Final Results of a Single Arm Phase III Multicenter, Open-Label Study of Rituximab Administered by Faster Infusion in Patients with Previously Untreated Diffuse Large-B Cell (DLBCL) or Follicular Non-Hodgkin's Lymphoma (FL)

For lymphoma patients (pts) receiving rituximab according to the prescribing information the first rituximab infusion typically requires 4−6 hrs and subsequent infusions require 3−4 hrs. Several pilot studies have investigated the feasibility of faster infusion of rituximab, but no phase III trials have prospectively analyzed safety in a larger population. In order to evaluate whether a faster infusion is feasible for the second and subsequent cycles of rituximab plus chemotherapy treatment, a prospective single arm, open-label phase III multicenter single-arm trial was performed to assess the safety of faster rituximab infusion in previously untreated pts with DLBCL and FL.

Previously untreated pts with DLBCL or FL scheduled to receive R-CHOP and R-CVP respectively were eligible for participation in this study. Pts with a history of clinically significant cardiac disease were excluded. Pts received acetaminophen, an antihistamine and the oral steroid component of their chemotherapy regimen before each rituximab infusion. No additional steroid premedication was permitted. The first rituximab infusion was administered at an initial rate of 50 mg/hr and in the absence of toxicity increased by 50 mg/hr to a maximum of 400 mg/hr. Pts with infusion-related SAEs or grade 3/4 IRRs in the first cycle went off study. Rituximab in subsequent cycles was to be administered over a planned duration of 90 minutes: 20% of the total rituximab dose over 30 minutes, and the remaining 80% over the next 60 minutes. The primary outcome of this study was the rate of grade 3/4 IRRs during or within 24 hrs of Cycle 2 Day 1 in pts who received the faster infusion of rituximab. The definition of infusion-related AE required onset within 24 hrs of the start of infusion and encompassed MedDRA terms mapped to a prespecified list of AE terms derived from previous phase III rituximab studies. Secondary endpoints included other AEs, AEs leading to drug discontinuation, deaths, SAEs, and duration of administration (by cycle).

Assuming the point estimate of the incidence of grade 3/4 IRRs was no larger than 5%, a sample size of at least 300 pts receiving faster infusion was needed to estimate the incidence with a margin of error of no greater than 2.5%. This sample size also allowed a fatal IRR rate of 1% or higher to be ruled out with a type I error less than 5% if no fatal IRRs were observed in the study.

Between July 2008 and November 2010, 451 pts were enrolled at 93 centers in the U.S. 425 pts received the first dose of rituximab at a median infusion duration of 2–0 minutes (92–390 minutes). Fifty-three pts (12.4%) discontinued prior to receiving the faster infusion: 5.6% discontinued the study because of Grade 3/4 IRRs, SAEs (including 5 deaths) and other AEs; and 6.8% discontinued for other reasons.

The faster infusion of rituximab was administered starting at cycle 2 to 363 patients (250 R-CHOP, 113 R-CVP). R-CHOP pts had a median age=64 (range 20–86) and stage III-IV=63.4%. R-CVP pts had a median age=65 (range 33–88) and stage III-IV=77.0%.

A total of 1764 infusions were administered at the faster rate. The median infusion duration at cycle 2 was 90 minutes (range 60–233) and was maintained over all subsequent cycles. For pts receiving the faster infusion at Cycle 2 Day 1, the rate of grade 3/4 IRR at cycle 2 was 1.1% (4 patients; 95%CI [0.3%, 2.8%]); the events included rash, bronchospasm, hypersensitivity, and abdominal pain. The rate of grade 3/4 IRRs occurring during cycle 2 or beyond was 2.8% (10 patients; 95%CI [1.3%, 5.0%]). IRR of any grade occurred in 38.3% of pts at Cycle 2 Day 1 with a decreased incidence in subsequent cycles. No fatal IRRs were observed. Thirteen deaths occurred on study outside of the infusion period (5 during cycle 1, 8 during or after cycle 2).

The target duration of faster infusion was maintained while observing a rate of grade 3/4 IRRs of 1.1% at Cycle 2 and 2.8% at Cycle 2 and beyond with no fatal IRRs. Based on these results, the faster infusion of rituximab in pts without clinically significant cardiac disease who receive the first cycle of rituximab without a grade 3/4 IRR is feasible and associated with a safety profile comparable to historical data for patients with previously untreated DLBCL or FL who receive either R-CHOP or R-CVP.

Off Label Use: Rituximab. Treatment of patients with Non-Hodgkin's Lymphoma (NHL). Chai:Genentech: Employment. Hurst:Genentech: Employment. Fine:Genentech: Employment.