Phase II Trial of Ofatumumab (OFA) in Previously Untreated Follicular Non-Hodgkin Lymphoma (NHL): CALGB 50901 (Alliance)
Authors: Rosenbaum Cara A. , Pitcher Brandelyn , Bartlett Nancy L , Smith Sonali M. , Liu Jane Jijun , Hsi Eric D. , Jung Sin-Ho , Leonard John P. , Cheson Bruce D. 
Published: October 2019

Abstract
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 1st 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 2nd 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

Disclosures
Rosenbaum: Celgene: Speakers Bureau. Off Label Use: Ofatumumab is an anti CD20 monoclonal antibody not approved for use in follicular lymphoma.. Bartlett:Genentech: Research Funding; Pfizer: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding; Gilead: Consultancy, Research Funding; Insight: Research Funding; Janssen: Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Hsi:Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau; Cellerant Therapeutics: Research Funding; Eli Lilly: Research Funding; Abbvie: Research Funding. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:Roche/Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Celgene: Consultancy, Research Funding; MedImmune: Research Funding; Astellas: Consultancy; Ascenta: Research Funding; Teva: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Spectrum: Consultancy.