Background and Significance. Approximately 30% of patients with large B-cell lymphoma (LBCL) treated with autologous anti-CD19 CAR T-cell therapy (CART) achieve a partial response (PR) on day 30 (D30) assessment. Of those, up to 30% may spontaneously convert to a complete response (CR) during subsequent re-staging. While up to 70% of patients with D30 PR eventually progress, reliable biomarkers that help identify patients at risk are not yet available, and the current standard approach is close monitoring. CD19 expression is retained in most tumors of patients who relapse or progress after CART. Potential reasons for resistance in these tumors include T-cell dysfunction and tumor intrinsic mechanisms that resist T-cell mediated killing. Therefore, targeting such tumors with agents that have an alternative mechanism of action is likely to improve outcomes. To this regard, loncastuximab tesirine (Lonca) is an anti-CD19 antibody conjugated to a cytotoxic pyrrolobenzodiazepine dimer approved by the FDA for LBCL patients who relapse after at least 2 lines of systemic therapy. In the phase 2 LOTIS-2 study, Lonca was associated with an overall response rate of 48% and a CR rate of 24%, and included patients previously treated with CART. Grade 3-4 adverse events were observed in less than one third of patients, and were mainly represented by myelosuppression, skin toxicity and isolated GGT elevation.

Study Design and Methods. This is a phase 2 single center study to investigate the safety and efficacy of Lonca as a consolidation strategy for LBCL patients with D30 PR after standard of care CART (NCT05464719). Patients with LBCL, including diffuse large B-cell lymphoma, high grade B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed follicular lymphoma, treated with standard of care CART (in second line and beyond) and with PET-CT evidence of D30 PR are eligible for this study. Patients with absolute neutrophil count < 1000/uL and/or platelet count < 50,000/uL, and those with previous or active central nervous system involvement are excluded. Tissue biopsy for confirmation of PR will be performed; CD19 expression is not required for eligibility.

Lonca is administered intravenously, on day 1 of a 21-day cycle, at a dose of 150 mcg/kg for the first 2 cycles, and 75 mcg/kg subsequently, for a total of 6 cycles. Response is assessed by PET-CT, according to 2014 Lugano criteria, after 3 cycles and at the end of treatment. The primary objective is efficacy, measured as conversion from D30 PR to CR. Using a one arm binomial exact test, hypothesizing an increase in conversion rate to CR from 30% to 60%, a sample size of 30 patients has a 90% power to observe a significant difference, with an alpha error of 0.05; a futility analysis, based on efficacy and toxicity, will be performed after the first 10 patients are treated.

Secondary objectives are safety and other measurements of efficacy, including duration of CR.

Exploratory objectives include identification of biomarkers of response and resistance. Peripheral blood samples will be collected pre-treatment, after 3 cycles, post-treatment and at time of progression, as well as collection of a pre-treatment tissue biopsy and at time of progression. Blood and tissue samples will be analyzed by multi-parameter flow cytometry and hiplex imaging assays (Phenocycler-Fusion/CODEX) to identify immune signatures of response and resistance to Lonca, and to assess CAR T-cell persistence; blood samples will be analyzed by CAPP-Seq to measure minimal residual disease. Finally, total metabolic tumor volume will be assessed on pre-treatment PET-CT scans, and association with response to consolidation therapy will be analyzed.

Westin:Kymera: Research Funding; Abbvie: Consultancy; BMS: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Nurix: Consultancy; Calithera: Research Funding; AstraZeneca: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; SeaGen: Consultancy; MonteRosa: Consultancy; Genentech: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding. Shpall:Fibrobiologics: Membership on an entity's Board of Directors or advisory committees; Axio: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: License agreement; Affimed: Other: License agreement; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Navan: Membership on an entity's Board of Directors or advisory committees; Celaid Therapeutics: Membership on an entity's Board of Directors or advisory committees; NY Blood Center: Membership on an entity's Board of Directors or advisory committees; Syena: Other: License agreement. Nastoupil:AstraZeneca: Honoraria; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Genentech, Inc., Genmab, Gilead/Kite, Janssen, Merck, Novartis, Takeda: Honoraria, Research Funding; Regeneron: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; DeNovo: Honoraria; Caribou Biosciences: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria. Flowers:Burroghs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Jannsen Pharmaceuticals: Research Funding; National Cancer Institute: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; V Foundation: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Beigene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech Roche: Consultancy, Research Funding; Genmab: Consultancy; Adaptimmune: Research Funding; Acerta: Research Funding; 4D: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Pharmacyclics Jansen: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; CPRIT Scholar in Cancer Research: Research Funding. Ahmed:ADC Therapeutics: Consultancy; Servier: Consultancy; Kite/Gilead: Consultancy; Chimagen: Research Funding; Genmab: Research Funding; Merck: Research Funding; Seagen: Research Funding; Tessa Therapeutics: Research Funding. Neelapu:Bluebird Bio: Consultancy, Other: Advisory board member; Longbow Immunotherapy: Current holder of stock options in a privately-held company; Merck: Consultancy, Other: Advisory Board Member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Takeda: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Caribou: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property); Janssen: Consultancy, Other: Advisory board member; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Synthekine: Consultancy, Other: Advisory board member; Orna Therapeutics: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Sellas Life Sciences: Consultancy, Other: Advisory board member; Precision Biosciences: Research Funding; Carsgen: Consultancy; Fosun Kite: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Allogene: Consultancy, Other: Advisory board member, Research Funding; Incyte: Consultancy, Other: Advisory board member; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding. Strati:Hutchinson MedoPharma: Consultancy; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astrazeneca Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Genentech: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding.

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2023
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