COLLEGEVILLE, Pa., May 31 /PRNewswire-FirstCall/ -- Wyeth Pharmaceuticals, a division of Wyeth , today announced results of a three-arm phase 3 clinical trial that show patients with relapsed and/or refractory mantle cell lymphoma (MCL), a form of non-Hodgkin's lymphoma, treated with the mTOR (mammalian target of rapamycin) inhibitor TORISEL(R) (temsirolimus) experienced a statistically significant improvement in median progression-free survival (PFS), compared with single-agent therapy selected by the investigator (4.8 months vs. 1.9 months, P=0.0009). These results are being presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
"Relapsed/refractory mantle cell lymphoma is extremely difficult to treat, and this is the first comparative phase 3 study to show a significant improvement in progression-free survival for these patients," says Georg Hess, M.D., Johannes Gutenberg-Universitat, Mainz, Germany. "These data further support the antitumor activity seen in phase 2 studies of temsirolimus in relapsed/refractory mantle cell lymphoma and indicate that mTOR inhibition may be a viable approach in this disease area."
MCL accounts for approximately 6 percent of non-Hodgkin's lymphoma cases.
"These findings reinforce the clinical potential of mTOR inhibition with TORISEL. Wyeth is committed to the continued exploration of mTOR inhibition with TORISEL for the treatment of a variety of cancers," says Joseph S. Camardo, M.D., Senior Vice President, Global Medical Affairs, Wyeth Pharmaceuticals.
TORISEL was approved in May 2007 for the treatment of advanced renal cell carcinoma (RCC) and is the only mTOR inhibitor approved to treat RCC. TORISEL specifically inhibits the mTOR kinase, an important regulator of cell proliferation, cell growth and cell survival and is the only renal cancer therapy proven to extend median overall survival compared with interferon-alpha in patients with advanced RCC.
Study Design and Results
This three-arm, open-label, randomized, phase 3 trial compared two different dose regimens of TORISEL with investigators' choice of therapy (IC) in patients with relapsed or refractory MCL who had received two to seven prior therapies, which could include hematopoietic stem cell transplantation. Patients were randomly assigned to receive intravenous (IV) TORISEL at 175 mg for three successive weekly doses followed by 75 mg IV weekly; TORISEL 175 mg IV for three successive weekly doses followed by 25 mg IV weekly; or investigators' choice of one of the following single agents at predefined doses: gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine, alemtuzumab or lenalinomide. The primary end point was PFS based on independent review. Secondary end points were objective response rate and overall survival.
Median PFS for patients treated with TORISEL 175 mg/75 mg was 4.8 months, compared with 1.9 months for patients treated with IC. In the TORISEL 175 mg/25 mg arm, median PFS was 3.4 months, but this difference was not statistically different from IC (P=0.0618).
Patients receiving TORISEL 175 mg/75 mg showed a nonsignificant trend toward longer overall survival than those treated with IC (13.6 months vs. 9.7 months; HR=0.80). TORISEL 175 mg/75 mg led to a statistically significant improvement over IC in objective response rates (22 percent vs. 2 percent, P=0.0019).
The most frequently occurring grade 3 or 4 adverse events among patients treated with TORISEL 175 mg/75 mg, TORISEL 175 mg/25 mg, or IC were thrombocytopenia (59 percent vs. 52 percent vs. 36 percent of patients, respectively), anemia (20 percent vs. 11 percent vs. 17 percent), neutropenia (15 percent vs. 22 percent vs. 26 percent) and asthenia (13 percent vs. 19 percent vs. 8 percent).
The clinical data for TORISEL presented at the meeting represent only a portion of the totality of the safety and efficacy data from the ongoing clinical development of TORISEL.
TORISEL is an mTOR inhibitor. Inhibition of mTOR in treated cancer cells blocked the translation of genes that regulate the cell cycle. In in vitro studies using renal cancer cell lines, TORISEL inhibited the activity of mTOR and resulted in reduced levels of certain cell growth factors involved in the development of new blood vessels, such as vascular endothelial growth factor.
TORISEL is approved for the treatment of advanced RCC in the United States, European Union and other markets, based on results of a phase 3 clinical study that demonstrated that TORISEL improves overall survival for patients with advanced RCC compared with interferon-alpha.
An application for the use of TORISEL for the treatment of relapsed and/or refractory MCL is currently under review with the European Medicines Agency (EMEA). TORISEL received Orphan Medicinal Product designation for the treatment of MCL in the European Union in November 2006.
Important Safety Information
Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing and chest pain have been observed with TORISEL.
Serum glucose, serum cholesterol and triglycerides should be tested before and during treatment with TORISEL.
The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.
Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.
Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea and/or acute abdomen.
Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL.
Due to abnormal wound healing, use TORISEL with caution in the perioperative period.
Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.
Live vaccinations and close contact with those who received live vaccines should be avoided.
Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.
The most common (incidence greater than or equal to 30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence greater than or equal to 30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).
Most common Grades 3/4 adverse events included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%) and triglycerides increased (44%).
Strong inducers of CYP3A4/5 (e.g., dexamethasone, rifampin) and strong inhibitors of CYP3A4 (e.g., ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.
St. John's Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.
The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).
Please see TORISEL full Prescribing Information at http://www.TORISEL.com.
Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, infectious disease, gastrointestinal health, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines and nutritional products.
Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of pharmaceuticals, vaccines, biotechnology products, nutritionals and non-prescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare and Fort Dodge Animal Health.
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