Phase 1 Study of TT-01488, a Novel, Non-Covalent, Reversible BTK Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies

Background: Bruton's tyrosine kinase (BTK) plays a critical role in the B-cell receptor signaling pathway, functioning as an important regulator of cell proliferation and cell survival in various B-cell malignancies. Currently there are 5 approved irreversible and covalent BTK inhibitors (BTKis). Due to the off-target side effects and the emergence of mutants at the BTK binding sites (C481) resulting in acquire resistance to the irreversible BTKis, there is a high unmet medical need to develop next generation of BTKi. TT-01488 is a novel, non-covalent, reversible and potent BTKi and C481-mutant BTKi which can overcome acquired resistance to irreversible BTKi. In the preclinical study, TT-01488 demonstrated antitumor activity in B-cell lymphoma CDX models . Here it is first time to present the phase 1 study of TT-01488. Methods: TT01488CN02 is a phase 1, open-label, multi-center study of TT-01488 monotherapy in pts with R/R B-cell Non-Hodgkin Lymphomas (B-NHL). This study contains a dose escalation phase, followed by dose expansion in several cohorts. Dose escalation is performed using “3+3” design. Adverse events (AE) are evaluated per CTCAE v5.0 criteria. Tumor responses are evaluated per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for pts with chronic lymphocytic leukemia (CLL), per the 7th International Workshop on Waldenström Macroglobulinemia (IWWM-7) criteria for pts with Waldenström macroglobulinemia (WM), and per 2014 Lugano criteria for other B-NHL ps. Pts receive single or twice daily oral administration of TT-01488 continuously for 28-day cycles. The primary endpoint is to evaluate dose limiting toxicity (DLT) and identify the maximum tolerated dose (MTD) and/or dose recommended for dose expansion (DRDE). Results: As of the data cut-off date on July 16, 2024, 11 patients (pts) have received TT-01488 treatment in 50 mg (n=4), 100 mg (n=4) and 150 mg (n=3) at QD dose levels, including 1 with CLL, 1 with WM, 1 with marginal zone lymphoma (MZL), 2 with follicular lymphoma (FL), 3 with mantle cell lymphoma (MCL) and 3 with diffuse large B-cell lymphoma (DLBCL). Median age was 59.8 (43~69), 6 (54.5%) were males, all had ECOG PS ≤1, 7 (63.6%) were relapsed disease, 4 (36.4%) were refractory disease. The median number of prior therapies was 3 (range 1~6), all pts had prior chemotherapy, 10 (90.9%) had prior anti-CD20 antibody therapy, 8 (72.7%) had prior irreversible BTKi therapy. No DLT was observed. Treatment -related AEs (TRAEs) were reported in 10 (90.9%) pts, grade 3 in 4 (36.4%), grade 4 in 1 (9.1%), and no grade 5. The most common TRAE (≥20%) were hypertriglyceridemia (63.6%), nausea (36.4%), hypokalemia (27.3%) and anemia (27.3%). Among 8 efficacy evaluable pts, 2 complete remission (CR) and 1 partial remission (PR) were achieved in ≥100mg dose cohorts, including WM (n=1, PR) and MCL (n=2, CR). One pt with MCL who previously received Orelabrutinib and had a BTK C481S mutation achieved CR lasting for over 13 months. Another pt with WM who previously received Ibrutinib achieved PR lasting for over 11 months. PK/PD and biomarker data will be presented. Conclusion: TT-01488 monotherapy was well-tolerated in pts with heavy R/R B-NHL. No DLT occurred at daily doses up to 150mg. The preliminary antitumor activity was observed. Further evaluation of dose and dosing schedule is to provide the DRDE. Clinical trial information: NCT05683717