First-in-Human (FIH) Study of the Fully-Human Kappa-Lambda CD19/CD47 Bispecific Antibody TG-1801 in Patients (pts) with B-Cell Lymphoma (2022)

Introduction: Cancer cells elude anti-tumor immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Blockade of signal regulatory protein (SIRP)-α on macrophages, or of its ligand CD47 expressed on tumor cells, improves tumor cell elimination however CD47 is a challenging target given its ubiquitous distribution in healthy tissues. Combination of CD47 blockade with the anti-CD20 antibody rituximab has resulted in encouraging clinical activity (Advani 2018), and CD19 is also an established target of multiple B-NHL therapies. TG-1801 is a bispecific agent designed with a CD19 high-affinity arm and a blocking CD47 arm for concurrent target engagement on the tumor cells surface. Herein we report results of the FIH study for the first time. Methods: The primary objectives were to characterize the safety profile and to determine the recommended phase 2 dose (RP2D) of TG-1801. Other objectives included assessment of pharmacokinetics (PK), preliminary antitumor activity (Lugano 2014), and pharmacodynamics (PD: B-cell depletion). Eligible patients must have had relapsed/refractory (R/R) B-cell lymphoma after at least one prior standard therapy. A 3+3 design was utilized to evaluate sequentially higher doses of TG-1801 at the following dose levels: 20 mg, 60 mg, 180 mg, 360 mg, and 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. Patients who had at least stable disease after 2 cycles were given the option of receiving TG-1801 once every 4 weeks for an additional 4 infusions. Intra-patient dose escalations were permitted. An additional arm was enrolled with the combination therapy of ublituximab (anti-CD20 mAb) plus TG-1801. Patients received TG-1801 and ublituximab infusions in a 4 week-cycle: D1, D8, and D15 of C1; D1 of C2 thru C6; and D1 of C9 and every 3 cycles thereafter, up to 24 cycles. A 3+3 design was also utilized to evaluate two dose levels of TG-1801 (300 mg and 400 mg) with a standard dose of ublituximab (900 mg). Results: As of May 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). Patients were heavily pretreated: median 3 prior systemic therapies (range, 1 - 8), all had received ≥1 prior anti-CD20; 14 pts (46%) were refractory to their last prior therapy. Twenty-one (70%) had extranodal disease, and 9 (30%) had bulky disease. One DLT of grade (G) 4 thrombocytopenia occurred at the 500 mg dose level. The most common (>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 TEAE occurring in >20% of pts. Combination therapy was also well tolerated (TG-1801 at 300 mg N=3, 400 mg N=13) without DLT. The most common TEAE (≥20%) for combination therapy were: anemia (31%), headache, abdominal pain, fatigue, and thrombocytopenia (25% each), with no G3/4 TEAE occurring in >20% of pts. There were 2 permanent treatment discontinuations due to TEAE (1 infusion reaction [500 mg monotherapy], 1 rash [360 mg monotherapy]). Three partial responses (PR) were observed on monotherapy (n=14), all at 360 mg TG-1801, including 1 MZL pt with 7 prior lines that included PI3Ki, BTKi, auto transplant, and multiple prior anti-CD20s. All 3 pts completed 6 cycles of treatment and continued to further cycles of re-treatment. In the combination arm (n=16), a 44% response rate 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 for DLBCL patients and 50% ORR for FL patients. The median duration of combination therapy exposure was 8.7 mo (range of 1-20 mo). Responses appear durable, with ten pts remaining on study, with 1 pt receiving 360 mg monotherapy and 9 pts receiving combination therapy. Dose dependent increases in exposure were observed and pharmacodynamic analysis demonstrated a >50% depletion of circulating lymphocytes within 7 days of the first infusion in all evaluable pts. Conclusions: TG-1801 monotherapy and combination therapy demonstrates clinical activity, particularly in relapsed and refractory DLBCL, with an acceptable preliminary safety profile. This study (NCT03804996) has completed enrollment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal