Non-small Cell Lung Cancer
Conditions
Brief summary
This trial is a multi-center, single-arm, open-label, Phase I clinical trial in 3 phases: dose escalation phase, dose expansion phase and indication expansion phase, which will explore the safety, tolerability, PK and preliminary efficacy of TGRX-326 in patients with ALK-positive or ROS1-positive advanced NSCLC.
Detailed description
This is the first-in-human trial with TGRX-326 which aims to evaluate the safety profile and preliminary efficacy profile in patients with ALK-positive or ROS1-positive advanced NSCLC. The primary purpose of this study is to evaluate the safety profile of TGRX-326, 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 profiles of TGRX-326 is also evaluated according to RECIST Version 1.1. The safety, tolerability and efficacy profiles, along with pharmacokinetic analysis, will be assessed together to determine the optimal dose for expansion.
Interventions
DRUGTGRX-326
Participants are given TGRX-326 tablets orally at one of the dose levels as pre-determined.
Sponsors
Sun Yat-sen University
Shenzhen TargetRx, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing to follow the treatment protocol and visit schedule, and participate in the study with the ICF signed; * ≥ 18 years of age on the day of ICF signing, regardless of gender. * Diagnosis of ALK-positive or ROS1-positive advanced NSCLC by histopathology or cytology in a Grade-A tertiary hospital or central laboratory. * Provision of the following information: archived tissue samples and/or fresh tumor tissue samples obtained during the screening period for biomarker detection; previous biomarker detection results from a Grade-A tertiary hospital (exempt from the above-mentioned biomarker detection); previous NGS results; the consent of medical monitors for the participation of subjects who fail to provide tumor tissue samples (e.g., samples are exhausted due to previous diagnostic tests but high clinical risk may be brought about by re-puncture, etc.). * Metastases to central nervous system (CNS) with the following conditions met: a. asymptomatic: no current need for corticosteroid therapy, or only stable dose or a dose reduced to ≤ 10 mg of prednisone (QD) or equivalent required; or b. past diagnosis, treatment completed, complete recovery from acute effects of radiation therapy or surgery prior to the first dose, discontinuation of corticosteroid therapy for these metastases for at least 4 weeks, and neurologically stable; * Drug discontinuation for ≥ 5 half-lives prior to the first dose for subjects previously treated with a targeted therapy (e.g., ALK or ROS1 inhibitors); * At least one measurable (longest diameter for non-lymph nodes: ≥ 10 mm; shortest diameter for lymph nodes: ≥ 15 mm) target lesion (a previously irradiated lesion cannot be regarded as a target lesion unless it is significantly progressive) according to criteria in RECIST version 1.1; * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0-1 point in dose escalation and dose expansion phases; 0-2 points in indication expansion phase; * Recovery from any AEs associated with prior surgery and cancer therapy (to ≤ Grade 1), with the following exceptions: a. alopecia; b. pigmentation; c. long-term toxicity due to radiotherapy that, in the judgment of the investigator, is not recoverable; d. Grade 2 and below neurotoxicity due to platinum; e. hemoglobin within the range of 90-100 g/L (inclusive); * Adequate bone marrow, liver, kidney, coagulation and pancreatic functions; * Expected survival ≥ 3 months; * Willing to take effective contraceptive measures (for men of reproductive potential and women of reproductive age only) from ICF signing to 6 months after administration of the investigational drug. Women of reproductive age include women in perimenopause and within 2 years after menopause. Those women must have a negative pregnancy test ≤ 7 days prior to the first dose of the investigational drug.
