Tolerability and Pharmacokinetics Study of TQB3702 Tablets in Hematologic Tumor Subjects

Study Overview
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Brief Summary
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This project is an open, dose escalation and expansion phase I clinical study. The first phase is a dose escalation study, and the second phase is a dose expansion study based on the Maximum tolerated dose (MTD) / Recommended Phase II Dose (RP2D) obtained in the first phase. The purpose is to evaluate the tolerability and preliminary efficacy of TQB3702 tablets in hematological tumor subjects.

Official Title
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Phase I Clinical Trial of Tolerability and Pharmacokinetics of TQB3702 Tablets in Hematologic Tumor Subjects

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Drug: TQB3702 tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects voluntarily joined the study, signed informed consent form, and with good compliance. ≥18 years old and ≤ 80 years old; Eastern Cooperative Oncology Group (ECOG) physical status: 0-2; at least 3 months expected survival period. Clearly diagnosed recurrent / refractory hematological tumors that meet the WHO definition; At least 1 measurable lesion for efficacy evaluation. The function of main organs is normal. Female patients of childbearing age should agree to use contraceptive measures during the study period and for at least 6 months after study is stopped; a negative serum pregnancy test within 7 days prior to study enrollment and must be non-lactating subjects; male patients should agree to use contraception during the study period and for at least 6 months after study is stopped. Exclusion Criteria: Patients has had or is currently having other malignant tumors within 3 years. The following two conditions can be included in the group: other malignant tumors treated with a single operation to achieved 5 consecutive years of disease free survival (DFS)s. Cured cervical carcinoma in situ, non-melanoma skin cancer, nasopharyngeal carcinoma and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor infiltrating basement membrane)]. Subjects with central nervous system aggression (CNS); Received allogeneic hematopoietic stem cell transplantation (allo-HSCT) or had active graft-versus-host disease (GVHD) requiring immunosuppressive therapy within 12 months before the first dose; Multiple factors that affect the absorption of oral medications (e.g., inability to swallow, chronic diarrhea, and intestinal obstruction); Unrelieved toxicity of ≥CTC AE grade 1 due to any previous treatment, excluding alopecia and fatigue; Major surgical treatment, open biopsy, and significant traumatic injury were received within 28 days before the start of study treatment. The presence of active or uncontrolled primary autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) and primary immune thrombocytopenia (ITP); Patients with evidence or history of bleeding constitution; Or any bleeding event (such as gastrointestinal bleeding) greater than or equal to CTC AE level 3 within 4 weeks before the first medication; Subjects had an arteriovenous thrombosis event within 6 months. Subjects have history of psychotropic substance abuse and are unable to abstain or have mental disorders; Subjects with any severe and/or uncontrolled disease. Within 2 weeks before the first treatment, the subjects had received proprietary Chinese medicines with anti-tumor indications specified in the NMPA approved drug instructions; Uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage (investigator judgment); Study treatment related: subjects received live or mRNA vaccines within 4 weeks before the first treatment or were scheduled to receive live or mRNA vaccines during the study; Participated in clinical trials of other antitumor drugs within 4 weeks before the first treatment; According to the investigator's judgment, there are concomitant diseases that seriously endanger the safety of the subjects or affect the completion of the study, or subjects who are considered unsuitable for enrollment for other reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: TQB3702 tablets<br>TQB3702 tablets were administered orally, 28 days as a treatment cycle until the progressive diseases or the investigator judges that it is not suitable for subject to continue to take this medicine. | Drug: TQB3702 tablets<br>* TQB3702 tablets are selective BTK inhibitors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | To evaluate the maximum tolerated dose of TQB3702 tablets in the treatment of relapsed/refractory hematologic tumors. | Baseline up to 104 weeks | 
| Dose limited toxicity (DLT) | To evaluate the dose-limiting toxic dose of TQB3702 tablets in the treatment of relapsed/refractory hematologic tumors. | Baseline up to 104 weeks | 
| Recommended Phase II Dose (RP2D) | To evaluate the phase II recommended dose of TQB3702 tablets in the treatment of relapsed/refractory hematological tumors. | Baseline up to 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach the Maximum Plasma Concentration (Tmax)-single dose | Time to Reach the Maximum Plasma Concentration after single dose | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72hours after administration. | 
