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This trial, called EVOLUTION(1), builds on positive results from previousstudies of VELCADE based combinations in this setting. The presentationreported the first clinical data with the novel four-drug combination. Thesafety results allow the trial to proceed to Phase II, which will randomizepatients to receive VcDR, VcDC or VcDCR.
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Results from the 25 patients treated in this trial with VcDCR for a medianof four cycles (range: 2-11 cycles), which were presented by Shaji Kumar,M.D., Mayo Clinic, showed:
-- The maximum tolerated dose of cyclophosphamide in the VcDCR regimen wasnot reached. The recommended doses for the Phase II portion of the trialinclude 500 mg/m(2) of cyclophosphamide, the highest planned dose, 1.3 mg/m(2)of VELCADE, 40 mg of dexamethasone and 15 mg of lenalidomide.
-- The only two dose-limiting toxicities reported were febrile neutropeniaand reactivation of the Herpes Zoster virus infection.
-- The overall rate of serious adverse events (AEs) was 40 percent. Themost common treatment-emergent AEs were constipation (64 percent), fatigue (60percent) and nausea (52 percent).
-- There were no reports of deep-vein thrombosis or pulmonary embolism.
-- As initial therapy, all patients had a partial response or better, with36% of patients achieveing a CR.
"We are committed to advancing multiple myeloma treatment that deliversthe best patient outcomes," said Nancy Simonian, M.D., Chief Medical Officer,Millennium. "The tolerability of this novel four-drug combination allows us tostudy its efficacy relative to two of the most active three-drug regimens forpreviously untreated multiple myeloma patients."
During Phase I, patients received VELCADE at 1.3 mg/m(2) on days 1, 4, 8and 11 on a 21-day cycle for up to eight cycles; dexamethasone at 40 mg ondays 1, 8 and 15; lenalidomide at 15 mg on days 1 through 14; andcyclophosphamide at 100, 200, 300, 400 or 500 mg/m(2) on days 1 and 8 for upto eight 21-day cycles. This was followed by VELCADE at 1.3 mg/m(2) on days 1,8, 15 and 22 for four 42-day maintenance cycles. The primary endpoint of thisPhase I trial was the determination of the maximum tolerated dose ofcyclophosphamide in combination with VcDR. The primary endpoints of theongoing Phase II portion of the trial are complete response and very goodpartial response rates, while the secondary endpoints include progression-freesurvival, overall survival, safety and tolerability.
About Multiple Myeloma
Multiple myeloma is the second most common hematologic malignancy andalthough the disease is predominantly a cancer of the elderly (the median ageof onset is 70 years), recent statistics indicate both increasing incidenceand younger age of onset. In the U.S., more than 50,000 individuals have MMand 20,000 new cases are diagnosed each year. Worldwide there areapproximately 74,000 new cases and over 45,000 deaths annually.
About VELCADE
VELCADE is co-developed by Millennium Pharmaceuticals, Inc. and Johnson &Johnson Pharmaceutical Research & Development, L.L.C. Millennium isresponsible for commercialization of VELCADE in the U.S., Janssen-Cilag isresponsible for commercialization in Europe and the rest of the world. JanssenPharmaceutical K.K. is responsible for commercialization in Japan. VELCADE isapproved in more than 87 countries worldwide.
Important Safety Information
In the U.S., VELCADE is indicated for the treatment of patients withmultiple myeloma. VELCADE also is indicated for the treatment of patients withmantle cell lymphoma who have received at least one prior therapy. VELCADE iscontraindicated in patients with hypersensitivity to bortezomib, boron ormannitol. VELCADE should be administered under the supervision of a physicianexperienced in the use of antineoplastic therapy.
