Interim Data from a Phase 1 Study Evaluating Pyrrolobenzodiazepine-Based Antibody Drug Conjugate ADCT-402 (Loncastuximab Tesirine) Targeting CD19 for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: Outcomes of patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival <20%.Expression of CD19, which is normally restricted to B-cell developmental stages, is universally present in patients with B-ALL. ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) composed of a humanized CD19-targeting monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, loncastuximab tesirine (Lonca-T) demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present interim data from a Phase 1 study evaluating Lonca-T in patients with R/R B-ALL.

Methods: A Phase 1, open-label, dose-escalation (part 1) and expansion (part 2), multicenter, US study is enrolling patients with R/R B-ALL to assess the tolerability and safety of Lonca-T. Secondary objectives include evaluation of clinical activity, characterization of the pharmacokinetic (PK) profile, and evaluation of anti-drug antibodies. Eligible patients are ≥12 years of age with R/R B-ALL and an Eastern Cooperative Oncology Group performance status of 0-2 who have failed, or are intolerant to, established therapy, or have no other treatment options available in the opinion of the investigator. In part 1, patients were assigned to treatment according to a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Lonca-T was given intravenously on Day 1 of each cycle. The first cohort received a dose of 15 μg/kg on a 21-day (q3w) treatment cycle. Part 2 will further evaluate the safety, tolerability, PK and clinical activity at the dose recommended from part 1.

Results: As of June 23, 2017, 23 patients (14 male, 9 female) with B-ALL have been treated with Lonca-T. The median age was 57 years [range 21-80] and patients had received a median of 2 (range: 1-12) previous chemotherapies. Nine (39%) patients had received prior allogeneic stem cell transplantation. No dose-limiting toxicities were observed up to the highest evaluated dose of 150 µg/kg q3w. A total of 204 treatment-emergent adverse events (TEAEs) were reported from all patients. The most common TEAEs were nausea (n=7) and fatigue (n=6) followed by diarrhea, febrile neutropenia and headache (all n=5). Grade ≥3 TEAEs were reported in 19/23 (83%) patients, of which febrile neutropenia (n=5), bacteremia (n=3) and sepsis (n=3) were the most common. There have been no treatment-related deaths. Four patients experienced TEAEs leading to a dose delay or reduction, but no TEAEs led to treatment discontinuation. There were 16 liver toxicity events recorded in 5 patients, leading to dose delay in 1 patient; 3 patients experienced Grade ≥3 events, all of which were reversible and not related to veno-occlusive disease. Two Grade 2 and one Grade 3 infusion-related reactions were observed. Two patients achieved a complete response with no minimal residual disease (MRD), at a dose of 30 μg/kg and 120 μg/kg q3w after five and two treatment cycles, respectively. Both responders had previously received blinatumomab. PK data show PBD-conjugated antibody concentrations below quantifiable levels well before end of cycle, which in combination with the absence of dose-limiting toxicities (DLTs) support weekly dosing.

Conclusions:

In this Phase 1 study in patients with R/R B-ALL, single-agent Lonca-T was well tolerated with no DLTs and showed two MRD-negative complete remissions in a heavily pre-treated population. Dose escalation will continue to find the MTD for a weekly regimen. A dose-expansion phase in part 2 of the study is planned to further evaluate the tolerability, safety, PK and activity of Lonca-T.

Study sponsored by ADC Therapeutics. https://clinicaltrials.gov/ct2/show/NCT02669264