jueves, 25 de febrero de 2010

Rituximab by FDA

On February 18, 2010, the U.S. Food and Drug Administration granted approval to rituximab (Rituxan, Genentech), in combination with fludarabine and cyclophosphamide (FC), for the treatment of previously untreated and previously treated patients with chronic lymphocytic leukemia (CLL). The approval was based on a clinically meaningful and statistically significant increase in progression-free survival (PFS) observed in two randomized multicenter open-label trials in patients randomized to receive either FC or the combination of FC with rituximab (R-FC).

In both studies patients received intravenous (i.v.) fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day, daily for 3 days, repeated every 28 days for a total of 6 cycles. Rituximab 375 mg/m2 by i.v. infusion was administered on day 1 of the first cycle (the day before chemotherapy) and 500 mg/m2 i.v. on day 1 of subsequent cycles (on the same day as chemotherapy). The primary efficacy outcome was PFS, defined as the time from randomization to either disease progression, relapse, or death. Secondary endpoints included overall survival (OS) and overall response rates determined by the 1996 National Cancer Institute-sponsored Working Group Guidelines.

Study ML17102, also known as CLL8, was conducted by the German CLL Study Group and enrolled treatment-naïve patients. A total of 408 patients were randomized to the R-FC arm and 409 patients to the FC arm. The median age was 61 years (30% were ≥ 65 years old), 74% were male, 31% were Binet stage C, 45% had B symptoms, and more than 99% had ECOG performance status (PS) 0-1.

The primary efficacy endpoint was PFS as determined by the investigators. The median PFS were 39.8 months and 31.5 months in the R-FC and FC arms, respectively [HR 0.56 (95% CI: 0.43, 0.71), p <0.01, log rank test]. Overall response rates were 86% (95% CI 82, 89) in the R-FC arm and 73% (95% CI 68, 77) in the FC arm.

Study BO17072, also known as REACH, conducted by Roche and Biogen Idec, enrolled 552 patients with relapsed or refractory CLL following prior systemic therapy. Patients were randomized to receive either R-FC (n=276) or FC (n=276). The median age was 62 years old (44% ≥65 years old), and 67% were male. Eighty-two percent received a prior alkylator-containing regimen and 18% received a fludarabine-containing regimen. “B” symptoms were present in 28% and 100% were ECOG PS 0-1.

The median PFS was 26.7 versus 21.7 months for the R-FC and FC arms, respectively, as determined by an independent review committee [HR 0.76 (95% CI: 0.60, 0.96), p= 0.022, log-rank test]. Overall response rates were 54% (95% CI: 48, 60) in the R-FC arm and 45% (95% CI: 37, 51) in the FC arm.

Too few events occurred at the time of regulatory submission to conduct a meaningful analysis of OS in either study. Follow-up of patients for OS is ongoing.

Across both studies, 100 patients who received R-FC and 89 patients who received FC were ≥70 years old. The results of exploratory analyses in this elderly population did not suggest a treatment benefit for the addition of Rituxan to FC in either the previously untreated [HR 1.17 (95% CI: 0.51, 2.66)] or previously treated settings [HR 1.22 (95% CI: 0.73, 2.04)].

The safety of rituximab when combined with FC was assessed in 676 patients who received the R-FC regimen. In both studies, 71% received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Grade 3-4 infusion reactions occurred in 7-9% of R-FC treated patients. The following Grade 3-4 adverse events were more frequently observed in the R-FC arm compared to FC arm alone: neutropenia, febrile neutropenia, leukopenia thrombocytopenia, hypotension, hepatitis B, and pancytopenia.

Rituxan is approved as a single agent for the treatment of relapsed or refractory low-grade or follicular CD-20 positive non-Hodgkin’s lymphoma (NHL) and for the treatment of patients with non-progressing low-grade CD-20 positive NHL following first-line CVP chemotherapy, or in conduction with CVP for first-line treatment of previously untreated CD20, B-cell follicular NHL and in combination with CHOP or other anthracycline-based chemotherapy regimens for the treatment of previously untreated diffuse, large B-cell CD20 positive NHL.

Serious adverse reactions of Rituxan include fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML). Adverse reactions occurring in more than 25% of Rituxan-treatment patients with lymphoid malignancies are infusion reactions, fever, lymphopenia, chills, infection, and asthenia.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf1

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm2, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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