Risks associated with VELCADE therapy include new or worsening peripheralneuropathy, hypotension throughout therapy, cardiac and pulmonary disorders,reversible posterior leukoencephalopathy syndrome, gastrointestinal adverseevents, thrombocytopenia, neutropenia, tumor lysis syndrome and hepaticevents. Women of childbearing potential should avoid becoming pregnant whilebeing treated with VELCADE. Nursing mothers are advised not to breastfeedwhile receiving VELCADE. Cases of severe sensory and motor peripheralneuropathy have been reported. The long-term outcome of peripheral neuropathyhas not been studied in mantle cell lymphoma. Acute development orexacerbation of congestive heart failure, and new onset of decreased leftventricular ejection fraction has been reported, including reports in patientswith no risk factors for decreased left ventricular ejection fraction. Therehave been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration andAcute Respiratory Distress Syndrome in patients receiving VELCADE. Some ofthese events have been fatal. There have been reports of Reversible PosteriorLeukoencephalopathy Syndrome (RPLS) in patients receiving VELCADE. RPLS is arare, reversible, neurological disorder which can present with seizure,hypertension, headache, lethargy, confusion, blindness, and other visual andneurological disturbances. VELCADE is associated with thrombocytopenia andneutropenia. There have been reports of gastrointestinal and intracerebralhemorrhage in association with VELCADE. Transfusions may be considered.Complete blood counts (CBC) should be frequently monitored during treatmentwith VELCADE. Cases of acute liver failure have been reported in patientsreceiving multiple concomitant medications and with serious underlying medicalconditions. Patients who are concomitantly receiving VELCADE and drugs thatare inhibitors or inducers of cytochrome P450 3A4 should be closely monitoredfor either toxicities or reduced efficacy. Patients on oral antidiabeticmedication while receiving VELCADE should check blood sugar levels frequently.
Adverse Reaction Data
Safety data from Phase II and III studies of single-agent VELCADE 1.3mg/m(2)/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163patients with previously treated multiple myeloma (N=1008, not including thePhase III, VELCADE plus DOXIL(R) [doxorubicin HCl liposome injection] study)and previously treated mantle cell lymphoma (N=155) were integrated andtabulated. In these studies, the safety profile of VELCADE was similar inpatients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported adverse eventswere asthenic conditions (including fatigue, malaise and weakness) (64%),nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC(including peripheral sensory neuropathy and peripheral neuropathy aggravated)(39%), thrombocytopenia and appetite decreased (including anorexia) (each36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache,paresthesia and dysesthesia and headache (each 22%), dyspnea (21%), cough andinsomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness(excluding vertigo) (each 17%), pain in limb and abdominal pain (each 15%),bone pain (14%), back pain and hypotension (each 13%), herpes zoster,nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia(each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%).Twenty percent (20%) of patients experienced at least 1 episode of greaterthan or equal to Grade 4 toxicity, most commonly thrombocytopenia (5%) andneutropenia (3%). A total of 50% of patients experienced serious adverseevents (SAEs) during the studies. The most commonly reported SAEs includedpneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea,dehydration, dyspnea and thrombocytopenia (each 3%).
In the Phase 3 VELCADE + melphalan and prednisone study, the safetyprofile of VELCADE in combination with melphalan/prednisone is consistent withthe known safety profiles of both VELCADE and melphalan/prednisone. The mostcommonly reported adverse events for VELCADE in combination with MP vs MP,respectively, were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%),nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%),anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%),leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue(29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21%vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%),dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain inextremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%),herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%),hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12%vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).
About Millennium
Millennium: The Takeda Oncology Company, a leading biopharmaceuticalcompany based in Cambridge, Mass., markets VELCADE, a novel cancer product,and has a robust clinical development pipeline of product candidates.Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical CompanyLtd. ("Takeda", TSE: 4502) in May, 2008. The Company's research, developmentand commercialization activities are focused in oncology. Additionalinformation about Millennium is available through its website,www.millennium.com.
(1) Evaluation of VELCADE, dexamethasOne, and Lenalidomide with or withoutcyclophosphamide Using Targeted Innovative ONcology strategies in thetreatment of front-line multiple myeloma
Editors' Note: This press release is also available under the Mediasection of the Company's website at: www.millennium.com.Contacts: Manisha Pai Karen Gobler (617) 551-7877 (617) 444-1392 [email protected] [email protected]
SOURCE Millennium: The Takeda Oncology Company
