TGRX-678 Chinese Phase I in Chronic Myelogenous Leukemia (CML) Patients

Study Overview
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Brief Summary
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The purpose of this single- arm, open-lable, dose escalation + dose expansion study is to evalulate the safety, tolerability, pharmacokinetic and preliminary efficacy of TGRX-678 in Chronic Myelogenous Leukemia patients who had failure with or are intolerant to TKI treatments.

Detailed Description
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This is the first-in-human trial with TGRX-678 which aims to evaluate the safety profile and preliminary efficacy profile in advanced or refractory CML patients with previous failure or intolerence to TKI treatments. The primary purpose of this study is to evaluate the safety profile of TGRX-678, including determination of the maximal tolerated dose (MTD) and recommended phase II dose (RP2D), and other safety measures of the investigational drug, such as adverse events and abnormal clinical outcomes. Preliminary efficacy profile of TGRX-678 is evaluated based on the changes in peripheral blood cells and disease-associated cytogenetic markers. The safety, tolerability and efficacy profiles, along with pharmacokinetic analysis, will be assessed together to determine the optimal dose for expansion.

Official Title
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A Single-arm, Open-label, Dose Escalation and Dose Expansion Phase 1 Trial to Determine the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TGRX-678 in Patients With Refractory or Advanced CML

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: TGRX-678


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate in the study with informed consent; 18-75 years of age at the time of screening; Male or female; Diagnosis of CML-CP by cytomorphological examination of the bone marrow, molecular biology examination, or cytogenetic testing during the screening period (according to the NCCN guidelines (NCCN, 2021); Received prior treatment with imatinib, dasatinib or nilotinib; patients must be intolerant or resistant to the above drugs according to MD Anderson or ELN guidelines; ECOG performance status ≤ 2; Minimum life expectancy of 3 months; Adequate renal function, defined as serum creatinine <1.5× upper limit of normality (ULN) Adequate liver function, defined as total bilirubin <1.5× ULN, AST and ALT <2.5×ULN; if liver function is compromised due to CML, AST and ALT <5×ULN; Adequate coagulation function, defined as PT<1.5×ULN, INR<1.5×ULN, and APTT<1.5×ULN; Normal pancreatic function, defined as lipase and amylase <1.5× ULN; Normal QTc interval, defined as ≤450 ms in males and ≤470 ms in females, as indicated by ECG screening results; For women with child-bearing potential, negative pregnancy test result at screening period; Pregnant or breast feeding and female patients of childbearing potential must agree to use effective methods of contraception. Exclusion Criteria: Received TKI treatment within 7 days of first dosing of the investigational drug, or AEs related to previous treatment has not been recovered to Grade 1 or lower (except for alopecia); Exposure to other antineoplastic therapies and either of the following: hydroxyurea or anagrelide within 24 h prior to the first dose; interferon or immunotherapy within 14 days prior to the first dose, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy (excluding any TKI therapy) within 28 days prior to the first dose; Stem cell transplant < 60 days prior to the first dose, with evidence of graft versus host disease (GVHD) or GVHD requiring immunosuppressive therapy; Concomitant immunosuppressive therapy (other than short term corticosteroid treatment); Exposure to drugs related to torsade de pointes within 1 month of the screening period; Cytological or pathological diagnosis of active central nervous system disorder; CML-CP patients already achieved complete cytogenetic response; CML-AP patients already achieved major hematological response; Significant uncontrolled cardiac disease; Uncontrolled hypertension (Diastolic BP > 85mm Hg; Systolic > 145 mm Hg; achieved with or without medication); Exposure to herbal preparations or over-the-counter medications containing herbal ingredients within 2 weeks prior to the first dose; Severe hemorrhagic disorders unrelated to CML; History of grade 3-4 pancreatitis or history of alcohol abuse; Uncontrolled hyper-triglyceridemia (TG>450 mg/dL); Malabsorption syndrome or other illness that could affect oral absorption; Diagnosis of another primary malignancy in the past 3 years (other than non-melanoma skin cancer, cervical carcinoma in situ, or controlled prostate cancer that have been cured within 3 years; Invasive/extensive surgery within 14 days prior to initiating TGRX-678 therapy; Active clinically significant infections, including syphilis, HIV, Hepatitis B or Hepatitis C; Other criteria in the opinion of the investigator or the medical monitor that is unsuitable for the study, including diseases that could compromise the patients safety or the evaluation of the drugs safety or poor compliance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TGRX-678<br>Subjects to be treated with the investigational drug TGRX-678 | Drug: TGRX-678<br>* Participants are given TGRX-678 tablets orally at one of the dose levels as pre-determined for the dose escalation sequence.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerated dose (MTD) | To determine the MTD of TGRX-678 in CML patients | At end of Cycle 1 (each cycle is 28 days) when the posterior probability of DLT of a dose level is higher than 33% | 
| Recommended phase II dose (RP2D) | To detemine the RP2D of TGRX-678 in CML patients for Phase II | At completion of the study, an average of 1.5 years | 
| Safety profile (DLT) | to record and analyse subjects with dose-limiting toxicities (DLTs) | DLT: collect during Cycle 1 (28 days) | 
| Safety profile (AEs/SAEs) | to record and analyse subjects with adverse events (AEs) and serious adverse events (SAEs), and | AE and SAE: through completion of the study, an average of 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Response | To record and analyse the hematologic response of subjects. Subjects will be determined whether complete hematologic response (CHR) or no evience of leukemia (NEL) is reached. | at screening period, weekly in Cycle 1, bi-weekly in Cycle 2 and monthly starting from Cycle 3 (each cycle is 28 days) | 
| Cytogenetic Response | To record and analyse the cytogenetic response of subjects subjects will be determined whether partial or complete cytogenetic response (Ph+ < 35%) is reached. | at screening period, weekly in Cycle 1, bi-weekly in Cycle 2 and monthly starting from Cycle 3 (each cycle is 28 days) | 
| Molecular Response | To record and analyse the molecular response of subjects Subjects will be detmined whether major molecular response (BCR-ABL1 (IS) no more than 0.1%) is reached. | at screening period, weekly in Cycle 1, bi-weekly in Cycle 2 and monthly starting from Cycle 3 (each cycle is 28 days) | 
| Plasma Cmax | Cmax of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma Tmax | Tmax of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma T1/2 | Half life of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma AUClast | AUClast of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma AUCinf | AUCinf of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma Cmin | Cmin of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma AUCss | steady state AUC of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma Cmax,ss | steady state Cmax of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Plasma Tmax,ss | steady state Tmax of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| CL | Clearance of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 | 
| Vd | Volume of distribution of TGRX-678 as measured in plasma | Day 1, 7, 21, 28 of Cycle 1, Cycle 2 Day 28 and Cycle 3 Day 28 |