Background: CD71/TfR1 (transferrin receptor 1) is highly expressed in proliferative malignancies, including acute leukemias, and is associated with poor prognosis. INA03 is a first-in-class antibody-drug conjugate (ADC), transferrin competitive, targeting CD71, designed to exploit the iron dependency and high metabolic demands of leukemic blasts. INA03 selectively delivers MMAE, a cytotoxic payload to malignant cells while sparing normal tissues with low CD71 expression. Here we report the final results of the first in human (FIH) trial of INA03 in patients with relapsed or refractory (R/R) acute leukemia.

Methods: This is an open-label, multicenter Phase I study (NCT03957915) evaluating the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of INA03 administered as a single agent IV infusion every 2 weeks in adult patients with R/R acute leukemia. Eligible patients must have exhausted standard treatment options. The study was conducted in 2 parts. In Part 1, 14 patients were treated across dose levels ranging from 0.02 to 1.5 mg/kg on Day 1, combined with either 0.02 or 0.10 mg/kg on Day 15 of each 28-day cycle. In Part 2, 20 patients received higher doses ranging from 1.5 to 3.0 mg/kg on Day 1 and 0.5 to 2.0 mg/kg on Day 15. The dose escalation design used a Bayesian Approach, with dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) as the primary endpoints. Secondary endpoints include PK parameters, pharmacodynamic (PD) biomarkers, and clinical response as defined by European LeukemiaNet (ELN) 2017 recommendations.

Results: A total of 34 patients have been treated across 12 different dose sequences of INA03 administered intravenously on Day 1 and Day 14 of a 28-day cycle. Diagnoses included acute myeloid leukemia (AML); n=33, and mixed-phenotype acute leukemia (MPAL); n=1. Median age was 75 [39-83] years (74% male). According to ELN 2017 classification (available for 33 patients), 51.5% were classified as adverse risk, 45.5% as intermediate, and 3% as favorable. No DLTs were observed in Part 1 of the study. 4 DLTs occurred at the highest dose levels tested (2 out of 6 patients at 2.5/1.5 mg/kg and 2 out of 2 patients at 3.0/2.0 mg/kg). Adverse events were reported in all patients. A total of 11 patients (79%) in Part 1 and 19 patients (95%) in Part 2 experienced Grade 3–4 AEs. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 35.9% of patients; most common were gastro-intestinal (GI, 14.7% including stomatitis [8.8%], colitis [5.9%], large intestine perforation [2.9%] and ileus [2.9%]), and infusion related reaction (14.7%). No Grade 5 TRAEs were reported. Treatment discontinuation due to adverse events occurred in 26.4% of patients. The most frequent TRAEs of any grade were infusion related reaction (38.2%), gastro-intestinal disorders (35.3%) and rash (17.6%). PK analysis of MMAE confirmed dose-proportional exposure, with a terminal half-life of approximately 56 hours. Early signs of clinical activity were observed starting at 1 mg/kg. An exploratory efficacy cohort included 20 patients treated at dose levels ≥1 mg/kg. In this cohort, at time of analysis, 9 patients (45%) experienced a blast reduction >50%, 4 patients (20%) achieved an objective response per ELN2017: 2 complete responses (CR/CRi) and 2 partial responses (PR).Conclusions: INA03, first in class CD71/TfR1-targeted ADC, demonstrated a manageable safety profile and favorable pharmacokinetics in patients with relapsed or refractory acute leukemia. The MTD was defined at 2 mg/kg. Early signs of biological and clinical activity above benchmark of this novel targeted asset support continued investigation in Phase II studies and rational combination strategies.

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2025
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