FDA Approval for Bortezomib
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On June 20, 2008, the U.S. Food and Drug Administration (FDA) approved bortezomib for injection (Velcade®, of Millennium Pharmaceuticals, Inc., Takeda Oncology Company, and Johnson and Johnson Pharmaceutical Research and Development) for the treatment of patients with multiple myeloma. This approval results from a clinical trial using bortezomib as an initial treatment for patients with multiple myeloma.
Bortezomib was previously approved in 2005 for the treatment of patients with multiple myeloma who had received at least one prior therapy and in 2003 for the treatment of more refractory multiple myeloma.
The current approval was based on an international, multicenter, open label, active-control trial in previously untreated patients with symptomatic multiple myeloma. Patients were randomized to receive either nine six-week cycles of oral melphalan (M) plus prednisone (P), or MP plus bortezomib. Patients received M (9 mg/m2) plus prednisone (60 mg/m2) daily for four days every six weeks or the same MP schedule with bortezomib, 1.3 mg/m2 iv on days 1, 4, 8, 11, 22, 25, 29, and 32 of every six-week cycle for four cycles then once weekly for four weeks on days 1, 8, 22 and 29 of every six-week cycle for five additional cycles.
Time-to-progression (TTP) was the primary efficacy endpoint. Overall survival (OS), progression-free survival (PFS), and response rate (RR) were secondary endpoints. The majority of the patients enrolled were ≥ 65 years of age. A total of 682 patients were randomized: 338 to receive MP and 344 to receive the combination of bortezomib plus MP. Demographics and baseline disease characteristics were similar between the two groups.
The trial was stopped following a pre-specified interim analysis showing a statistically significant improvement in TTP with the addition of bortezomib to MP (median 20.7 months) compared with MP (median 15 months) [HR: 0.54 (95 percent CI: 0.42, 0.70), p= 0.000002]. OS, PFS, and RR also were significantly superior for the bortezomib-MP combination.
The most common adverse reactions (incidence ≥30 percent) in clinical studies of bortezomib include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia and anemia. Dose adjustment guidelines for hematologic and neurologic toxicity are detailed in the label (package insert).
Back to Top
On December 8, 2006, the FDA granted approval to bortezomib for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.
An open-label, single-arm, multi-center study of 155 patients with progressive mantle cell lymphoma who had received at least one prior therapy was performed to assess response rate and duration. Seventy-five percent had one or more extra-nodal disease sites and 77 percent were stage 4.
In 91 percent of patients, prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Thirty-seven percent were refractory to their last prior therapy. Patients received bortezomib,1.3 mg/m2 intravenously, on days 1, 4, 8, and 11 of each three week cycle.
Response rates were determined according to the International Workshop Response Criteria (1999) and were based on an independent radiologic CT scan review. The overall response rate (CR plus CRu plus PR) was 31 percent and the median response duration was 9.3 months. The CR plus CRu response rate was 8 percent and the median response duration was 15.4 months. The median number of cycles in responding patients was eight. The median time to response was 40 days (range 31 to 204 days).
Adverse events, irrespective of their relationship to bortezomib, were similar to those observed in the previously reported myeloma studies (see product labeling). The most commonly reported treatment-emergent adverse events were asthenic conditions (72 percent), peripheral neuropathies (55 percent), constipation (50 percent), diarrhea (47 percent), nausea (44 percent), and appetite decreased (39 percent). The most common adverse event leading to discontinuation was peripheral neuropathy. For safe use of bortezomib, patients must be kept well hydrated.
Back to Top
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.