| Time to Reach the Maximum Plasma Concentration (Tmax)-multiple dose | Time to Reach the Maximum Plasma Concentration after multiple dose | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| Maximum plasma concentration (Cmax)-Single dose | Cmax is the maximum plasma concentration of TQB3702 after single dose | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72hours after administration. | 
| Maximum plasma concentration (Cmax)-Multiple dose | Cmax is the maximum plasma concentration of TQB3702 after multiple dose | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| Elimination half-life (t1/2)-Single dose | t1/2 is time it takes for the blood concentration of TQB3702 or metabolite(s) to drop by half after single dose. | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72 hours after administration. | 
| Elimination half-life (t1/2)-Multiple dose | t1/2 is time it takes for the blood concentration of TQB3702 or metabolite(s) to drop by half after multiple dose. | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| Area under the plasma concentration-time curve from time zero to time t (AUC0-t)-Single dose | To characterize the pharmacokinetics of TQB3702 by assessment of area under the plasma concentration time curve from the first dose to a certain time. | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72hours after administration. | 
| Area under the plasma concentration-time curve from time zero to time t (AUC0-t)-Multiple dose | To characterize the pharmacokinetics of TQB3702 by assessment of area under the plasma concentration time curve from the first dose to a certain time. | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| Maximum (peak) steady-state plasma drug concentration during a dosage interval (Cmax,ss)-Single dose | Maximum (peak) steady-state plasma drug concentration during a dosage interval (Cmax,ss) after Single dose | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72hours after administration. | 
| Maximum (peak) steady-state plasma drug concentration during a dosage interval (Cmax,ss)-Multiple dose | Maximum (peak) steady-state plasma drug concentration during a dosage interval (Cmax,ss) after Multiple dose | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| steady state area under the concentration-time curve over a dosing interval (AUCtau, ss)-single dose | steady state area under the concentration-time curve over a dosing interval (AUCtau, ss) after single dose | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72hours after administration. | 
| steady state area under the concentration-time curve over a dosing interval (AUCtau, ss)-multiple dose | steady state area under the concentration-time curve over a dosing interval (AUCtau, ss) after multiple dose | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| Minimum steady-state plasma drug concentration during a dosage interval (Css-min)-Single dose | Minimum steady-state plasma drug concentration during a dosage interval (Cmin-ss) after Single dose | before administration, 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 48, 72hours after administration. | 
| Minimum steady-state plasma drug concentration during a dosage interval (Css-min)-multiple dose | Minimum steady-state plasma drug concentration during a dosage interval (Cmin-ss) after multiple dose | before administration (-1 0h), 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24 hours after administration at Day 8/15/28 of Cycle1, Day 28 of Cycle 6; when withdrawn from the group due to disease progression or at the end of study treatment. | 
| Objective Response Rate (ORR) | The proportion of patients with tumor size reduction of a predefined amount and for a minimum time period | Baseline up to 104 weeks | 
| Complete Remission Rate (CRR) | The proportion of tumors that have a complete response after treatment | Baseline up to 104 weeks | 
| Disease Control Rate (DCR) | The percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a cancer treatment in clinical trials. | Baseline up to 104 weeks | 
| Duration of Response (DOR) | The time from the date of first documentation of a CR or PR or PD to the date of first documentation of tumor progression. | Baseline up to 104 weeks | 
| Progression Free Survival (PFS) | The time from the first dose to the first documentation of progressive disease (PD) or death from any cause, whichever occurs first | Baseline up to 104 weeks | 
| Overall Survival (OS) | the time from start of study treatment to date of death due to any cause | Baseline up to 104 weeks | 
| Adverse events (AE) | The occurrence of all adverse events (AE) | Baseline up to 104 weeks | 
| Serious adverse events (SAE) | The occurrence of all serious adverse events (SAE) | Baseline up to 104 weeks | 
| Bruton's tyrosine kinase (BTK) occupancy | The BTK occupancy in peripheral blood mononuclear cell (PMBC) | Baseline up to 104 weeks |