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