Preliminary results of a phase 1, first-in-human study of INA03, an anti-CD71 antibody-drug conjugate, in patients with relapsed or refractory (R/R) acute leukemias.

Abstract

7045 Background: R/R acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the role of iron metabolism in various proliferative tumor models including AL including the over-expression of the transferrin receptor (TfR1/CD71). Our strategy is thus to harness CD71 overexpression to specifically target cytotoxic agents to leukemic cells. INA03 is an antibody drug conjugate (ADC) constituted of a humanized monoclonal IgG4 against CD71 and the microtubule disrupting agent monomethyl auristatin E (MMAE). We herein report the preliminary safety and efficacy data of INA03 from a phase 1/2 trial in patients (pts) with R/R AL (NCT03957915). Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose (LD)) followed by maintenance injections on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are: R/R AL after at least one line of treatment including high dose chemotherapy and/or Vidaza and Venetoclax, AlloSCT > 18y, with FEVG > 50%, Creatinine Clearance > 30ml/min, normal liver function, ECOG < 2. The study design is based on a continuous reassessment method and includes 2 parts: a LD Titration study (Part 1, completed), followed by a Dose Escalation Part 2. During Part 1, sequential cohorts of 2 pts were included to receive ascending LD of INA03 followed by subsequent fixed dose of INA03 to deal with a potential sink effect related to the high expression of CD71 in normal erythroblasts. During Part 2, sequential cohorts of 3 pts received escalating doses of INA03 Q2 weeks in 28-day cycles. The objectives were to establish the MTD for subsequent administration and both safety/tolerability and anti-leukemic activity. Results: With a cutoff date of January 18, 2023, 22 pts across 8 cohorts were included in the study. The median age was 73 (range: 39 – 83), 20 (91%) pts had AML and two (9%) had ALL. Three (13.6%) pts had a prior allo-SCT and 12 (54.5%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 2 mg/kg. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated IV, while INA03 PK exhibits target-mediated drug disposition without accumulation. No DLT was observed among the 18 DLT-evaluable pts, up to the highest dose of 2 mg/kg. No grade 2-4 TEAEs were observed. One related grade 1 TEAE (hyperkalemia/phosphatemia) was reported. Transient decrease of reticulocyte count and erythroblasts percentage were observed at 0.5 mg/kg and above. Blasts reductions were seen in 3/18 evaluable pts at dose > 1 mg/kg including two partial responses. Conclusions: INA03 is well tolerated up to the dose of 2 mg/kg with some efficacy signals in R/R AL. The trial continues to accrue patients. Clinical trial information: NCT03957915 .