Interim Futility Analysis of a Phase 2 Study of Loncastuximab Tesirine, a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Authors: Carlo-Stella Carmelo , Zinzani Pier Luigi Luigi , Kahl Brad S. , Caimi Paolo F , Solh Melhem , Townsend William , Stathis Anastasios , Cull Elizabeth H. , Hamadani Mehdi , Spira Alexander I. , Feingold Jay , Ungar David , He Shui , Qin Yajuan , Radford John 
Published: February 2020

Introduction: Patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after hematopoietic cell transplant or chimeric antigen receptor T-cell therapy, or those who are ineligible for such therapies, need more treatment options. Loncastuximab tesirine (ADCT-402; Lonca) is an antibody-drug conjugate (ADC) comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. Its target, the human CD19 antigen, is a classic B-cell marker expressed at normal-to-high levels on the majority of malignant B-cells. Preliminary data from a Phase 1 dose-escalation and dose-expansion trial of Lonca in R/R B-cell non-Hodgkin lymphoma showed significant clinical activity in DLBCL, with an acceptable safety profile, and the recommended Phase 2 dose of 150 μg/kg was identified. Here, we present the planned interim analysis for futility on the first 52 pts with R/R DLBCL treated with Lonca in Phase 2.
Methods: This single-arm, multi-center, open-label, two-stage, Phase 2 trial is currently enrolling pts ≥18 years of age with R/R DLBCL following ≥2 multi-agent systemic treatment regimens and without bulky disease (tumor ≥10 cm). The primary objective is to evaluate the efficacy of single-agent Lonca by overall response rate (ORR). The secondary objectives are to further evaluate efficacy (including duration of response [DOR], progression-free survival [PFS], and overall survival [OS]), to characterize the safety, pharmacokinetics and immunogenicity profile of Lonca, and to evaluate the impact of Lonca on health-related quality-of-life. Pts received 30-minute intravenous infusions of Lonca once every 3 weeks (1 cycle) at a dose of 150 μg/kg for the first 2 cycles, then 75 μg/kg for subsequent cycles, for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. A preplanned interim analysis for futility was conducted when the 52nd pt would have had 2 tumor assessments (approximately 12 weeks after the start of study drug), with the study planned to proceed to full enrollment if ≥10 of the first 52 pts responded to Lonca. ORR (complete response [CR] + partial response [PR]) was determined by an independent reviewer.
Results: 52 pts with DLBCL were included in the interim analysis. Pts had a median age of 62.5 years [range 24-84] and had received a median of 3 previous therapies (range 2-7; Table 1). As of the data cut-off of May 01, 2019, pts had received a median of 2.5 (range 1-9) cycles of Lonca.
ORR among the futility analysis population (52) was 44.2%, meeting futility requirements. A total of 10/52 (19.2%) and 13/52 (25.0%) pts attained CR and PR, respectively. In addition, 11 pts (21.2%) had stable disease (Figure 1).
All (100%) pts had at least 1 treatment-emergent adverse event (TEAE), and 37 (71.2%) pts had grade ≥3 TEAEs. The most common all-grade non-hematological TEAEs, regardless of relationship to study treatment, were gamma-glutamyltransferase (GGT) increase (24 [46.2%]), pyrexia (18 [34.6%]) and hypokalemia (15 [28.8%]); pleural effusions and peripheral edema were reported in 5/52 pts (9.6%) and 6/52 pts (11.5%), respectively; 1 of these pts had a grade ≥3 event (pleural effusion). The most common grade ≥3 TEAEs were GGT increase (11 [21.2%]), hypercalcemia (4 [7.7%]) and hypokalemia (3 [5.8%]). No grade ≥3 skin-related TEAEs have been reported. The most common all-grade hematological abnormalities were platelet count decreased* (34 [65.4%]), neutrophil count decreased* (27 [51.9%]) and anemia (14 [26.9%]), and the most common grade ≥3 hematological abnormalities were neutrophil count decreased* (15 [28.8%]), platelet count decreased* (10 [19.2%]) and anemia (6 [11.5%]). Overall, 26 (50%) pts had TEAEs leading to dose reductions/delays and 10 (19.2%) pts had TEAEs leading to treatment discontinuation.
Conclusions: Lonca has demonstrated encouraging single-agent anti-tumor activity and manageable toxicity in pts with R/R DLBCL. Futility requirements were met and pts are now enrolling in stage 2 of the trial. Updated efficacy results will be presented at the meeting.
*Laboratory abnormality data are reported for platelet count decreased and neutrophil count decreased to avoid under-reporting of these events.
Study sponsored by ADC Therapeutics SA. http://clinicaltrials.gov/show/NCT03589469

Disclosures
Carlo-Stella: Amgen: Honoraria; Boehringer Ingelheim: Consultancy; AstraZeneca: Honoraria; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Other: Travel, accommodations; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Genenta Science srl: Consultancy; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Janssen: Other: Travel, accommodations; Janssen Oncology: Honoraria; BMS: Honoraria; MSD: Honoraria. Zinzani:VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Caimi:ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Townsend:Roche: Consultancy, Honoraria. Stathis:PharmaMar: Other: Renumeration; Roche: Other: Institutional research funding; Pfizer: Other: Institutional research funding; MEI-Pharma: Other: Institutional research funding; Novartis: Other: Institutional research funding; Merck: Other: Institutional research funding; Bayer: Other: Institutional research funding; Abbvie: Other: Renumeration; ADC Therapeutics: Other: Institutional research funding. Cull:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Takeda: Research Funding; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Merck: Research Funding. Spira:Novartis: Research Funding; Roche: Research Funding; Boehringer Ingelheim: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Newlink Genetics: Research Funding; BMS: Consultancy; Virginia Cancer Specialists: Employment; MedImmune: Research Funding. Feingold:ADC Therapeutics: Employment, Other: Potential equity interest. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. He:ADC Therapeutics: Employment, Other: Potential equity interest. Qin:ADC Therapeutics: Consultancy, Other: Potential equity interest. Radford:AstraZeneca: Equity Ownership, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; GSK: Equity Ownership; Seattle Genetics: Consultancy, Honoraria.