Background: Hu5F9-G4 (5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers leading to phagocytosis of tumor cells. Pre-clinically, 5F9 synergizes with rituximab to eliminate lymphoma by enhancing antibody-dependent cellular phagocytosis. 5F9+rituximab demonstrated encouraging safety/efficacy in a Phase (Ph)1b dose escalation cohort in patients with relapsed/refractory (r/r) DLBCL and FL that were rituximab-refractory (Advani et al., NEJM 2018). Herein we report on extended follow up of this Ph1b cohort and preliminary Ph2 data. Aims: The primary objectives were to determine the safety/efficacy of escalating doses of 5F9+rituximab in patients with r/r DLBCL and indolent lymphoma. Methods: The Ph2 enrolled: 1) DLBCL: primary refractory or r/r to at least 2 prior therapies, ineligible for CAR-T therapy; and 2) indolent lymphoma (FL and MZL) r/r to at least 2 prior therapies. A 5F9 prime/maintenance dose regimen was used to mitigate on-target anemia; followed by weekly or Q2 week maintenance doses. Based on a potential dose-response seen in Ph1b, 5F9 maintenance doses of 30 and 45 mg/kg were tested with rituximab. Results: A total of 100 patients (63 DLBCL, 35 FL, 2 MZL) have been treated across both Ph1b+2 cohorts. Median age (range) was 66 years (21–88) with 3 median prior therapies (range 1–10). 84% were rituximab-refractory and 72% refractory to their last therapy. 5F9+rituximab was well-tolerated at 5F9 doses up to 45 mg/kg with no maximum tolerated dose reached. No significant dose-dependent toxicities were observed. Treatment-related AEs occurring in >10% of patients included infusion reactions (38%), headache (34%), chills (30%), fatigue (30%), anemia (27%), nausea (24%), pyrexia (23%) vomiting (13%), and back pain (11%). The majority were G1/2 with 7% or lower being G3/4, except G3 anemia (15%) which was an expected transient first-dose effect. Treatment discontinuation due to drug-related AEs occurred in only 4/100 (4%) patients. As of February 2019, for Ph1b patients dosed from 10–30 mg/kg (n = 22), at a median follow up of 12 months (DLBCL) and 18 months (FL), the median duration of response had not been reached (DLBCL range: 2.4 – 20+ months and FL range: 6.2 – 22.6+ months), including some durable CRs for > 20 months. Of 100 total patients enrolled, 75 patients were evaluable for efficacy, 8 were not evaluable, and in 17 first response assessment is pending. Pooled efficacy results from Ph1b+2 efficacy evaluable patients (n = 75) show an objective response rate (ORR) and CR rate of 49% and 21%, respectively. For indolent lymphoma (n = 28 FL, 1 MZL), the ORR and CR rate was 66% and 24%, respectively. In DLBCL (n = 46), the ORR/CR rate was 39/20%. Median time to response for responding patients was rapid at 1.8 months. The ORR for patients treated with 30 mg/kg 5F9 (n = 59) was 47% and in a small number of evaluable patients treated at 45 mg/kg (n = 7) was 71%. Accrual is ongoing and data on additional patients treated at the 45 mg/kg dose will be presented. Summary/Conclusion: 5F9+rituximab is a novel immunotherapy blocking a key macrophage/cancer checkpoint. It is well tolerated with rapid and durable responses observed in both heavily pre-treated DLBCL and indolent lymphoma patients. Ph2 enrollment is ongoing (NCT02953509). Funded by Forty Seven and the Leukemia and Lymphoma Society.