Safety and Efficacy of Tgrx-678, a Potent BCR::ABL1 allosteric Inhibitor, in Patients with Tyrosine Kinase Inhibitor Resistant and/or Intolerant Chronic Myeloid Leukemia: Updated Results of Phase 1 Study Tgrx-678 -1001
Authors: Jiang Qian , Weiming Li , Zhang Yanli , Wang Qiang , Chen Suning , Liu Bingcheng , Liu Zhuogang , Jin Jie , Liu Zhenfang , Weng Jianyu , Du Xin , Zhao Xielan , Meng Li , Lin Lie , Ye Wanlin , Yan Shujie , Wang Yihan , Cao Jingrong 
Published: December 2024

Background: TGRX-678 a novel allosteric inhibitor of ABL kinases that specifically targets the ABL Myristoyl Pocket (STAMP). Study TGRX-678-1001 (NCT05434312) is a phase Ia/Ib, first-in-human, open-label trial designed to evaluate the safety, efficacy and pharmacokinetics (PK) of TGRX-678 in TKI resistant/intolerable (R/I) patients with chronic myeloid leukemia in the chronic phase or accelerated phase (CML-CP or CML-AP). Here we present the updated data.

Methods: In phase Ia, CML-CP and CML-AP patients who were R/I at least to imatinib, dasatinib and nilotinib were enrolled. Patients received escalating doses of TGRX-678, ranging from 10 to 80 mg (BID) or 40 to 240 mg (QD). MTD was not reached. In phase Ib, patients were enrolled in 3 cohorts: CML-CP without T315I mutation and failure of ≥ 2 TKIs, CML-CP with T315I mutation and failure of ≥ 1 TKI, and CML-AP with failure of ≥ 1 TKI. TGRX-678 was given at the dosages of 80 and 240 mg QD. Primary objective was maximum tolerated dose (MTD) based on dose limiting toxicity. Secondary objectives included safety, preliminary efficacy, such as major hematologic response (MaHR), complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), and PK.

Results: As of the data cut-off (June 02, 2024), 158 patients (CP n = 108, AP n = 50) received TGRX-678. Of these, 67 (43%) patients were female. The median age was 46 (range 19-74, IQR 36-56) years, and median interval from diagnosis to initial TGRX-678 treatment was 93 (IQR 29-151) months. Patients were heavily pretreated; 71 (66%) CP and 44 (88%) AP patients had received ≥ 3 prior TKIs; 40 (37%) CP and 30 (60%) AP patients had previously received ponatinib, olverembatinib, asciminib, and/or HS-10382 (a new STAMP inhibitor). 91 (84%) CP and 46 (92%) AP patients had BCR::ABL &gt;10%. 25 (23%) CP and 17 (34%) AP patients had a single T315I mutation; 8 (7%) CP and 3 (6%) AP patients had T315I + an additional mutation; 14 (13%) CP and 14 (28%) AP patients had other mutations; 61 (56%) CP and 16 (32%) AP patients had no mutation.

The median treatment duration of TGRX-678 was 13 months (IQR 9-18 ). At the cut-off date, treatment was ongoing in 90 (83%) CP and 29 (58%) AP patients. Patients discontinued treatment due to disease progression (n = 10), adverse events (AEs, n = 5), physician's decision (n = 9), or consent withdrawal (n = 12). There was one death occurred, which was not drug related. With a median follow-up of 16 months (IQR 11-21), ≥ G3 hematological TRAE included thrombocytopenia (46%), neutropenia (44%), leukopenia (28%) and anemia (27%). The most common non-hematological TRAEs were grade 1 or 2, including hypertriglyceridemia (54%), hyperuricemia (44%), hypercholesterolemia (30%) and hyperglycemia (29%).

In evaluable CP patients, 40/49 (82%) achieved CHR within 3 cycles. Among all 108 CP patients, the 18-month cumulative incidences of MCyR, CCyR, and MMR were 52%, 40%, and 26%, respectively. In patients with a single T315I mutation, 16/20 (80%) achieved CHR, the 18-month cumulative incidences of MCyR, CCyR, and MMR were 76%, 69%, and 50%, respectively. In patients receiving prior 3G-TKI or STAMP inhibitors, the 18-month cumulative incidences of MCyR and CCyR were 32% and 17%, respectively.

In evaluable AP patients, 35/42 (83%) and 33/42 (79%) achieved MaHR and CHR within 3 cycles. The 18-month cumulative incidences of MCyR, CCyR, and MMR were 35%, 30%, and 14%, respectively. In patients with a single T315I mutation, the 18-month cumulative incidences of MCyR, CCyR, and MMR were 36%, 30%, and 15%, respectively. In those receiving prior 3G-TKI or STAMP inhibitors, the 18-month cumulative incidences of MCyR and CCyR were 23% and 17%, respectively.

The PK results suggested that TGRX-678 exposure (Cmax and AUCtau) was dose-proportional. The terminal half-life was found to be long (&gt; 120 hrs), resulting in substantial drug accumulation.

Conclusions: With more patients and extended follow-up, TGRX-678 showed well tolerated with no new safety signals identified. The updated data indicate promising efficacy in both CP and AP patients including those with the T315I mutation and those who failed 3G-TKI or STAMP inhibitors. Ongoing Phase 2 trials in China (NCT NCT06453902) and Phase 1 trials in US (NCT06088888) are further evaluating TGRX-678, underscoring the need for continued assessment.