First-in-Human (FIH) Study of the Fully-Human Kappa-Lambda CD19/CD47 Bispecific Antibody TG-1801 in Patients (pts) with B-Cell Lymphoma

Introduction: CD19 is an established target of multiple B-cell lymphoma therapies. Blockade of CD47, a macrophage immune checkpoint inhibitory ligand, induces tumor-cell phagocytosis. TG-1801 is a CD19/CD47 bispecific antibody designed to selectively block CD47 on CD19+ cells, while retaining a functional IgG1 Fc domain. Herein we report updated results from the FIH study. Methods: The primary objectives of this phase I 3+3 study were to characterize the safety profile and determine the recommended phase 2 dose (RP2D) as monotherapy and in combination with ublituximab. Pharmacokinetics, pharmacodynamics, and preliminary antitumor activity were also assessed. Eligible patients (pts) had relapsed/refractory (R/R) B-cell lymphoma after ≥1 prior standard therapy. TG-1801 doses evaluated included: 20 mg, 60 mg, 180 mg, 360 mg, & 500 mg. In the monotherapy arm, treatment consisted of weekly fixed dosing 1h-infusions of TG-1801 in a 4-week cycle: day (D)1, D8, D15, and D22 of cycle (C) 1 and C2. Pts who had at least stable disease after 2 cycles continued with TG-1801 once every 4 weeks for 4 further infusions. Intra-pt dose escalations were permitted. A second arm explored the combination of TG-1801 with ublituximab; an anti-CD20 mAb. Pts received TG-1801 and ublituximab, IV every 4 weeks: D1, D8, and D15 of C1; D1 of C2-C6; and D1 of C9 and every 3 cycles thereafter, up to 24 cycles. 2 dose levels of TG-1801 (300 mg and 400 mg) with 900 mg of ublituximab were tested. Responses were assessed by Lugano 2014 criteria. Results: As of October 2022, 14 pts (MZL = 5, DLBCL including Richter’s transformation = 5, FL = 4) received monotherapy and 16 pts received combination therapy (DLBCL = 9, FL = 4, MZL = 2, MCL = 1). Pts had a median of 3 prior therapies (range, 1–8) with 16 pts (53%) refractory to their last therapy. One DLT of grade (G) 4 thrombocytopenia occurred at 500 mg monotherapy. Most frequent (>20%) treatment emergent adverse events (TEAEs) at monotherapy doses of 20 mg to 360 mg (n = 10) included fatigue, thrombocytopenia, and infusion-related reaction (3 pts each), with no G3/4 TEAEs occurring in >20% of pts. Combination therapy was also well tolerated (TG-1801 at 300 mg N = 3, 400 mg N = 13) without DLT. Most common TEAEs (≥20%) for combination therapy were anemia, headache, and fatigue (5 pts each), with no G3/4 TEAEs occurring in >20% of pts. 2 pts permanently discontinued therapy due to TEAEs (1 infusion reaction [500 mg monotherapy], 1 rash [360 mg monotherapy]). Among 13 evaluable monotherapy pts, there were 3 (ORR = 23%) partial responses (PR). In combination (n = 16), a 44% ORR was observed with 1 complete response (CR) in a pt with FL and 6 PR (5 pts with DLBCL and 1 pt with FL) for a 56% ORR in DLBCL and 50% ORR in FL. The research was funded by: TG Therapeutics Inc. Keywords: Combination Therapies, Immunotherapy, Targeting the Tumor Microenvironment Conflicts of interests pertinent to the abstract. E. A. Hawkes Consultant or advisory role: Advisory board and speaker fees (institutional or personal) from Roche, Merck Sharpe & Dohme, Astra Zeneca, Gilead, Antigene, Novartis, Regeneron, Janssen, Specialised Therapeutics, outside the submitted work Research funding: Roche, Bristol Myers Squibb, Merck KgA, Astra Zeneca and Merck K. L. Lewis Consultant or advisory role: Astrazeneca, Roche, Loxo/Lilly, IQVIA, MSD Honoraria: Astrazeneca, Janssen, Roche H. P. Miskin Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. P. Sportelli Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. K. S. Kolibaba Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. E. Normant Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. T. Turpuseema Employment or leadership position: TG Therapeutics Inc. Stock ownership: TG Therapeutics Inc. C. Y. Cheah Consultant or advisory role: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS Honoraria: Roche, Janssen, Gilead, AstraZenecca, Lilly, TG therapeutics, Beigene, Novartis, Menarini, Daizai, Abbvie, Genmab. BMS Research funding: BMS, Roche, Abbvie; MSD, Lilly