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

Background: R/R acute leukemias (AL) represent major therapeutic challenges. Several reports have highlighted the deregulation of iron metabolism in various proliferative tumor models (and notably AL) which includes 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 MMAE (Bratti M. et al. Mol Cancer Ther 2024). We herein report the final analysis of INA03 phase 1 first in human study in patients with R/R AL (NCT03957915).

Methods: INA03 is given as 30 minutes IV infusion on days 1 (Loading dose, LD) followed by maintenance infusions on D15 for cycle 1 and on D1 and D15 of cycle 2 and beyond. Eligibility criteria are age >18y, ECOG<2, R/R AL after at least one line of treatment with high dose chemotherapy and/or Vidaza and Venetoclax, LVEF>50%, Creatinine Clearance >30ml/min, normal liver function. The study design was based on a continuous reassessment method and included 2 parts: a LD Titration study (Part 1) followed by a Dose Escalation (Part 2). During Part 1, sequential cohorts of 2 patients (pts) were included to receive ascending LD of INA03 followed by repeated fixed doses 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 RP2D for subsequent administration and both safety/tolerability and anti-leukemic activity.

Results: As of July 30^th, 2024, the completed study included 34 pts across 12 cohorts. The median age was 73 (range: 39 – 83), 32 (94.1%) pts had AML and two (5.9%) had ALL. Four (11.7%) pts had a prior allo-SCT and 18 (52.9%) had prior VEN exposure. Pts received escalating doses of INA03 of 0.02 mg/kg to 3 mg/kg. Two out of 6 pts in the 3 mg/kg and 2/6 pts (33.3%) in the 2.5 mg/kg loading dose cohorts presented DLT (1 pt with grade 3 toxic erythema, grade 3 hepatitis and grade 3 mucositis, 1pt with grade 4 colonic perforation, 1 pt with grade 3 mucositis and 1 pt with grade 3 diverticulitis). Up to the 2 mg/kg dose, no grade 2-4 treatment emerging adverse events (TEAE) were observed among the 27 evaluable pts and only 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 12/18 evaluable pts at dose > 1 mg/kg including one complete and two partial responses. MMAE pharmacokinetics (PK) appears dose-proportional with a small accumulation after repeated I.V, while INA03 PK exhibits target-mediated drug disposition without accumulation.

Conclusions: The results of this first-in-human 1 study indicate that INA03 is well tolerated for doses up to 2 mg/kg and that GI toxicity was dose-limiting. Induction of transient erythroblastopenia and blast reduction showed effective targeting of CD71 in vivo and early signs of antileukemic efficacy have been observed in patients with refractory AL. Overall, study results indicate a RP2D of 2 mg/kg.