Interim Results from the First-in-Human Trial of Antibody Drug Conjugate ADCT-402 in B-Cell Malignancies

In a first-in-human trial of loncastuximab tesirine, the CD19-targeting antibody drug conjugate (ADC) appeared to have manageable toxicity and encouraging efficacy as a single agent in patients with B-cell non-Hodgkin lymphomas (NHLs), with “low-grade, but persistent toxicities” and an overall response rate (ORR) of 60 percent.

Brad S. Kahl, MD, from the Washington University School of Medicine in St. Louis, Missouri, presented the interim results of this phase I trial in a standing-room-only session discussing new agents and upfront approaches in the treatment of aggressive lymphoma.

The study is recruiting a difficult-to-treat patient population, Dr. Kahl noted. All patients had relapsed/refractory B-cell lineage NHL that failed to respond or was intolerant to established therapies or who have no other treatment options. As of November 1, 2017 (data cutoff), 138 patients (median age = 65.5 years; range = 24-85 years) were enrolled in the trial, including 85 patients with diffuse large B-cell lymphoma (DLBCL).

Patients received a median of three previous therapies (range = 1-10 therapies).

In the dose-escalation phase of the study, patients received a one-hour infusion of loncastuximab tesirine at doses ranging from 15 to 200 µg/kg for a median of two, three-week cycles (range = 1-16 cycles). One dose-limiting toxicity (worsening of thrombocytopenia at the 200 µg/kg dose) was observed in one patient, but the maximum tolerated dose for the dose-expansion phase of the study had not yet been reached.

Nearly all patients experienced a treatment-related adverse event (AE; n=135; 97.8%), with 46 patients (57.5%) experiencing a grade ≥3 treatment-related AE. The most common non-hematologic, all-grade AEs included fatigue (n=35; 43.8%), peripheral edema (n=21; 26.3%), and nausea (n=20; 25.0%). Non-hematologic grade ≥3 AEs included increased gamma-glutamyltransferase (n=7; 8.8%), dyspnea (n=4; 5.0%), and fatigue (n=4; 5.0%).

The most common hematologic abnormalities included decreased hemoglobin (all-grade, n=74 [96.1%]; grade ≥3, n=9 [11.7%]), neutropenia (all-grade, n=42 [60.9%]; any-grade, n=29 [42.0%]), and thrombocytopenia (all-grade, n=55 [71.4%]; any-grade, n=21 [27.3%]).

“Almost everybody had some toxicity, the most common of which were skin-related changes (n=72; 52.2%),” Dr. Kahl reported, with “excessive toxicities more likely to appear in cycles two and three.” Though not severe, he added, “toxicities could be very persistent.”

Eight patients (10%) discontinued treatment due to AEs (including increased gamma-glutamyltransferase [n=4]; increased blood alkaline phosphatase [n=1]; periorbital edema [n=1]; fatigue [n=1]; abdominal pain [n=1]; and thrombocytopenia [n=1]).

Response was evaluable in 68 patients receiving loncastuximab tesirine ≥120 µg/kg. The ORR was 60.3 percent (n=41), with 24 patients (35.3%) experiencing complete response (CR) and 17 (25.0%) experiencing partial response (PR).

In the subset of 49 patients with DLBCL treated with doses ≥120 µg/kg, the ORR was 55.1 percent (n=27), with 18 CRs (36.7%) and nine PRs (18.4%).

“Follow-up is short and early,” Dr. Kahl noted as a limitation of the analysis, but “the agent shows encouraging single-agent activity in fairly unfavorable patients.” Future studies will evaluate loncastuximab tesirine in specific NHL subtypes, Dr. Kahl concluded, adding that a dose-expansion phase in patients with DLBCL is being planned.

The authors report financial relationships with ADC Therapeutics, the manufacturer of loncastuximab tesirine.


Reference

Kahl BS, Hamadani M, Caimi P, et al. Encouraging early results from the first-in-human clinical trial of Adct-402 (loncastuximab tesirine), a novel pyrrolobenzodiazepine-based antibody drug conjugate, in relapsed/refractory B-cell Lineage non-Hodgkin lymphoma. Abstract #187. Presented at the 2017 ASH Annual Meeting, December 9, 2017; Atlanta, GA.

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