Clinical Trial to Evaluate the Tolerance of TQB3201 Tablets

A Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TQB3201 Tablets in Patients With Advanced Prostate Cancer

TQB3201 is an orally administered targeted protein chimera (PROTAC) drug in which one end of the drug is attached to a ligand that binds to Androgen Receptor (AR) and the other end to a ligand of E3 ligase (CRBN) via a linker. The phase I phase of this trial aims to evaluate the safety, tolerability, and pharmacokinetic characteristics of TQB3201 tablets for the treatment of advanced prostate cancer.

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of the prostate;

2. Age≥ 18 years old (calculated from the date of signing the informed consent form);

3. Eastern Cooperative Oncology Group Performance Status(ECOG )score 0-1 points;

4. Presence of metastatic disease confirmed by imaging;

5. Serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at screening;

6. Sufficient samples should be provided for gene mutation detection to determine androgen receptor gene status.

7. Patients who have progressed on the basis of at least 1 new endocrine drug;

8. The laboratory inspection meets the following standards:

   • Hemoglobin (HGB) ≥90g/L;
   • Absolute neutrophil value (NEUT) ≥1.5×109/L;
   • Platelet count (PLT) ≥75×109/L.
   • Total bilirubin (TBIL) ≤2 times the upper limit of normal (ULN); (3×ULN for patients with Gilbert syndrome ≤);
   • Alanine transferase (ALT) and aspartate transferase (AST) ≤2.5× ULN. If accompanied by liver metastasis, ALT and AST ≤ 5× ULN;
   • Serum creatinine (CR) ≤1.5× ULN or creatinine clearance estimated by the Cockcroft-Gault glomerular filtration formula ≥ 60 mL/min.
   • Urine routine: urine protein <; If the urine protein is ≥, the 24-hour urine protein quantitative ≤ 1.0 g should be confirmed.
   • Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤1.5× ULN (no anticoagulant therapy);
   • Cardiac color ultrasound assessment: left ventricular ejection fraction (LVEF) ≥50%; > 12-lead ECG assessment: QT interval corrected by Fridericia's formula (QTcF) <450ms (males).

9. Men of childbearing potential and their partners of the opposite sex must agree to take effective contraceptive measures from the signing of the informed consent form until 6 months after the last dose of study drug;

10. Subjects voluntarily joined this study, signed the informed consent form, and had good compliance.

Exclusion Criteria:

1. Subjects with brain metastases with symptoms or symptom control time of less than 1 month;
2. Within 5 years before the first dose of medication or other malignant tumors at the same time.
3. Imaging ( Computed Tomography or Magnetic Resonance Imaging) shows that the tumor/metastasis has invaded important blood vessels, or the tumor/metastasis is very likely to invade important blood vessels during the follow-up study period, causing major bleeding;
4. Severe bone damage caused by bone metastasis; Pathological fractures and spinal cord compression of important parts that occurred within the past 6 months or are expected to occur in the near future as judged by the investigator;
5. Pleural effusion, pericardial effusion or ascites that cannot be controlled and still needs to be repeatedly drained (judged by the investigator);
6. Diseases affecting intravenous injection and intravenous blood collection, or having multiple factors affecting oral drugs (such as inability to swallow, chronic diarrhea and intestinal obstruction, etc.);
7. Adverse reactions of previous treatment have not recovered to Common Terminology Criteria (CTC) adverse event (AE) v5.0 grade ≤1, except for grade 2 alopecia, grade 2 peripheral neurotoxicity, grade 2 anemia, non-clinically significant and asymptomatic laboratory abnormalities, hypothyroidism stable on hormone replacement therapy, and other toxicities judged by the investigator to have no safety risk;
8. Have previously used or plan to use other similar drugs during the study;
9. Those who have received surgery, radiotherapy, radiotherapy, or local therapy (such as radiofrequency ablation, freezing, high-energy focused ultrasound, etc.) for prostate cancer after being diagnosed with metastatic prostate cancer;
10. Previous use of 5-ɑ reductase inhibitors within 4 weeks before the first dose; Systemic treatment with estrogens, progesterones, steroids (except for temporary use for anti-allergic use); First-generation AR antagonists; targeted therapy; biological therapy; immunotherapy; nuclide therapy; Botanicals known to have antitumor or PSA-lowering effects; Study treatments in other clinical trials.
11. Those who have undergone major surgical treatment, obvious traumatic injuries, or are allowed to undergo major surgery during the expected study treatment period within 4 weeks before the first dose, or have long-term unhealed wounds or fractures. (Major surgery is defined as: surgery of grade 3 or above in the 2022 edition of the National Surgical Grading Catalogue).
12. Subjects with any bleeding or bleeding event ≥Common Terminology Criteria for Adverse Events（CTCAE ）grade 3 within 4 weeks before the first dose.
13. Active viral hepatitis with poor control.
14. Active syphilis infection requiring treatment; Presence of active tuberculosis, history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, radiation pneumonitis requiring treatment, or active pneumonitis with clinical symptoms; Active or uncontrolled serious infection (≥CTC AE grade 2 infection);
15. Those who have a history of psychotropic substance abuse and cannot abstain from it, or have mental disorders or have a history of drug use.
16. Those who are ready to undergo or have previously received allogeneic bone marrow transplantation or solid organ transplantation, or have received hematopoietic stem cell transplantation within 60 days before the first dose, or have obvious host transplant responses;
17. Decompensated cirrhosis (Child-Pugh liver function grade B or C) or history of hepatic encephalopathy.
18. Suffering from major cardiovascular and cerebrovascular diseases；
19. Renal failure requiring hemodialysis or peritoneal dialysis;
20. History of immunodeficiency, including HIV positive or other acquired or congenital immunodeficiency diseases;
21. Subjects who require immunosuppressive agents, or systemic, or absorbable topical hormone therapy for immunosuppressive purposes and continue to use it within 7 days prior to the first dose (daily dose of glucocorticoids <except 10 mg prednisone or other equivalent efficacy hormones);
22. Known allergy to the excipient components of the study drug;
23. History of pituitary or adrenal dysfunction;
24. Diseases that are serious or not well controlled and judged by the investigator to be at greater risk of entering this study, such as type 1 or type 2 diabetes, hyperlipidemia, thyroid disease, etc. that cannot be controlled by drugs.
25. Estimated insufficient compliance to participate in this clinical study.