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398 Interim Results from the First-in-Human Clinical Trial of Adct-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: New Agents
Hematology Disease Topics & Pathways:
Adult, Diseases, Biological, Therapies, B-Cell Lymphoma, Study Population, Lymphoid Malignancies
Sunday, December 2, 2018: 12:15 PM
Pacific Ballroom 20 (Marriott Marquis San Diego Marina)

John Radford, MD, FRCP1*, Brad S. Kahl, MD2*, Mehdi Hamadani, MD3, Carmelo Carlo-Stella, MD4, Paolo Caimi, MD5, Kirit M. Ardeshna, MBBChir6, Jay Feingold, MD, PhD7*, Shui He, PhD8*, Erin Reid, MD9*, Melhem Solh, MD10, Ki-Young Chung, MD11*, Leonard Heffner, MD12, David Ungar, MD13 and Owen A. O'Connor, M.D., Ph.D.14

1Manchester Academic Health Centre, The University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom
2Siteman Cancer Center, Washington University, St Louis, MO
3Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI
4Hematology, Humanitas Cancer Center, Rozzano, Milano, Italy
5University Hospitals of Cleveland, Cleveland, OH
6Department of Haematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
7ADC Therapeutics, Inc, Murray Hill, NJ
8ADC Therapeutics, Inc., Murray Hill, NJ
9Department of Hematology/Oncology, Moores Cancer Center, University of California, San Diego, CA
10Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA
11Department of Hematology and Oncology, Greenville Health System, Greenville, SC
12Winship Cancer Institute / Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
13ADC Therapeutics America, Inc, Murray Hill
14Center for Lymphoid Malignancies, Department of Medicine, Columbia University, New York, NY

Introduction: Diffuse large B-cell lymphoma (DLBCL) represents 33% of the non-Hodgkin lymphomas (NHL) and expresses CD19, a classic B-cell marker found on B lymphocytes. ADCT-402 (loncastuximab tesirine; Lonca-T) is an antibody drug conjugate comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. This first-in-human clinical study evaluated the safety and efficacy of Lonca-T in patients (pts) with relapsed/refractory (R/R) B-cell lineage NHL. Here we present interim results in the subgroup of pts with DLBCL. Interim efficacy and safety of Lonca-T in pts with follicular lymphoma and mantle cell lymphoma are presented in a separate abstract.

Methods: Pts ≥18 years of age with R/R DLBCL who have failed or are intolerant to established therapies, or have no other treatment options available, were enrolled in this Phase 1, multicenter, open-label, single-arm study, including dose-escalation and dose-expansion parts. The primary objectives are to evaluate the safety and tolerability of Lonca-T, and determine the recommended dose(s) to use for expansion cohorts. The secondary objectives are to evaluate the clinical activity (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival [OS]), pharmacokinetics, pharmacodynamics, and anti-drug antibody activity. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle), with a 3+3 dose-escalation design for the dose-escalation part of the study. No intra-pt dose escalation is allowed.

Results: As of June 20, 2018, 183 pts had been enrolled on the study, including 137 with DLBCL (79 male, 58 female). Pts with DLBCL had a median age of 63 years [range 20–86], and had received a median of
3 previous therapies (range 1–10; Table). Pts received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1–13]). Treatment-emergent adverse events (TEAEs) were reported in 136/137 (99.3%) pts, and grade ≥3 TEAEs in 100/137 (73.0%) pts. The most common all-grade TEAEs (≥20% pts), regardless of relationship to study treatment, were fatigue (57 [41.6%]), nausea (44 [32.1%], peripheral edema (44 [32.1%]), anemia (39 [28.5%]), rash (35 [25.5%]), gamma-glutamyltransferase (GGT) increased (33 [24.1%]), constipation (30 [21.9%]), dyspnea (29 [21.2%]), and thrombocytopenia (28 [20.4%]). The most common grade ≥3 TEAEs (>10% pts) were GGT increased (21 [15.3%]), neutropenia (20 [14.6%]), neutrophil count decreased (19 [13.9%]), anemia (15 [10.9]), thrombocytopenia (15 [10.9%]) and platelet count decreased (14 [10.2%]. Approximately 66% and 72% of pts in the 120 and 150 µg/kg groups, respectively, tolerated at least 2 cycles before any AE leading to dose reduction/delay occurred.

The figure depicts tumor response data. Out of 132 evaluable pts with DLBCL, the ORR was 40.2% (53/132 pts), comprising 29/132 (22.0%) complete responses (CRs) and 24/132 (18.2%) partial responses (PRs). Median DoR was 4.17 months and PFS was 2.79 months after a median follow-up of 5.13 months. Median DoR was not reached in pts achieving a CR and was 2.76 months in pts with a PR. In pts with non-bulky disease, the ORR was 44.2% (50/113 pts); 28/113 (24.8%) pts attained a CR and 22/113 (19.5%) pts attained a PR. The majority of pts (122/132) received doses ≥120 µg/kg; in these pts, the ORR was 41.8% (51/122 pts), with 28/122 (23.0%) pts attaining a CR and 23/122 (18.9%) pts attaining
a PR.

Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging and durable single-agent antitumor activity and manageable toxicity in pts with R/R DLBCL at doses ≥120 µg/kg. Updated safety, tolerability, and efficacy results will be presented at the meeting.

Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017.

Disclosures: Radford: ADC Therapeutics: Consultancy, Research Funding; Celgene: Research Funding; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Pfizer: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership. Kahl: Seattle Genetics: Consultancy; Genentech: Consultancy; ADC Therapeutics: Research Funding. Hamadani: Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Research Funding; Cellerant: Consultancy; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy; Merck: Research Funding. Carlo-Stella: Boehringher Ingelheim Italia: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Genenta Science: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau. Caimi: Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Ardeshna: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Feingold: ADC Therapeutics: Employment, Equity Ownership. He: ADC Therapeutics: Employment, Equity Ownership. Reid: AbbVie: Research Funding; Millenium Pharmaceuticals: Research Funding; ADC Therapeutics: Research Funding. Solh: ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Chung: ADC Therapeutics: Research Funding. Heffner: Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Ungar: ADC Therapeutics: Employment, Equity Ownership. O'Connor: ADC Therapeutics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.

*signifies non-member of ASH