Millennium: The Takeda Oncology Company announced that Phase II results of a clinical trial examining VELCADE® (bortezomib) in patients with previously untreated aggressive lymphoma were published in the Journal of Clinical Oncology. The study was designed to examine the efficacy of VELCADE in combination with the current standard of care (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-CHOP) in 76 patients with two aggressive subtypes of lymphoma: mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL).

Subsets of these tumors exhibit NF-κB activation. In this trial, VELCADE-R-CHOP was also evaluated for efficacy in the genomically defined subtype of DLBCL called non-germinal center B-cell (non-GCB) lymphoma. Prior studies have indicated that patients with non-GCB type tumors do not respond well to R-CHOP therapy due to the activation of the NF-κB pathway.

The endpoints of the Phase II trial included progression-free survival (PFS), response rate and overall survival (OS).

Highlights include:

- Among 35 evaluable DLBCL patients overall response rate was 100 percent, and the complete response rate was 86 percent

- After a median follow-up of 51 months, two-year PFS in DLBCL patients was 64 percent and two-year OS was 70 percent; median PFS and OS had not been reached

- No survival differences were observed between the GCB and the typically poor prognostic non-GCB subtypes

- Among 32 evaluable MCL patients, the overall response rate was 91 percent, and the complete response rate was 72 percent

- After a median follow-up of 34 months, two-year PFS in MCL patients was 44 percent and two-year OS was 86 percent; median PFS was 23 months, and median OS had not been reached

- The most common adverse events of any grade in the study were anemia (79 percent), thrombocytopenia (78 percent) and neutropenia (55 percent)

- The most common adverse events of grade 3 or higher were neutropenia (41 percent), thrombocytopenia (25 percent) and febrile neutropenia (17 percent)

"The growth of the non-GCB subtype of DLBCL depends on the activity of the NF-κB survival pathway, which is one of the pathways known to be inhibited by VELCADE. The concept of this trial was to test proteasome inhibition as a means to intervene in a critical lymphoma survival pathway," said John Leonard, M.D., Center for Lymphoma and Myeloma, Weill Cornell Medical College and principal investigator of the study. "Prior studies have indicated that even with R-CHOP therapy, which is the current standard of care in DLBCL, the non-GCB patients have inferior survival. Thus, we are encouraged to see the survival results from this study for this particular high-risk population."

"These data were part of the foundation for two ongoing randomized trials that evaluate VELCADE specifically in patients with this NF-κB dependent subtype of DLBCL," said Nancy Simonian, M.D., Chief Medical Officer, Millennium. "The U.S.-based PYRAMID study compares standard of care (R-CHOP) to VELCADE-R-CHOP in patients defined as non-GCB by a central laboratory. Additionally, our Phase III study examining a VELCADE based combination in previously untreated MCL includes an assessment of the NF-κB pathway status in each patient."

"This study adds to the growing body of evidence supporting the importance of VELCADE in subtypes of non-Hodgkin lymphoma with survival pathways involving NF-kB," said Sven De Vos, M.D., Ph.D., UCLA Medical Center.

VELCADE is currently approved for use in patients with multiple myeloma and relapsed MCL.

Important Safety Information

Contraindication

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.

Adverse Reactions

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%).

Source:
Velcade
Millennium

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