nine (24%) patients, including in one patient who did not complete 1 cycle of therapy.

Study Details:

Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary endpoint was response rate. Patients received temozolomide (75 mg/m2/day x 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/day with dose escalation to 400 mg/day for patients < 70 years old or 100 mg/day with dose escalation to 250 mg/day for patients > or equal to 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred.

Thirty-eight patients (median age, 62 years) with stage IV (3 M1a, 8 M1b, and 26 M1c) or stage IIIc (1 patient) melanoma and a median of 4 metastatic sites were enrolled and received a median of 2 cycles of therapy. Twelve (32%) patients had an objective tumor response, including 1 with an ongoing complete response of 25+ months' duration and 11 with partial responses. Five patients achieving partial response with > 90% reduction of disease were converted to a complete response with surgery. Median survival was 9.5 months with a median follow-up among survivors of 24.3 months.

About Melanoma:

Melanoma is a very serious form of skin cancer. It begins in melanocytes- cells that make the skin pigment called melanin. Although melanoma accounts for only about 4% of all skin cancer cases, it causes most skin cancer-related deaths. The chance of developing melanoma increases with age, but it affects all age groups and is one of the most common cancers in young adults. The number of new melanomas diagnosed in the United States is increasing. Since 1973, the incidence rate for melanoma (the number of new melanomas diagnosed per 100,000 people each year) has more than doubled from 5.7 to 14.3. The American Cancer Society estimates that about 53,600 new melanomas will be diagnosed in the United States during 2002. About 7,400 people in the US are expected to die of melanomas during 2002.

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.). 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.


SOURCE: Celgene Corporation

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