Exclusion criteria
* Previous use of any third-generation ALK inhibitors or second-generation ROS1 inhibitors other than TGRX-326. * Known hypersensitivity to any of the active ingredients or excipients of TGRX-326; an identified history of allergy to protein-based drugs; a history of atopic allergy (asthma, rheumatism, eczematous dermatitis); previous history of other severe allergic reactions that makes himself/herself unsuitable for TGRX-326 treatment in the judgment of the investigator; * Having another type of cancer except for lung cancer, excluding malignant tumors including cervical cancer in situ and non-melanoma skin cancer that have been curatively treated and have not recurred within 5 years; * Having previously received antibodies or pharmacotherapy against T cell costimulation or immune checkpoint pathways, including but not limited to anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death protein ligand 1 (anti-PD-1), anti-programmed cell death protein ligand 2 (anti-PD-L2), anti-cluster of differentiation 137 (anti-CD137) antibody or anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) antibody; * Major surgery within 4 weeks prior to the first dose. Minor surgery such as infusion port placement is not listed in the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety profile (DLT) | Collect during Cycle 1 (each cycle is 21 days) | To record and analyse subjects with dose-limiting toxicities (DLTs) |
| Safety profile (AEs/SAEs) | Through completion of the study, an average of 1.5 years | To record and analyse subjects with adverse events (AEs) and serious adverse events (SAEs) |
| Maximal tolerated dose (MTD) | At end of Cycle 1 (each cycle is 21 days) when the probability of DLT of a dose level is higher than 33% | To determine the MTD of TGRX-326 in NSCLC patients |
| Recommended phase II dose (RP2D) | At completion of the dose expansion study, an average of 1 year | To determine the RP2D of TGRX-326 in NSCLC patients for Phase II |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma AUCinf | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | AUCinf of TGRX-326 as measured in plasma |
| Plasma Cmin | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Cmin of TGRX-326 as measured in plasma |
| Plasma AUCss | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | AUCss of TGRX-326 as measured in plasma |
| Plasma Cmax,ss | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Cmax at steady state of TGRX-326 as measured in plasma |
| Plasma Tmax,ss | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Tmax at steady state of TGRX-326 as measured in plasma |
| CL | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Clearance of TGRX-326 as measured in plasma |
| Vd | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Volume of distribution of TGRX-326 as measured in plasma |
| ORR | At screening, Day 1 of every other cycle starting from Cycle 3, and Day 1 of every 4 cycles starting Cycle 17 (each cycle is 21 days) | Objective response rate (ORR) as the percentage of patients achieving a CR or PR |
| IC-ORR | At screening, Day 1 of every other cycle starting from Cycle 3, and Day 1 of every 4 cycles starting Cycle 17 (each cycle is 21 days) | Intracranial objective response rate (IC-ORR) as the percentage of patients achieving an intracranial CR or PR among those with confirmed intracranial lesions |
| DCR | At screening, Day 1 of every other cycle starting from Cycle 3, and Day 1 of every 4 cycles starting Cycle 17 (each cycle is 21 days) | Disease control rate (DCR) as the percentage of patients who achieve a response (PR + CR) and stable disease (SD) after the treatment |
| IC-DCR | At screening, Day 1 of every other cycle starting from Cycle 3, and Day 1 of every 4 cycles starting Cycle 17 (each cycle is 21 days) | Intracranial disease control rate (IC-DCR) as the percentage of patients achieving an intracranial response (PR + CR) and a stable disease (SD) after the treatment among those with confirmed intracranial lesions |
| DOR | At screening, Day 1 of every other cycle starting from Cycle 3, and Day 1 of every 4 cycles starting Cycle 17 (each cycle is 21 days) | Duration of response (DOR) as the length of time from the first confirmation of CR or PR until the date of the first occurrence of PD or death, applicable to subjects achieving a response only |
| IC-DOR | At screening, Day 1 of every other cycle starting from Cycle 3, and Day 1 of every 4 cycles starting Cycle 17 (each cycle is 21 days) | Intracranial duration of response (IC-DOR) as the length of time from the first confirmation of intracranial CR or intracranial PR until the date of the first occurrence of PD or death, applicable to subjects achieving an intracranial response only |
| Plasma T1/2,ss | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | T1/2 at steady state of TGRX-326 as measured in plasma |
| Plasma Cmax | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Cmax of TGRX-326 as measured in plasma |
| Plasma Tmax | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Tmax of TGRX-326 as measured in plasma |
| T1/2 | Day1/3 of single-dose period; Day1/8/15 of Cycle 1; Day1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Half life of TGRX-326 as measured in plasma |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cmax, CSF | Day 1/3 of single-dose period; Day 1/8/15 of Cycle 1; Day 1 of Cycle 2-5, Day 1 of every other cycle starting from Cycle 7; Day 1 of every 4 cycles starting from Cycle 17 (each cycle is 21 days) | Cmax of TGRX-326 as measured in cerebral-spinal fluid |
Countries
China
Outcome results
None listed