Millennium: The Takeda Oncology Company today reported new correlative science data from the pivotal PINNACLE trial of VELCADE® (bortezomib) in patients with relapsed/refractory mantle cell lymphoma (MCL). The data, derived from an analysis of archived tumor samples, tested pre-specified biomarkers for their association with time to progression and response to treatment with VELCADE in patients with relapsed MCL. The results add to the body of data supporting the potential usefulness of biomarkers in predicting outcome of MCL and predicting responsiveness to single agent VELCADE. The study is published in the July issue of Leukemia & Lymphoma.
“Since its foundation Millennium has tried to find ways to better personalize therapy, and this trial is one example of our continued commitment to helping physicians and patients choose the most appropriate therapy for their disease,” said Nancy Simonian, M.D., Chief Medical Officer, Millennium. “This analysis of the PINNACLE study opens the door for additional research into targeted approaches to VELCADE treatment.”
“We look forward to the results of further studies, which will help us better understand the critical cellular pathways regulated by VELCADE, and ultimately accelerate clinical research in lymphoma by predicting which drugs could work best in individual patients in clinical trial settings,” said lead author Andre Goy, M.D., M.S., Chief, Lymphoma, the John Theurer Cancer Center at Hackensack University Medical Center.
The biomarkers identified and their corresponding roles indicate:
The PINNACLE trial was a Phase II, open-label, single-arm, multicenter study of 155 patients with relapsed/refractory MCL and was the basis of the 2006 approval of VELCADE for the treatment of patients with relapsed/refractory MCL who had received one prior therapy. The overall response rate in the trial was 31 percent, with a median duration of response of 9.3 months; the CR rate was 8 percent, with a median duration of response of 15.4 months.
The Goy analysis used archived tumor samples from 73 patients who participated in the PINNACLE trial. The biopsies were examined for biomarkers associated with poor prognosis in MCL or those regulated by the proteasome. The biomarker levels were then compared to the effect of VELCADE on patients, according to response rates including overall survival and time to progression.
VELCADE is co-developed by Millennium and Ortho Biotech Oncology Research & Development, a unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S., Janssen-Cilag is responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. entered into a co-promote agreement in May 2010 for VELCADE in Japan. VELCADE is approved in more than 90 countries and has been used to treat more than 160,000 patients worldwide.
Important Safety Information
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
WARNINGS AND PRECAUTIONS
VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.
Pregnancy and Nursing: Women should avoid breastfeeding or becoming pregnant while being treated with VELCADE.
Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with pre-existing symptoms may experience worsening peripheral neuropathy (including = Grade 3). Patients should be monitored for symptoms of peripheral neuropathy.
Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope and those who are dehydrated.
Cardiac Disorders including acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported. Isolated cases of QT-interval prolongation have been reported. Patients with risk factors for, or existing heart disease should be closely monitored.
Pulmonary Disorders, some fatal, including pneumonitis interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS), have been reported. Pulmonary hypertension in the absence of left heart failure or significant pulmonary disease has also been reported.
Gastrointestinal Adverse Events including nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement.
Thrombocytopenia/Neutropenia can occur – manage with dose and/or schedule modifications. Platelets should be monitored prior to each dose of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage. Transfusions may be considered.
Patients with Hepatic Impairment:VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be started at a lower dose of VELCADE, which can be adjusted after cycle 1 depending on tolerability.
Patients with Diabetes: Hypoglycermia and hyperglycemia have been reported with VELCADE use. Patients may require close monitoring and adjustment of the antidiabetic medications.
Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome (RPLS) and acute hepatic failure have been reported.
Previously Untreated MM: In the phase 3 VELCADE with melphalan and prednisone study, the most commonly reported adverse events 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%).
Relapsed MM and MCL: In the integrated analysis of 1163 patients in phase 2 and 3 studies, the most commonly reported adverse events were 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) (each 36%), pyrexia (34%), vomiting (33%).
In the integrated analysis, a total of 50% of patients experienced serious adverse events (SAEs). The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).
For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).
Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, and has a robust clinical development pipeline of product candidates. Millennium Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. in May, 2008. The Company’s research, development and commercialization activities are focused in oncology. Additional information about Millennium is available through its website, www.millennium.com.
Editors’ Note: This press release is also available under the Media section of the Company’s website at: http://www.millennium.com/media.Business Wire
Last updated on: 27/08/2010