In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 9, 2014, bortezomib (Velcade) was granted approval for use in treating previously untreated mantle cell lymphoma in combination with the combination regimen VcR-CAP (rituximab [Rituxan]), cyclophosphamide, doxorubicin, and oral prednisone).1 The drug has prior approval for previously treated mantle cell lymphoma and is approved for use in multiple myeloma.
Approval in previously untreated mantle cell lymphoma was based on findings in an open-label phase III trial in which adult patients with stage II to IV disease who were ineligible or not considered for bone marrow transplantation received VcR-CAP (n = 243) or R-CHOP (n = 244; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
The VcR-CAP regimen consisted of bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 (rest period, days 12–21), rituximab at 375 mg/m2 on day 1, cyclophosphamide at 750 mg/m2 on day 1, doxorubicin at 50 mg/m2 on day 1, and prednisone at 100 mg/m2 on days 1 to 5 every 21 days for six cycles. Patients in both groups with a response first documented at cycle 6 could receive two additional cycles.
Patients had a median age of 66 years, 74% were male, 66% were Caucasian and 32% were Asian, 69% had positive bone marrow aspirate or biopsy, 54% of patients had an International Prognostic Index score ≥ 3, and 76% had stage IV disease.
Median progression-free survival on independent radiographic assessment, the primary endpoint, was 25 vs 14 months (hazard ratio [HR] = 0.63, P < .001). The overall response rate was 88% vs 85%, with complete response in 44% vs 34%.
How It Works
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, a protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway regulates intracellular concentrations of specific proteins, maintaining cellular homeostasis.
Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple intracellular signaling cascades and lead to cell death. Bortezomib is cytotoxic to a variety of cancer cell types in vitro and delays tumor growth in tumor models, including multiple myeloma models.
How It Is Given
In previously untreated mantle cell lymphoma, bortezomib is given at 1.3 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period on days 12 to 21 in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin (50 mg/m2) on day 1 and prednisone (100 mg/m2) on days 1 to 5. On day 1, bortezomib is given first, followed by rituximab.
For patients with a response first documented at cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of bortezomib.
Prior to the first day of each cycle other than cycle 1, platelet count should be ≥ 100 × 109/L, absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, hemoglobin should be ≥ 8 g/dL, and nonhematologic toxicity should have recovered to grade 1 or baseline.
Bortezomib should be interrupted for grade 3 hematologic or nonhematologic toxicities, excluding neuropathy. For hematologic toxicity, treatment should be withheld for up to 2 weeks until recovery of ANC and platelet count; the bortezomib dose should be reduced by 1 level—from 1.3 to 1.0 mg/m2 or from 1.0 to 0.7 mg/m2—if recovery occurs, and treatment should be discontinued if recovery does not occur.
For peripheral neuropathy, dosing should be reduced to 1.0 mg/m2 for grade 1 with pain or grade 2, withheld until resolution and continued at 0.7 mg/m2 once per week upon resolution for grade 2 with pain or grade 3, and discontinued for grade 4.
Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2 during the first cycle. Subsequent escalation to 1.0 mg/m2 or further reduction to 0.5 mg/m2 may be considered based on patient tolerance.
Coadministration of bortezomib with strong CYP3A4 inhibitors (eg, ritonavir, idinavir, clarithromycin, ketoconazole, itraconazole) can increase bortezomib exposure, requiring close monitoring. Coadministration with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John’s wort) can decrease bortezomib exposure and should be avoided.
The most commonly reported adverse events of any grade (> 20%) in clinical trials of bortezomib include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.
In the phase III trial in previously untreated mantle cell lymphoma, the most common grade ≥ 3 hematologic adverse events in the VcR-CAP and R-CHOP groups were neutropenia (83% vs 65%), thrombocytopenia (57% vs 4%), and leukopenia (43% vs 27%). Infections occurred in 31% vs 23%, including pneumonia in 8% vs 5% (5% vs 3% grade ≥ 3). Grade ≥ 3 peripheral neuropathy occurred in 7% vs 4%.
Apart from these, the most common nonhematologic grade ≥ 3 adverse events were fatigue (5% vs 2%) and diarrhea (5% vs 1%). Herpes zoster reactivation occurred in 4.6% vs 0.8% of patients; antiviral prophylaxis was mandated by protocol amendment.
Grade ≥ 3 bleeding events occurred in 3 patients vs 1 patient. Adverse events led to discontinuation of treatment in 8% vs 6%, with the most common causes being peripheral sensory neuropathy in the VcR-CAP group (1%) and febrile neutropenia in the R-CHOP group (< 1%).
Bortezomib carries warnings/precautions for peripheral neuropathy, hypotension, cardiac toxicity, pulmonary toxicity, posterior reversible encephalopathy syndrome, gastrointestinal toxicity, thrombocytopenia and neutropenia, tumor lysis syndrome, hepatic toxicity, and embryo-fetal risk. Patients with preexisting severe neuropathy should be treated with bortezomib only after careful risk-benefit assessment.
Liver enzymes should be monitored during treatment. Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088). ■
1. VELCADE® (bortezomib) for injection prescribing information, Millennium Pharmaceuticals, Inc, 2014. Available at www.velcade.com/Files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf.