A Clinical Trial of TQB3909 Tablets in Subjects With Advanced Malignant Tumors

Study Overview
=================
Brief Summary
-----------------
TQB3909 is an inhibitor targeting at B-cell lymphoma (BCL)-2 protein. By binding to BCL-2 protein, TQB3909 releases Pro apoptotic proteins such as BCL-2-Anatagonist/Killer 1(BAK), BCL-2 associated X (BAX) protein and BCL-2 associated death (BAD) protein, promotes the release of cytochrome c from mitochondria, phosphatidylserine eversion, stimulates caspase 3 / 7 activity and caspase 3 / 9 cleavage, and induces apoptosis.

Official Title
-----------------
A Phase I Clinical Trial Evaluating the Tolerance and Pharmacokinetics of TQB3909 Tablets in Patients With Relapsed or Refractory Advanced Malignant Tumors

Conditions
-----------------
Advanced Malignant Tumor

Intervention / Treatment
-----------------
* Drug: TQB3909 Tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The subjects volunteered to join the study and signed informed consent form (ICF)with good compliance. Age: ≥ 18 years old (when signing ICF); Eastern Cooperative Oncology Group (ECOG) performance status score: 0-1; The expected survival period is more than 3 months. Advanced malignant tumor diagnosed by histology or cytology. Relapse or failure after previous standard treatment, or intolerance to standard treatment, and no other better treatment options. Subject population:a)Dose escalation stage: non-Hodgkin's lymphoma;b) Dose expansion stage: non-Hodgkin's lymphoma, plasmacytoma, acute myeloid leukemia, myelodysplastic syndrome, etc. At least 1 lesion / measurable disease for efficacy evaluation. The function of main organs are well, and the following examination results are good: routine blood examination, biochemical examination, blood coagulation function examination, and heart color Doppler ultrasound evaluation. Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine device, contraceptive or condom) during the study period and within 6 months after the end of the study; The serum pregnancy test iss negative within 7 days before the enrollment and must be non-lactating subjects; Male subjects should agree to avoid childbirth during the study period and within 6 months after the end of the study period. Exclusion Criteria: Combined disease and History: There were other malignant tumors in 3 years before the first medication. The following two cases can be included: other malignant tumors treated by single operation have achieved 5-year disease-free survival (DFS) in a row; The cured cervical carcinoma in situ, non melanoma skin cancer and superficial bladder tumor [ta (non-invasive tumor), tis (carcinoma in situ) and T1 (tumor infiltrating basement membrane)]; The diagnosis was Burkitt lymphoma, lymphoblastic lymphoma / leukemia, etc; Central nervous system (CNS) invasion was found; He has received allogeneic hematopoietic stem cell transplantation in the past; Autologous hematopoietic stem cell transplantation was performed 3 months before the first administration; There are many factors influencing oral medication (such as inability to swallow, chronic diarrhea and intestinal obstruction); Unrelieved toxicity of ≥ circulating tumor cells(CTC) AE 1 due to any previous treatment, excluding alopecia; Major surgical treatment, open biopsy and obvious traumatic injury were performed within 28 days before the study; There are active or uncontrolled primary autoimmune hemocytopenia, including autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), etc; Arteriovenous thrombotic events occurred within 6 months before the first medication, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep venous thrombosis and pulmonary embolism; Have a history of psychotropic drug abuse and can not quit or have mental disorders; Subjects with any severe and / or uncontrolled disease included: Patients with ≥ 2 grade myocardial ischemia 6 months between the first administration or myocardial infarction, arrhythmia (male corrected QT interval (QTc) > 450ms, female QTc > 470ms) and ≥ 2 grade congestive heart failure (NYHA classification), Cardiac color Doppler ultrasound to evaluate left ventricular ejection fraction（LVEF）<50%; There was active severe infection (≥ CTC AE grade 2 infection); Fever and neutropenia were found within 1 week before the first medication; Diabetes was poorly controlled (fasting blood glucose (FBG) > 10mmol/L). Active hepatitis *; * active hepatitis (hepatitis B reference: hepatitis B surface antigen (HBsAg) positive, and hepatitis B virus(HBV) DNA detection value > 2000 copies /mL or 500 internation unit (IU)/mL; Hepatitis C reference: hepatitis C virus(HCV) antibody was positive, and HCV titer detection value exceeded the upper limit of normal value); History of immunodeficiency, including HIV positive or other acquired or congenital immunodeficiency diseases, or organ transplantation; Patients with epilepsy and need treatment. tumor related symptoms and treatment: Subjects who have received chemotherapy, radiotherapy within 4 weeks prior to the first dose or received immune checkpoint inhibitors and CAR-T treatment 12 weeks before the first medication, or other anti-tumor treatment within 5 half-life prior to the first dose (the washing and removing period is calculated from the end of the last treatment) ; Subjects who have previously received BCL-2 inhibitors. Subjects who have received the vaccine within 4 weeks prior to the first dose, or is planning to be vaccinated during the study period. Subjects who have participated in clinical trials of other anti-tumor drugs within 4 weeks before the first dose. According to the judgment of the investigator, subjects with concomitant diseases that seriously endanger the safety of the subjects or affect the completion of the study, or subjects with other reasons which are not suitable for inclusion.