A Phase I/IIa Study of Lemzoparlimab, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS): Initial Phase I Results

Abstract

Background Lemzoparlimab (also known as TJC4 or TJ011133), a novel, RBC-sparing CD47 antibody with a unique epitope, is in early phase clinical development in both the U.S. and China. Like other anti-CD47 antibodies, lemzoparlimab blocks the interaction of CD47 and SIRPα, leading to phagocytosis of various CD47+ tumor cell lines and primary AML cells. Mono-treatment of lemzoparlimab inhibited tumor growth completely and extended the overall survival of treated mice in a patient-derived AML xenograft model. Here we report initial findings in the ongoing phase I trial which is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lemzoparlimab in relapsed and/or refractory (r/r) AML and MDS patients. Methods The trial (NCT04202003) adopted a modified 3+3 dose escalation design with weekly lemzoparlimab at dose levels of 1, 3, 10, 20 and 30 mg/kg. The initial two lower dose cohorts (1 mg/kg and 3 mg/kg) was designed to enroll one patient each, and the study would escalate to the next level (10 mg/kg) if no DLT and no predefined toxicity events (e.g. grade 2 or above drug-related non hematologic toxicity, except for isolated lab abnormality with no clinical manifestation) were observed. If the first DLT or predefined toxicity event was observed, the cohort size would be expanded at the current dose level and the study would revert to the standard 3+3 design. Safety, PK/PD parameters, and preliminary efficacy were evaluated. Results As of 24 July 2020, 5 r/r AML patients (pts) including 1 relapsed, 1 relapsed/refractory and 3 primary refractory, were enrolled across 3 dose cohorts (1 at 1 mg/kg, 1 at 3 mg/kg and 3 at 10 mg/kg). Patients had 2-4 prior therapies. Median age was 45 years (range 25-66). Four of 5 pts developed treatment emergent AEs. Most of the AEs were grade 1 or 2. Treatment-related AEs that occurred in > 1 patient included thrombocytopenia (2/5 pts, 1 with grade 1 and 1 with grade 3) and positive anti-erythrocyte antibody (2/5 pts). No dose dependent hematologic toxicities have been observed so far. There was no treatment-related dose interruption or dose discontinuation. No patient developed treatment-related SAE or death. The maximum tolerated dose (MTD) has not yet been reached and the drug was well tolerated in r/r AML pts in the background of significantly impaired hematopoietic function with or without supportive blood transfusion. The anti-CD47 interferences on the blood bank testing were mitigated before blood transfusion. With doses from 1 mg/kg to 10 mg/kg, lemzoparlimab exhibited a supraproportional increase in exposure, which can be attributed to target (CD47) mediated drug disposition at low doses. CD47 receptor occupancy (RO) was evaluated as a PD marker. The mean RO on peripheral T cells at Cmax was 74.0%, 82.0% and 84.9% for 1, 3 and 10 mg/kg, respectively. The mean RO on CD33+ tumor cells at Cmax was 45.9%, 75.8% and 82.2% for 1, 3 and 10 mg/kg, respectively. Of note, one patient with primary refractory AML achieved morphologic leukemia-free state (MLFS) after 2 cycles of lemzoparlimab treatment at 1 mg/kg. Conclusion Lemzoparlimab was well tolerated in r/r AML pts in the doses tested and importantly, consistent with preclinical data, there were no serious hematological AEs so far. No DLTs or MTD was observed up to 10 mg/kg weekly dosing so far. The PK/PD profile of lemzoparlimab is also consistent with preclinical findings. The preliminary efficacy observed was encouraging. Dose escalation will continue until MTD or RP2D is reached. Disclosures No relevant conflicts of interest to declare.

Targeting CD47 for cancer immunotherapy

“…TJC4 barely affected the hemoglobin and other blood indexes in the tested animals, showing significantly better safety than 5F9. Compared to the CD47 mAb 5F9, TJC4 binds more weakly to human erythrocytes and does not cause HA [ 70 ]. Initial results of lemzoparlimab (NCT04202003) in phase I/IIa study indicated a well-tolerated safety profile with certain clinical efficacy among 5 R/R AML and MDS patients with 2–4 prior therapies.…”

“…Initial results of lemzoparlimab (NCT04202003) in phase I/IIa study indicated a well-tolerated safety profile with certain clinical efficacy among 5 R/R AML and MDS patients with 2–4 prior therapies. Of special note, one patient with primary refractory AML achieved morphologic leukemia-free state (MLFS) after 2 cycles of lemzoparlimab treatment at 1 mg/kg [ 70 ].…”

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

“…In addition, three out of seven patients had a CR, one had a partial response, and three achieved stable disease. In an ongoing phase I/II clinical trial (NCT04202003), r/r AML and MDS patients were treated with monotherapy of Lemzoparlimab [ 208 ]. Most adverse events were grade I or II, but one patient experienced grade III thrombocytopenia.…”

CD47‐SIRPα blocking‐based immunotherapy: Current and prospective therapeutic strategies

“…In line with this, deglycosylation by peptide‐N‐glycosidase (PNGase) treatment restored RBC binding 27 . Of these next‐generation antibodies, clinical results have only been reported for lemzoparlimab and AK117, with no serious haematological adverse effects or DLTs observed in lemzoparlimab doses up to 20–30 mg/kg weekly 28 . Treatment with AK117 similarly did not associate with haematological adverse effects, even up to 20 mg/kg.…”