TGRX-814 Chinese Phase I/II in Patients With Hematological Malignancies

Official title

A Single-arm, Open-label, Dose Escalation and Expansion Phase I/II Study Evaluating Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TGRX-814 Monotherapy and Combination Therapy in Patients With Hematological Malignancies

Overview

The purpose of this single- arm, open-label, dose escalation and dose expansion phase I/II study is to evaluate the safety, tolerability, pharmacokinetic and preliminary efficacy of TGRX-814 in patients with hematological malignancies including non-Hodgkin lymphoma, acute myeloid leukemia, aute lymphoblastic leukemia and myelodysplastic syndromes.

Detailed description

This is the first-in-human trial with TGRX-814 which aims to evaluate the safety, pharmacokinetic and preliminary efficacy profiles with hematological malignancies. The primary purpose of this study is to evaluate the safety profile of TGRX-814 in patients with non-Hodgkin lymphoma and to determine of the maximal tolerated dose (MTD) and recommended phase II dose (RP2D). Other purposes of the study include evaluating safety and preliminary efficacy of TGRX-814 monotherapy and combination therapy in patients with other types of hematological malignancies, including acute myeloid leukemia, aute lymphoblastic leukemia and myelodysplastic syndromes, as well as evaluating the pharmacokinetic profile of TGRX-814. The study is a phase I/II study, consisting a monotherapy dose escalation study, monotherapy dose expansion study and combination therapy study.

Interventions

• Drug TGRX-814
  Participants are given TGRX-814 tablets for oral, once daily administration at one of the dose levels as pre-determined for the dose escalation sequence.

Primary outcome measures

• Maximal tolerated dose (MTD) [Time frame: At end of dose escalation when the probability of DLT of a dose level is greater than 0.359]
• Recommended phase II dose (RP2D) [Time frame: At completion of the dose escalation study, an average of 1 year]

Secondary outcome measures (12)

• Dose-limiting toxicities (DLTs) [Time frame: DLT is collected during Cycle 1 (each cycle is 28 days)]
• Adverse Events (AEs)/Serious Adverse Events (SAEs) [Time frame: AE and SAE are collected throughout and until completion of the study, an average of 1 year.]
• Complete Response (CR) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Complete response with incomplete count recovery (CRi) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Partial response (PR) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Partial response with lymphocytosis (PRL) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Stable disease (SD) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Objective response rate (ORR) [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Duration of complete response (DCR) [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Duration of response (DOR) [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Overall Survival (OS) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]
• Morphologic leukemia-free state (MLFS) rate [Time frame: at screening period, at the end of week 8, 16, 24, 36, 48, subsequent every 24 weeks and the last visit of treatment period, at the end-of-treatment follow-up visit and safety follow-up visit]

Eligibility criteria

Inclusion criteria

• male or female ≥ 18 years of age
• fully understand the requirements of the study and voluntarily sign a written informed consent form
• diagnosis of NHL, ALL, AML or MDS
• Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 2
• adequate bone marrow function
• patients at high risk for Tumor Lysis Syndrome (TLS) determined by investigator and sponsor for agreement to enroll
• adequate disease indicator
• adequate coagulation, hepatic and renal function
• female subjects of childbearing potential and male subjects whose partners are women of childbearing potential must agree to use a medically approved highly effective contraceptive from the time of signing the Informed Consent Form until at least 3 months after the last dose of study drug; women of childbearing potential must have a negative blood or urine pregnancy test within 7 days prior to the first dose of study drug
• Expected survival time ≥ 12 weeks

Exclusion criteria

• received BCL-2 inhibitor therapy prior to the first dose of study drug, unless discontinued due to intolerance
• subjects with NHL have been diagnosed with Burkitt's lymphoma, lymphoblastoid lymphoma/leukemia, or post-transplant lymphoproliferative disease (PTLD)
• AML subjects with a diagnosis of acute promyelocytic leukemia or Ph chromosome positive or persistent extramedullary leukemia
• tumor infiltration of the central nervous system
• received allogeneic hematopoietic stem cell transplantation; or received autologous hematopoietic stem cell transplantation within 3 months
• received vaccination within 4 weeks prior to first dose or scheduled to be vaccinated during the study
• HBsAg-positive or HBcAb-positive; HCV antibody-positive; HIV antibody-positive
• monoclonal antibody antitumor therapy within 4 weeks prior to the first dose; participation in a clinical trial of another interventional drug within 4 weeks prior to the first dose; participation in CAR-T therapy within 12 weeks prior to the first dose; 9. 14 weeks prior to the first dose
• received anticancer therapy/investigational therapy within 14 days prior to the first dose, or has not recovered from clinically significant toxicity below grade 2 on prior therapy
• received steroidal anticancer therapy, CYP3A inhibitors, or CYP3A inducers within 7 days prior to the first dose of study drug
• consumption of grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or popcorn within 3 days prior to the first dose of the drug
• poorly controlled hypertension; left ventricular ejection fraction ≤ 50% as assessed by cardiac ultrasound; prolonged QT interval; Grade III atrioventricular block or other arrhythmia requiring medical intervention; New York Heart Association (NYHA) Class III or IV congestive heart failure; had myocardial infarction or experienced bypass surgery within 6 months prior to dosing; had arterial or venous thrombotic events within 6 months prior to the first dose of study drug; have other cardiovascular diseases that investigator deemed unfit for enrollment
• having a history of renal, neurological, psychiatric, pulmonary, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the Investigator, would adversely affect the subject's participation in this study
• having a history of active malignancy other than NHL, AML, or MDS within 3 years prior to participation in this clinical study
• having a condition of malabsorption syndrome or multiple factors that interfere with the oral administration and absorption of medication
• other uncontrolled conditions of clinical significance
• other factors that, in the opinion of the Investigator, may affect the results of the study and interfere with the patient's participation in the study, including previous or existing medical conditions, abnormalities in treatment or laboratory tests, unwillingness of the subject to comply with the procedures, restrictions and requirements of the study, and other conditions that make enrollment in the study unsuitable.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Institute of Hematology & Blood Diseases Hospital — Tianjin

Identifiers

NCT: NCT06206174 · TGRX-814-1001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