SMART STOP: A PHASE II CLINICAL TRIAL OF LENALIDOMIDE, TAFASITAMAB, RITUXIMAB, AND ACALABRUTINIB ALONE AND WITH RESPONSE ADAPTED CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED DLBCL

Background: Diffuse Large B-cell Lymphoma (DLBCL) is cured in ∼60% of patients by a chemotherapy-based approach which largely unchanged for decades. We have previously shown the feasibility and significant efficacy targeted therapy combination as initial treatment with newly diagnosed LBCL (Smart Start, Westin et al, JCO 2023). BTK inhibitors like acalabrutinib (A) immunomodulatory agent lenalidomide (L) activity single agents, result synthetic lethality when combined non-GCB DLBCL models. Both CD19 antibody tafasitamab (T) CD20 rituximab (R) demonstrated clinical L relapsed DLBCL. L, T, R, A are also immunomodulatory, shifting from tumor-mediated immune anergy to an anti-tumor response. Study Design Methods: Smart Stop phase II, open-label, single-center trial combining LTRA alone cyclophosphamide, doxorubicin, vincristine prednisone (CHOP) untreated (NCT04978584). Eligibility criteria include adult adequate organ bone marrow function. Patients receive 25 mg daily days 1-10, 12 mg/kg IV weekly, 375 mg/m2 day 1, 100 PO twice during 21 cycle. All four cycles, unless suspicion disease progression. PET/CT scan using 5 point Deauville score (5PS) will determine response, complete response (CR) defined 5PS 2, or 3. The two sequential cohorts 30 each. who achieve CR 6 additional cycles uLTRA, CHOP 2 (Cohort Group A) no (cohort C). less than (Group B D) LTRA-CHOP planned 10 all patients. utilize decision rules based upon results cohort 1 open 2: 1) probability sustained CRR at end therapy, 2) 7 months after first primary objectives 1A: overall rate 4 1B: +/-CHOP therapy. maximum sample size 60 Secondary survival outcomes, safety, outcomes without CHOP, CHOP. Exploratory determining ctDNA modulation driven LTRA, associated characteristics. opened 5/2022 actively recruiting research was funded by: Incyte/Morphosys, AstraZeneca, BMS Keywords: ongoing trials Conflicts interests pertinent abstract. J. Consultant advisory role Kite/Gilead, BMS, Novartis, Genentech, Morphosys/Incyte, ADC Therapeutics, Abbvie, SeaGen, MonteRosa, Regeneron Research funding: Kymera, Calithera