Phase II Trial of Ofatumumab (OFA) in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL): CALGB 50901 (Alliance)

Background: Rituximab has proven safety and efficacy in untreated patients with advanced stage follicular lymphoma (FL) with response rates upward of 67% (Ghielmini et al., Blood 2004). OFA is a fully humanized anti-CD20 mAb with higher CD20 antigen affinity and increased complement dependent cytotoxicity compared to rituximab. OFA has demonstrated activity in relapsed/refractory FL and high risk untreated FL in combination with chemotherapy. We therefore investigated OFA monotherapy as initial treatment for low/intermediate (int) risk, advanced stage FL in order to determine single agent efficacy as a platform for future studies.

Methods: We conducted a randomized, multicenter phase II study in which previously untreated CD20+, grade (gr) 1- 3a FL patients (pts) and low/int FLIPI scores in stages III, IV or bulky stage II were randomized to either 500 mg (n=15) or 1000 mg (n=36) OFA dose. Induction consisted of 4 weekly doses followed by an extended induction schedule every 8 weeks for 4 additional doses. The primary endpoint was overall response rate (ORR) with an ORR of 60% or lower considered inadequate, and 80% or higher of strong interest. Secondary endpoints included progression-free survival (PFS) and safety. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2 and extended induction infusions 5-8). Pts with gr 3/4 infusion reactions during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. Due to slower than anticipated accrual, the 500 mg arm was stopped in Oct 2013 in order to meet the primary endpoint in at least one dosing arm; pts enrolled on 500 mg prior to that date continued treatment at that dose.

Results: Fifty-one pts were accrued. The median age was 60 years (range 40-85). 86.3% were Caucasian; 54.9% were male. The majority had FL gr 1 (45.1%) or gr 2 (41.2%) and Stage III-IVA (84.3%). Five pts had B-symptoms. The majority of pts were int risk (72.5% FLIPI 2; 70.6% FLIPI2 1-2) or low risk (21.6% FLIPI 0-1; 19.6% FLIPI2 0). Of 36 pts allocated to the 1000 mg arm, 32 were evaluable for response. Four pts are excluded from response analysis: ineligible (n=3) and insufficient data (n=1). Two additional pts had no response assessment as therapy was stopped after the first dose; one withdrew consent and the other received alternative therapy per treating physician. The best response was CR (13.3%), PR (73.3%) and SD (10%). One pt progressed on treatment. The ORR of evaluable pts with evaluable defined as having at least one response assessed was 86.7% [95% CI (69.3%-96.2%)]. The ITT response rate was 81.3% [95% CI (63.6%- 92.8%)]. With a median (med) follow-up of 15.6 months (mo) (< 1 mo - 39.6 mo), the 1 year PFS in the 1000 mg arm is 96.6% [95% CI (77.9%, 99.5%)]; 12/33 (36.6%) pts progressed. Of 15 pts allocated to the 500 mg arm, the ORR was 60% [95% CI (32.2%-83.7%)]. The best response was CR (13.3%), PR (46.7%) and SD (40%). One pt progressed on treatment. The 1 year PFS is 85.1% [95% CI (52.3%, 96.1%)]; 9/15 (60%) pts progressed. All pts remain alive. Hematologic adverse events (AEs) in the 1000 mg arm included 1 pt with gr 3 neutropenia; no gr 4 hematologic AEs were reported. There were no gr 3/4 infections. Gr 3 infusion-related events occurred in 9/36 (25%) evaluable pts and all occurred with 1^st infusion; there were no gr 4 infusion-related events. Steroid-induced AEs included gr 3 hypertension in 3 pts and gr 3 hyperglycemia in 4 pts. Nine additional gr 3 events occurred (2 fatigue, 2, dyspnea, 1, syncope, 1 GI obstruction, 1 hyponatremia, 1 hypokalemia, 1 hyperkalemia). A single gr 4 AE was reported; ARDS with acute coronary syndrome occurring after the 2^nd infusion. The pt withdrew and made a full recovery.

Conclusions: OFA when given as a single agent in an extended induction dosing schedule is well tolerated and active as front line therapy in patients with low/int risk FLIPI, advanced stage FL in this multicenter study. Activity appears to be in a range comparable to that reported with other anti-CD20 antibodies in this setting, suggesting that significant improvements in efficacy will require novel combinations. NCT01190449.

Support: U10CA180821, U10CA180882