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TQB3909 Tablets<br>Take 100-1200mg once a day; Oral administration on an empty stomach, 28 days as a cycle. | Drug: TQB3909 Tablets<br>* TQB3909 is an inhibitor targeting BCL-2 protein<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity（DLT） | DLT describes side effects of a drug or other treatment that are serious enough to prevent an increase in dose or level of that treatment. | up to 18 months | 
| Recommended Phase II Dose (RP2D) | DLT describes side effects of a drug or other treatment that are serious enough to To evaluate RP2D of TQB3909 tablets in adult patients with advanced solid tumors | up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AEs) and serious adverse events (SAEs) | The incidence and severity of AEs and SAEs, as well as abnormal laboratory test indicators. | up to 18 months | 
| Time to reach maximum(peak )plasma concentration following drug administration (Tmax) | To characterize the pharmacokinetics of TQB3909 by assessment of time to reach maximum plasma concentration after single and multiple dosing | Within 32 weeks after administration | 
| Maximum (peak) plasma drug concentration (Cmax) | Cmax is the maximum plasma concentration of TQB3909. | Within 24 hours after administration | 
| Maximum (peak) steady-state plasma drug concentration during a dosage interval (Css-max) | Css-max is the steady state maximum concentration of TQB3909 . | Within 32 weeks after administration | 
| Area under the plasma concentration-time curve from time zero to time t (AUC0-t) | To characterize the pharmacokinetics of TQB3909 by assessment of area under the plasma concentration time curve from the first dose to a certain time point. | Within 24 hours after administration | 
| Area under the plasma concentration-time curve from time zero to infinity(AUC0-∞) | To characterize the pharmacokinetics of TQB3909 by assessment of area under the plasma concentration time curve from the first dose to infinity. | Within 24 hours after administration | 
| Area under the plasma concentration-time curve when reaching steady state (AUCss) | AUCss is the area under the curve of TQB3909. | Within 32 weeks after administration | 
| Apparent total clearance of the drug from plasma after oral administration (CL/F) | CL/F is total clearance rate for TQB3909. | Within 24 hours after administration | 
| Elimination half-life (t1/2) | t1/2 is time it takes for the blood concentration of TQB3909 to drop by half. | Within 24 hours after administration | 
| Mean residence time (MRT) | MRT describes the average time that TQB3909 remains in the body. | Within 24 hours after administration | 
| Minimum steady-state plasma drug concentration during a dosage interval (Css-min) | Css-min is the minimum plasma concentration of TQB3909. | Within 32 weeks after administration | 
| Degree of fluctuation(DF) | DF is the volatility coefficient of TQB3909. | Within 32 weeks after administration | 
| Average steady-state plasma drug concentration during multiple-dose administration (Css-av) | Css-av is the average of steady-state plasma concentration of TQB3909 . | Within 32 weeks after administration | 
| Apparent volume of distribution after non-intervenous administration (Vd/F) | Vd/F is the bioavailability corrected apparent distribution volume of TQB3909 | Within 24 hours after administration | 
| Progression-free survival (PFS) | PFS is defined as the time from randomization until the first documented progressive disease (PD) or death from any cause. | up to 18 months | 
| Overall response rate (ORR) | Percentage of participants achieving complete response (CR) and partial response (PR). | up to 18 months | 
| Complete response rate（CRR） | CRR refers to the percentage of patients who enter the clinical disappearance period of the disease after a certain treatment. | up to 18 months | 
| Disease control rate（DCR） | Percentage of participants achieving CR and PR and stable disease (SD). | up to 18 months | 
| Duration of Response (DOR) | The period from the participants first achieving CR or PR to disease progression. | up to 18 months | 
| Overall survival (OS) | OS is defined as the time from the first administration to all-cause death. | up to 18 months | 
| Protein concentration or gene expression level related to BCL-2 signaling pathway | To evaluate the changes of BCL-2 signaling pathway related to proteins or genes. | up to 18 months |