A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma.

Abstract

PURPOSE:

ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate comprising a CD19-targeting antibody and pyrrolobenzodiazepine dimers. A first-in-human study evaluated the safety and preliminary clinical activity of loncastuximab tesirine in patients with B-cell non-Hodgkin lymphoma (NHL).

PATIENTS AND METHODS:

A multicenter, phase I, dose-escalation and dose-expansion study enrolled patients ages ≥18 years with relapsed/refractory (R/R) B-cell NHL. Patients received loncastuximab tesirine every 3 weeks at doses assigned by a 3+3 dose-escalation design. Dose escalation was used to assess the safety and tolerability of loncastuximab tesirine to determine the dose for expansion. Secondary objectives evaluated clinical activity, characterized the pharmacokinetic profile, and evaluated antidrug antibodies.

RESULTS:

During dose escalation, 88 patients with R/R B-cell NHL were treated with loncastuximab tesirine at doses 15 to 200 μg/kg. Treatment-emergent adverse events (TEAEs) were experienced by 87/88 (98.9%) patients. Most common TEAEs (≥20% of patients) were hematologic abnormalities, fatigue, edema, liver test abnormalities, nausea, rash, and dyspnea. Grade ≥3 TEAEs (≥5% of patients) included hematologic abnormalities, liver test abnormalities, fatigue, and dyspnea. Overall response rate at doses ≥120 μg/kg was 59.4% (41 of 69 patients; 40.6% complete response; 18.8% partial response). Median duration of response, progression-free survival, and overall survival (all doses) were 4.8, 5.5, and 11.6 months, respectively. Drug exposure increased with increasing dose, showing moderate accumulation with multiple doses ≥150 μg/kg. There was no evidence of immunogenicity.

CONCLUSIONS:

Loncastuximab tesirine had promising activity with acceptable safety in this dose-escalation study. A phase II study with initial dosing at 150 μg/kg has been initiated based on these results.

• Authors: Brad S Kahl, Mehdi Hamadani, John Radford, Carmelo Carlo-Stella, Paolo Caimi, Erin Reid, Jay M Feingold, Kirit M Ardeshna, Melhem Solh, Leonard T Heffner, David Ungar, Shui He, Joseph Boni, Karin Havenith, Owen A O'Connor
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 23 Pg. 6986-6994 (12 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31685491 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antigens, CD19
• Antineoplastic Agents
• CD19 molecule, human
• Immunoconjugates
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• Benzodiazepines
• loncastuximab tesirine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antigens, CD19 (chemistry, immunology)
• Antineoplastic Agents (therapeutic use)
• Benzodiazepines (chemistry, therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Follow-Up Studies
• Humans
• Immunoconjugates (therapeutic use)
• Lymphoma, B-Cell (immunology, pathology, therapy)
• Male
• Middle Aged
• Neoplasm Recurrence, Local (immunology, pathology, therapy)
• Prognosis
• Pyrroles (chemistry)
• Salvage Therapy
• Survival Rate
• Young Adult