A Phase II Trial Evaluating the Safety of Rapid Infusion Ofatumumab (OFA) in Patients (pts) with Previously Treated Chronic Lymphocytic Leukemia (CLL)

Background: OFA is a fully humanized, anti-CD20 antibody that is approved for use with chlorambucil in previously untreated CLL and as a single agent in refractory CLL. Using the currently recommended administration scheme there is a low rate of severe infusion reactions. However, this scheme requires long infusion times with averages of 6.8 hrs, 6.8 hrs and 4.2-4.4 hrs for 2000 mg OFA doses 1, 2, and 3+, respectively. We evaluated whether an accelerated infusion regimen would allow OFA to be delivered safely over a shorter period of time.

Methods: This was a phase II, single-arm study, still enrolling patients. Eligibility criteria included pts with relapsed CD20+ CLL, ≥ 1 prior therapy, no antibody therapy in the prior 3 months, ECOG PS ≤1, negative hepatitis B serology, and adequate organ function. Previous treatment with OFA was allowed if the pt had maintained a PR or better for ≥ 6 months. Pts were pre-medicated with acetaminophen 1000mg PO, diphenhydramine 50 mg PO/IV or equivalent and dexamethasone 10 mg IV. The 1st dose of OFA (300 mg/500 mL [0.6 mg/mL]), was given on week 1 day 1 starting at 6 mL/hr and doubling every 30 min until a rate of 400 mL/hr was reached. The planned infusion durations of the 1st and 2nd infusions under this administration schema are 226 min and 167 min respectively. If tolerated, the 2nd dose (1000 mg/500 mL [2 mg/mL]) was given on week 1 day 3 starting at 25 mL/hr and doubling every 30 min until a rate of 400 mL/hr was reached. If no grade (G) 3 or 4 infusion reaction was encountered, a 3rd dose (2000 mg/500 mL [4 mg/mL]) was given on week 2 day 1 at 200 mL/hr over the first 30 min and if tolerated at 267 mL/hr over the next 90 min (goal infusion time 120 minutes). Subsequent infusions given in the same manner were planned weekly for 8 weeks and then monthly for 4 months. The primary endpoint was the number of subjects able to complete the 3rd dose (2000 mg) within 15 min of the goal infusion time.

Results: Between July 2013 and May 2014 23 pts were treated. Pts were 48% male and had a median age of 69 yrs. Rai stage was 12%/20%/20%/12%/32%/4% for stages 0/1/2/3/4/ unknown, respectively. IgVH was mutated in 40% of patients, non-mutated in 44% of patients and unknown in 16% of patients. CD38 was positive in 44%, negative in 44% and unknown in 12%. FISH studies were unknown in 4%, normal in 32% and abnormal in 64% (11q del 24%, 13q del 53%, 17p del 28%, trisomy 12 28%). At the time of analysis 8 pts (35%) were on active treatment, 8 pts (35%) had completed treatment, and 7 patients (30%) had stopped treatment prior to completion due to patient request (3pts), intercurrent illness (2 pts), toxicity (1 pt) and disease progression (1 pt) There were 4 G3 infusion-related reactions (3 occurred in a single patient) and 14 G1/G2 reactions. All but 1 infusion-related reaction occurred during the 1st 2 infusions. Nineteen patients have received the week 2 day 1 rapid infusion dose. There was only 1 infusion-related reaction (sneezing) and 14 of 19 pts (74%) received the full dose within 15 min of the planned 2 hr treatment duration. An additional 2 pts (11%) received the full dose within 20 min of the planned infusion time, and the remaining 2 pts completed within 30 min of the planned 2 hr treatment duration. Median infusion times were 303 min, 182 min and 126 min for infusions 1, 2, and 3 respectively. G 3/4 hematologic AEs observed regardless of cause were: thrombocytopenia (G3 8% and G4 4%), neutropenia (G3 8%), and pancytopenia (G3 8%). There were no treatment-related G3/4 non-hematologic toxicities with the exception of 2 infusion-related reaction (G3 9%).Response data is preliminary, but shows an overall response rate of 29%.

Conclusion: Using this stepped up dosing regimen, a rapid infusion of OFA is safe and well-tolerated. Almost all infusion related reactions occurred during the 1st 2 infusions (1 was associated with the 2000 mg rapid infusion). This accelerated infusion regimen decreased infusion times while preserving the delivery of OFA in a safe manner.