Elstrom, Rebecca

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 ) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received > 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m 2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.

Abstract Abstract 3680 Background: Current NHL radioimmunotherapy is administered with unlabeled antibody targeting the same B-cell antigen. This decreases sequestration of the radiolabeled antibody by normal B-lymphocytes, but potentially blocks access of the radiolabeled antibody to the tumor sites. In clinical studies, yttrium-90 radiolabeled anti-CD22 epratuzumab (90Y-epratuzumab) has demonstrated therapeutic activity with acceptable toxicity when given weekly × 2 at doses up to 20 mCi/m2 (Morschhauser et al., J Clin Oncol. 2010;28:3709–16), while separate studies showed that a 200-mg/m2 dose of anti-CD20 veltuzumab given weekly × 4 readily depletes peripheral blood B-cells and is also therapeutically active (Morschhauser et al., J Clin Oncol, 2009;27:3346–53). In mice bearing human B-cell lymphoma xenografts, this non-competing combination showed improved therapeutic responses over either agent alone (Mattes et al., Clin Cancer Res. 2008;14:6154–60). As such, a multicenter, phase I/II study was undertaken to evaluate combination therapy with 90Y-epratuzumab and veltuzumab. Methods: Adult patients with aggressive NHL who failed ≥ 1 prior standard regimen (excluding autologous SCT) were eligible if they had measurable CT lesions, ECOG 0–1 performance status, <25% bone marrow involvement, hemoglobin ≥ 10 g/dL, ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L and were >4 weeks beyond last treatment. All patients received a 4-week treatment regimen (weekly 200 mg/m2 veltuzumab, 3–5 mCi 111In-epratuzumab on week 2, 90Y-epratuzumab on weeks 3 and 4). Using NCI CTCAE v4.0 toxicity criteria, dose-limiting toxicity (DLT) was defined as Grade 4 hemoglobin, platelet or neutrophil levels >7 days or not recovered to Grade 1 by 12 weeks, or any non-hematologic Grade 3 or 4 events. Starting at 15 mCi/m2, a standard 3+3 dose escalation determined the MTD of 90Y-epratuzumab. Treatment response utilized CT-based 2007 IWG revised criteria. Serial 111In imaging and serum samples were used to assess biodistribution, tumor targeting and determine normal organ radiation dosimetry. ELISA-based assays were used to measure veltuzumab pharmacokinetics and any human anti-veltuzumab antibodies (HAHA). Results: Fifteen patients (10 male/5 female, 56 – 84 years old) with diffuse large B-cell lymphoma (DLBCL N=7), transformed follicular lymphoma (TFL, N=4) or mantle cell lymphoma (MCL, N=4) have now been enrolled. They had 3 median prior treatments (1 – 7) [RCHOP (N=15); bendamustine plus rituximab (N=5); ICE, lenalidomide, bortezomib (N=2 each); others (1 each)] and had low (N=3), low-intermediate (N=3), high-intermediate (N=7), or high (N=2) IPI risk scores. Treatment was well-tolerated with no infusion reactions. 111In-imaging showed normal biodistribution, with acceptable normal organ dosimetry for the scheduled 90Y dose, and tumor targeting occasionally visualized. There was no evidence of HAHA, and the serum clearance of veltuzumab and 111In-epratzumab in combination was comparable to that reported previously for these agents alone. The 90Y dose was repeatedly de-escalated from 15 (N=3) to 12 (N=3), 9 (N=6), and currently 6 (N=3) mCi/m2 due to 7 hematologic DLTs at ≥ 9 mCi/m2in 6 patients involving Grade 3-thrombocytopenia (N=5) or neutropenia (N=2). Clinically, there were 3 SAEs (pneumonia, non-infectious pneumonitis, fracture from fall), but no other major infections or bleeding. Of 11 patients who have now had treatment response assessments, 5 (45%) had objective responses, including one DLCBL patient with a complete response (CR) continuing 12 months later and 4 patients (1 DLBCL, 3 TFL) with partial responses (PRs), with one continuing at 4 weeks and 3 relapsed at 3 – 6 months. Four other patients (1 DLBCL, 3 MCL) achieved stable disease (SD) continuing up to 6 months as best response, resulting in a disease control rate of 82% (CR+PR+SD). Conclusions: Combination treatment was well-tolerated, with the PK behavior of the two agents substantially unchanged, and with initial evidence of therapeutic activity (including one durable CR) in these difficult-to-treat patients. Hematologic toxicity necessitated lowering the 90Y dose, most likely due to the prior aggressive chemotherapies or depletion of the normal sequestering B-cell pool by veltuzumab preceding 90Y-epratzumab. The trial is continuing to determine an acceptable 90Y dose and define the safety and efficacy profile of this combination approach. Disclosures: Sharkey: Immunomedics: Employment. Rojo:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was &gt;95% at all doses. Sustained complete (&gt;95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in &gt;2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.