A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies

INTRODUCTION: Overexpression of CD123, the alpha subunit of the IL-3 receptor, in multiple hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN), makes this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate comprising a novel humanized anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of cytotoxic compounds. In preclinical models, IMGN632 exhibited potent antitumor activity with a wide therapeutic index in AML, BPDCN, and ALL, suggesting the potential for robust efficacy along with favorable tolerability in patients with leukemia. We report the initial safety and antileukemia activity findings from the dose-escalation stage of the first-in-human trial of IMGN632.

METHODS: The objectives of this ongoing Phase I study (NCT03386513) include determination of the dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemia activity of IMGN632. Adult patients with CD123-positive, relapsed or refractory AML or BPDCN are eligible to enroll in the dose-escalation stage. IMGN632 is administered intravenously on Day 1 of a 21-day cycle using a standard 3+3 design. The starting dose of IMGN632 was 0.015 mg/kg, with escalation following a modified Fibonacci schema. Adverse events (AEs) are evaluated by CTCAE v4.03 and tumor responses assessed according to the European LeukemiaNet (ELN) response criteria.

RESULTS: At the time of this analysis, a total of 12 patients had received IMGN632 across four dose-escalation cohorts, with dosing successfully escalated from 0.015 mg/kg up to 0.18 mg/kg. The median age of the patients was 66 years (range, 40-80). All patients were diagnosed with AML, including five with relapsed refractory disease and six enrolled at first relapse. Eight patients had received prior intense therapy, including stem cell transplant in two individuals. Seven patients had adverse risk cytogenetics and 50% had secondary AML. No DLTs have been observed at doses up to 0.18 mg/kg (cohort 4) and no discontinuations due to an AE have occurred.

The most commonly observed treatment-emergent AEs of any grade were primarily gastrointestinal (decreased appetite, diarrhea, nausea; 25-42%), hematologic (febrile neutropenia; 42%), or vascular (peripheral edema, hypotension, sinus tachycardia; 25-33%). The most frequent Grade 3+ AEs were febrile neutropenia (5 patients; 42%) and lung infection (3 patients; 25%); none of these events were considered related to IMGN632. No grade 3 or higher vascular events were noted. No correlations between the severity, frequency, or nature of reported AEs with increasing dose have been observed. Post-infusion reactions were seen in nine patients (75%). These events typically manifested as mild (grade 1) fever, chills, tachycardia, or nausea/vomiting, occurred less than 24 hours following infusion, and resolved with standard medical care. Steroid premedication has now been implemented at cohort 4. Three deaths occurred, all due to disease progression and unrelated to study drug.

In 12 evaluable patients, four (33%) achieved an objective response, including one complete remission (CR) and three complete remissions with incomplete recovery (CRi). Maximal bone marrow blast decreases from baseline seen for patients are presented in Figure 1A.

PK analyses showed that systemic IMGN632 exposure and maximum concentrations increased with dose; similarly, PD determinations revealed that the extent and duration of CD123 saturation also increased with dose (Figure 1B).

CONCLUSIONS: Objective responses (CR and CRis) were seen in one third of relapsed/refractory AML patients during the initial stages of dose escalation in this first-in-human clinical trial with IMGN632, a novel CD123-targeting ADC. No dose limiting toxicities have been observed, and PK and PD data support continued dose escalation, which is ongoing.

Figure 1. A. Maximum percent changes in bone marrow blasts from baseline. Patients who achieved an objective response (CR or CRi) are shown in gray. B. CD123 receptor saturation. Average saturation curves for the first four cohorts are presented.

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