INITIAL PHASE 1 RESULTS OF THE FIRST-IN-CLASS ANTI-CD47 ANTIBODY HU5F9-G4 IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA PATIENTS
Author(s): ,
Paresh Vyas
Affiliations:
University of Oxford and Oxford University Hospitals,Oxford,United Kingdom
,
Steven Knapper
Affiliations:
Cardiff University School of Medicine,Cardiff,United Kingdom
,
Richard Kelly
Affiliations:
Leeds Teaching Hospital NHS Trust,Leeds,United Kingdom
,
Rahuman Salim
Affiliations:
Royal Liverpool University Hospital,Liverpool,United Kingdom
,
Marcin Lubowiecki
Affiliations:
University of Oxford and Oxford University Hospitals,Oxford,United Kingdom
,
Daniel Royston
Affiliations:
University of Oxford and Oxford University Hospitals,Oxford,United Kingdom
,
Hannah Johnson
Affiliations:
Oncology Clinical Trials Office,University of Oxford,Oxford,United Kingdom
,
Corran Roberts
Affiliations:
Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rhuematology and Muscoloskeletal Sciences,University of Oxford,Oxford,United Kingdom
,
James Chen
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
,
Balaji Agoram
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
,
Jie Liu
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
,
Jens-Peter Volkmer
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
,
Ravindra Majeti
Affiliations:
Stanford University,Stanford,United States
,
Irving Weissman
Affiliations:
Stanford University,Stanford,United States
,
Skanda Goudar
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
,
Chris Takimoto
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
,
Mark Chao
Affiliations:
Forty Seven, Inc.,Menlo Park,United States
Mike Dennis
Affiliations:
The Christie NHS Foundation Trust,Manchester,United Kingdom
EHA Library. Vyas P. 06/15/18; 214718; PF232
Paresh Vyas
Paresh Vyas
Contributions
Abstract

Abstract: PF232

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
Novel and well tolerated therapies are needed in relapsed/refractory (r/r) acute myeloid leukemia (AML). Hu5F9-G4 (5F9) is a first-in-class humanized antibody targeting CD47, a protective “don’t eat me” signal on cancers, that stimulates tumor cell phagocytosis and an anti-tumor T cell response.  Pre-clinically, 5F9 eliminates leukemic disease and induces durable remissions in patient-derived xenograft mouse models.  This trial is the first to investigate an anti-CD47 antibody in AML patients. 

Aims
The main objectives were to determine the safety, tolerability and recommended Phase 2 dose of 5F9 in r/r AML.

Methods
This Phase 1 trial enrolled r/r AML patients in a 3+3 dose escalation design (NCT02678338).  An intra-patient dose escalation design was used with escalation from 0.1 to 30 mg/kg twice weekly dosing of 5F9.  Safety, preliminary efficacy, pharmacokinetic and pharmacodynamic parameters were measured.

Results
15 r/r AML patients were enrolled across 5 dose cohorts as of 19 January 2018. Median age was 71 years (range 31-78) with a median of 2 prior therapies (range 1-5). 47% were relapsed, 47% relapsed/refractory and 7% primary refractory. 80% were intermediate to poor cytogenetic risk (20% not performed).  5F9 was well tolerated. Common treatment-related AEs were anemia (93%), hemagglutination (87%), pyrexia (27%), and headache (27%).  All AEs were grade 1 or 2 (except anemia, a known on target effect of CD47 blockade). No patient developed a grade 4 or 5 treatment-related AE.  79% of these patients had grade 3 anemia prior to study.  RBC transfusions were successfully administered and well tolerated with treatment despite interference with cross-matching in some patients due to 5F9 RBC binding.  Hemagglutination was observed on peripheral smear in most patients with no significant clinical sequelae.  No other significant myelosuppression was observed.  No DLTs were observed with no patients discontinuing therapy due to AEs.  The maximum tolerated dose (MTD) has not yet been reached up to 30 mg/kg twice weekly of 5F9 dosing.   CD47 receptor occupancy >90% was achieved on blood and bone marrow WBCs, indicating near-maximal leukemic cell target saturation.  A Phase 2 dose of 30 mg/kg 5F9 weekly after two weeks was selected. 73% of patients achieved stable disease with no objective responses.  40% of patients had a reduction in bone marrow blast count (mean decrease of 27%, range 5% - 67%).  Two patients had biologic activity, defined as significant reduction in marrow cellularity observed similarly in pre-clinical models.  Somatic mutation sequencing demonstrated that the first patient with an ASXL1 mutation had a 92% decrease in variant allele frequency (VAF) on treatment.  Significant reduction in myeloid mutation VAFs was observed in several patients (range 7.4 – 95% decrease in VAF).    The 2nd patient achieved a >50% blast count reduction and was on therapy for 11.8 months.  This patient had a significant increase in T cell infiltrate in the bone marrow during treatment, suggesting activation of the adaptive immune system by Hu5F9-G4.  

