S878 THE FIRST‐IN‐CLASS ANTI‐CD47 ANTIBODY HU5F9‐G4 IS ACTIVE AND WELL TOLERATED ALONE OR IN COMBINATION WITH AZACITIDINE IN AML AND MDS PATIENTS: INITIAL PHASE 1B RESULTS
Authors: D. Sallman, W. Donnellan, A. Asch, D. Lee, M. Al Malki, D. Pollyea, S. Kambhampati, R. Komrokji, J. Van Elk, M. Lin, B. Agoram, J. Chen, J. Volkmer, C. Takimoto, M. Chao, P. Vyas
Journal: HemaSphere (2019)

Background: Novel and effective therapies are needed in patients with myeloid malignancies. Hu5F9‐G4 (5F9) is a first‐in‐class antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers, that induces tumor cell phagocytosis. CD47 is also a leukemia stem cell (LSC) marker in AML. Pre‐clinically, CD47 blockade induces phagocytosis of AML cells and eliminates LSCs in animal models. Azacitidine (AZA) synergizes with 5F9 to eliminate AML by inducing pro‐phagocytic signals on AML, thus enhancing phagocytosis. This trial clinically investigated 5F9 alone or with AZA in AML/MDS patients and is the first report of a clinical study combining a CD47 targeting agent with a hypomethylating/cytotoxic agent. Aims: The primary objectives of this study were to evaluate the safety and efficacy of 5F9 treatment in relapsed/refractory (r/r) AML/MDS and 5F9 in combination with AZA in untreated AML and MDS patients. Methods: This Phase 1b trial enrolled: 1) relapsed/refractory (r/r) AML/MDS patients with 5F9 alone; and 2) untreated AML (induction ineligible) and intermediate‐very high risk MDS patients with 5F9+AZA. A 5F9 priming/intra‐patient dose escalation regimen (1–30 mg/kg weekly) was used to mitigate on‐target anemia. Standard AZA dosing was used. Results: 10 (6 AML, 4 MDS) r/r pts received 5F9 (median 2 prior therapies (range 1–6). 24 untreated pts (15 AML, 9 MDS) received 5F9+AZA. In total, median age was 73, 62% of AML pts were intermediate or poor cytogenetic risk (38% unknown), all MDS pts were intermediate or high risk by IPSS‐R. 5F9 alone or with AZA was well‐tolerated with no MTD reached. 5F9 did not potentiate AZA toxicities. Treatment‐related AEs (&gt;10% of pts) for 5F9+AZA were anemia (25%), thrombocytopenia (20%), and infusion reactions (15%). In 25 efficacy evaluable pts, 8/15 (53%) untreated AML/MDS pts had a CR/CRi to 5F9+AZA (5/10 (50%) in AML, 3/5 (60%) in MDS). 1/10 (10%) r/r AML/MDS pts had a response (MLFS) to 5F9 alone. LSCs were reduced/eliminated in the majority of 5F9+AZA responders. 50% of all responders were minimal residual disease (MRD) negative by flow cytometry. 4/10 (40%) previously red cell dependent AML pts became RBC transfusion independent and 4/5 (80%) MDS pts had hematologic improvement. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. As of Jan 2019, no responder has relapsed (median follow‐up of 3.4 mos (range 1.1 – 6.8 mos). 2 pts had successful allogeneic transplant. Additional patients and follow up will be reported. Summary/Conclusion: 5F9+AZA is a novel immunotherapy blocking a key macrophage/cancer checkpoint. It is well tolerated with promising activity in AML/MDS patients including rapid CRs with MRD negativity. Adding 5F9 to cytotoxic agents may be a promising treatment strategy. An expansion cohort is ongoing (NCT03248479). Funded by Forty Seven and California Institute for Regenerative Medicine.