Safety and Efficacy of Tgrx-678, a Potent <em>BCR::ABL1 </Em>allosteric Inhibitor, in Patients with Tyrosine Kinase Inhibitor Resistant and/or Intolerant Chronic Myeloid Leukemia: Updated Results of Phase 1 Study Tgrx-678 -1001

Jiang, Qian

Oral and Poster Abstracts
Oral
632. Chronic Myeloid Leukemia: Novel Molecules in Clinical Practice

Adult, Drug development, CML, Chronic Myeloid Malignancies, Diseases, Treatment Considerations, Myeloid Malignancies, Study Population, Human, Measurable Residual Disease

Qian Jiang, MD^1,2,3, Li Weiming⁴^*, Yanli Zhang, MD⁵^*, Qiang Wang, MD⁶^*, Suning Chen, MD, PhD⁷^*, Bingcheng Liu⁸^*, Zhuogang Liu⁹^*, Jie Jin, M.D.¹⁰, Zhenfang Liu, MD¹¹^*, Jianyu Weng, MD, PhD¹²^*, Xin Du¹³^*, Xielan Zhao¹⁴^*, Li Meng, MD¹⁵^*, Lie Lin, M.D.¹⁶^*, Wanlin Ye¹⁷^*, Shujie Yan, PhD¹⁷^*, Yihan Wang, PhD¹⁷^* and Jingrong Cao, PhD¹⁷

¹National Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, Beijing, China
²Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China
³Peking University People’s Hospital, Beijing, China
⁴Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
⁵Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
⁶Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
⁷The First Affiliated Hospital of Soochow University, Suzhou, China
⁸State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
⁹Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, China
¹⁰Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
¹¹The First Affiliated Hospital of Guangxi Medical University, Nanning, China
¹²Guangdong Provincial People's Hospital, Guangdong, China
¹³Department of Hematology, Shenzhen Second People's Hospital, Shenzhen, China
¹⁴Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
¹⁵Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
¹⁶Department of Hematology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
¹⁷Shenzhen TargetRx, Inc., Shenzhen, China

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 >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 (C_max and AUC_tau) was dose-proportional. The terminal half-life was found to be long (> 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.

Disclosures: Ye: Shenzhen TargetRx, Inc.: Current Employment, Current equity holder in private company. Yan: Shenzhen TargetRx, Inc.: Current Employment. Wang: Shenzhen TargetRx, Inc.: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: CEO of the company. Cao: Shenzhen TargetRx, Inc.: Current Employment, Current equity holder in private company, Other: COO of the company.

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477 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