Conclusion
5F9 is a novel immunotherapy inhibiting a key macrophage/cancer checkpoint. It is well tolerated in r/r AML with no DLTs or an MTD observed.  Biologic activity was seen with T cell bone marrow infiltration in a long-term treated patient and reduction in somatic myeloid mutations in several patients.  A Phase 1b trial of 5F9 in combination with azacitidine has been initiated based on these initial Phase 1 results (NCT03248479). 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, Antibody targeting, Macrophage

Abstract: PF232

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
Novel and well tolerated therapies are needed in relapsed/refractory (r/r) acute myeloid leukemia (AML). Hu5F9-G4 (5F9) is a first-in-class humanized antibody targeting CD47, a protective “don’t eat me” signal on cancers, that stimulates tumor cell phagocytosis and an anti-tumor T cell response.  Pre-clinically, 5F9 eliminates leukemic disease and induces durable remissions in patient-derived xenograft mouse models.  This trial is the first to investigate an anti-CD47 antibody in AML patients. 

Aims
The main objectives were to determine the safety, tolerability and recommended Phase 2 dose of 5F9 in r/r AML.

Methods
This Phase 1 trial enrolled r/r AML patients in a 3+3 dose escalation design (NCT02678338).  An intra-patient dose escalation design was used with escalation from 0.1 to 30 mg/kg twice weekly dosing of 5F9.  Safety, preliminary efficacy, pharmacokinetic and pharmacodynamic parameters were measured.

Results
15 r/r AML patients were enrolled across 5 dose cohorts as of 19 January 2018. Median age was 71 years (range 31-78) with a median of 2 prior therapies (range 1-5). 47% were relapsed, 47% relapsed/refractory and 7% primary refractory. 80% were intermediate to poor cytogenetic risk (20% not performed).  5F9 was well tolerated. Common treatment-related AEs were anemia (93%), hemagglutination (87%), pyrexia (27%), and headache (27%).  All AEs were grade 1 or 2 (except anemia, a known on target effect of CD47 blockade). No patient developed a grade 4 or 5 treatment-related AE.  79% of these patients had grade 3 anemia prior to study.  RBC transfusions were successfully administered and well tolerated with treatment despite interference with cross-matching in some patients due to 5F9 RBC binding.  Hemagglutination was observed on peripheral smear in most patients with no significant clinical sequelae.  No other significant myelosuppression was observed.  No DLTs were observed with no patients discontinuing therapy due to AEs.  The maximum tolerated dose (MTD) has not yet been reached up to 30 mg/kg twice weekly of 5F9 dosing.   CD47 receptor occupancy >90% was achieved on blood and bone marrow WBCs, indicating near-maximal leukemic cell target saturation.  A Phase 2 dose of 30 mg/kg 5F9 weekly after two weeks was selected. 73% of patients achieved stable disease with no objective responses.  40% of patients had a reduction in bone marrow blast count (mean decrease of 27%, range 5% - 67%).  Two patients had biologic activity, defined as significant reduction in marrow cellularity observed similarly in pre-clinical models.  Somatic mutation sequencing demonstrated that the first patient with an ASXL1 mutation had a 92% decrease in variant allele frequency (VAF) on treatment.  Significant reduction in myeloid mutation VAFs was observed in several patients (range 7.4 – 95% decrease in VAF).    The 2nd patient achieved a >50% blast count reduction and was on therapy for 11.8 months.  This patient had a significant increase in T cell infiltrate in the bone marrow during treatment, suggesting activation of the adaptive immune system by Hu5F9-G4.  

Conclusion
5F9 is a novel immunotherapy inhibiting a key macrophage/cancer checkpoint. It is well tolerated in r/r AML with no DLTs or an MTD observed.  Biologic activity was seen with T cell bone marrow infiltration in a long-term treated patient and reduction in somatic myeloid mutations in several patients.  A Phase 1b trial of 5F9 in combination with azacitidine has been initiated based on these initial Phase 1 results (NCT03248479). 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, Antibody targeting, Macrophage

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