Elucidating Exposure-Response (Safety and Efficacy) of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Containing Antibody Drug Conjugate, for Recommended Phase 2 Dose Determination in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Introduction: ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate (ADC) composed of a humanized CD19-specific IgG1 antibody stochastically conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin via a cleavable maleimide linker. In this Phase 1 dose escalation trial of heavily pre-treated patients with B-cell non-Hodgkin lymphoma (NHL), loncastuximab tesirine (Lonca-T) 15 to 200 µg/kg was administered every 3 weeks (q3w) by intravenous infusion. The dose and pharmacokinetic (PK) exposure of Lonca-T were modeled as drivers of safety (treatment-emergent adverse events [TEAEs]) and efficacy (reduction in tumor size) for the determination of the Recommended Phase 2 Dose (RP2D).

Methods:Concentrations of PBD-conjugated antibody (Ab) in serum were determined using a validated electrochemiluminescence immunoassay, then analyzed by population PK methodology using NONMEM (version 7.3, first-order conditional estimation). Associations between exposure (dose and Bayesian-estimated individual-patient exposure metrics) and the maximum severity of early (Cycle 1) and early or later (all cycles) TEAEs were evaluated for overall TEAEs, anemia, platelets, neutrophils, hemoglobin, fatigue, edema and pleural effusion. Associations of dose and PK with maximum change from baseline tumor size were also determined to identify potential relationships between exposure and activity (complete response plus partial response). For the PK population, drug concentrations were described using the log-transformed both sides approach with a 3-compartment open model and zero-order infusion. In the final population model, gender was retained as a covariate on central volume of distribution.

Results: Data from 44 patients (28 males and 16 females) were included in the population PK model. Patients had a mean (range) age of 67 years (24-85) and weight of 87 kg (42-143). A positive relationship was apparent for maximum severity TEAEs, anemia, and thrombocytopenia both in Cycle 1 and in later cycles. A positive relationship was evident for neutropenia, edema and pleural effusion in later cycles only. For patients with and without Grade 3/4 TEAEs, median (5^th, 95^th percentile) PBD-conjugated Ab area under the curve (AUC) was 13.6 mg*Day/L (0.359, 40.8), and 6.33 mg*Day/L (0.308, 35.0), respectively. Increased exposure to Lonca-T in Cycle 1 was associated with decreased tumor size, with the model giving a dosage of 120 µg/kg q3w as a median minimum dose necessary for requisite efficacy. To achieve at least a 50% tumor size reduction from baseline, the median (min, max) PBD-conjugated Ab AUC was ~66 mg*Day/L (4.69, 294), which is close to the median AUC values of 63.9 and 66.9 mg*Day/L from patients in the 120 and 200 µg/kg cohorts, respectively.

Conclusions: By quantitating the differences between exposure associated with grade of a given TEAE and the exposure necessary for efficacy, an optimal dose of Lonca-T associated with an acceptable set of toxicity thresholds was preliminarily identified. Since this trial is ongoing, supplemental pending data will be incorporated into the model, particularly for the 150 µg/kg dose, for an alternate dosage frequency (q6w), for individual patient CD19 status at baseline, and for NHL subtype, to provide the rationale for dosage and regimen selection and definition of the RP2D.