Clinical trial NCT04975204: A Clinical Trial of TQB3909 Tablets in Subjects With Advanced Malignant Tumors
Official title: A Phase I Clinical Trial Evaluating the Tolerance and Pharmacokinetics of TQB3909 Tablets in Patients With Relapsed or Refractory Advanced Malignant Tumors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Advanced Malignant Tumor
Lead sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2021-07-23
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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:

  1. 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 \[ta (non-invasive tumor), tis (carcinoma in situ) and T1 (tumor infiltrating basement membrane)\];
  2. The diagnosis was Burkitt lymphoma, lymphoblastic lymphoma / leukemia, etc;
  3. Central nervous system (CNS) invasion was found;
  4. He has received allogeneic hematopoietic stem cell transplantation in the past;
  5. Autologous hematopoietic stem cell transplantation was performed 3 months before the first administration;
  6. There are many factors influencing oral medication (such as inability to swallow, chronic diarrhea and intestinal obstruction);
  7. Unrelieved toxicity of ≥ circulating tumor cells(CTC) AE 1 due to any previous treatment, excluding alopecia;
  8. Major surgical treatment, open biopsy and obvious traumatic injury were performed within 28 days before the study;
  9. There are active or uncontrolled primary autoimmune hemocytopenia, including autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), etc;
  10. 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;
  11. Have a history of psychotropic drug abuse and can not quit or have mental disorders;
  12. Subjects with any severe and / or uncontrolled disease included:

      1. 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%;
      2. There was active severe infection (≥ CTC AE grade 2 infection);
      3. Fever and neutropenia were found within 1 week before the first medication;
      4. Diabetes was poorly controlled (fasting blood glucose (FBG) \> 10mmol/L).
      5. 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);
      6. History of immunodeficiency, including HIV positive or other acquired or congenital immunodeficiency diseases, or organ transplantation;
      7. Patients with epilepsy and need treatment.
* tumor related symptoms and treatment:

  1. 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) ;
  2. 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.

Primary outcomes:
measure: Dose-limiting toxicity（DLT）
timeFrame: up to 18 months
measure: Recommended Phase II Dose (RP2D)
timeFrame: up to 18 months
Secondary outcomes:
measure: Adverse events (AEs) and serious adverse events (SAEs)
timeFrame: up to 18 months
measure: Time to reach maximum(peak )plasma concentration following drug administration (Tmax)
timeFrame: Within 32 weeks after administration
measure: Maximum (peak) plasma drug concentration (Cmax)
timeFrame: Within 24 hours after administration
measure: Maximum (peak) steady-state plasma drug concentration during a dosage interval (Css-max)
timeFrame: Within 32 weeks after administration
measure: Area under the plasma concentration-time curve from time zero to time t (AUC0-t)
timeFrame: Within 24 hours after administration
measure: Area under the plasma concentration-time curve from time zero to infinity(AUC0-∞)
timeFrame: Within 24 hours after administration
measure: Area under the plasma concentration-time curve when reaching steady state (AUCss)
timeFrame: Within 32 weeks after administration
measure: Apparent total clearance of the drug from plasma after oral administration (CL/F)
timeFrame: Within 24 hours after administration
measure: Elimination half-life (t1/2)
timeFrame: Within 24 hours after administration
measure: Mean residence time (MRT)
timeFrame: Within 24 hours after administration
measure: Minimum steady-state plasma drug concentration during a dosage interval (Css-min)
timeFrame: Within 32 weeks after administration
measure: Degree of fluctuation(DF)
timeFrame: Within 32 weeks after administration
measure: Average steady-state plasma drug concentration during multiple-dose administration (Css-av)
timeFrame: Within 32 weeks after administration
measure: Apparent volume of distribution after non-intervenous administration (Vd/F)
timeFrame: Within 24 hours after administration
measure: Progression-free survival (PFS)
timeFrame: up to 18 months
measure: Overall response rate (ORR)
timeFrame: up to 18 months
measure: Complete response rate（CRR）
timeFrame: up to 18 months
measure: Disease control rate（DCR）
timeFrame: up to 18 months
measure: Duration of Response (DOR)
timeFrame: up to 18 months
measure: Overall survival (OS)
timeFrame: up to 18 months
measure: Protein concentration or gene expression level related to BCL-2 signaling pathway
timeFrame: up to 18 months
Other outcomes:
Locations:
city: Nanjing
country: China
facility: Jiangsu Provincial People's Hospital
state: Jiangsu
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College
state: Tianjin
Study officials:
References: