Clinical Trial of TQB3126 for Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy in Breast Cancer Subjects

• TQB3126 (Drug): TQB3126 is a targeted protein degrader.

Primary outcomes

• Dose Limiting Toxicity (DLT) [From first dose of TQB3126 to the end of Cycle 1, approximately 35 days.]: DLT is defined as toxicities that meet pre-defined severity criteria (according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 6.0) and are assessed as related to TQB3126, occurring from the first dose to the end of the first treatment cycle.
• Maximum Tolerated Dose (MTD) [From first dose of TQB3126 to the end of Cycle 1, approximately 35 days.]: MTD is the highest dose at which DLT occurs in less than 33% of evaluable subjects during the DLT assessment window, from the first dose of TQB3126 through the end of the first repeated-dose treatment cycle.
• Recommended Phase II Dose (RP2D) [Observation is expected to continue through Cycle 6 Day 28 throughout the study, around 6 months.]: The dose recommended for Phase II study based on integrated safety, tolerability, pharmacokinetic and efficacy data.
• Adverse Events (AEs) [From the time of first dose of TQB3126 to 28 days after the last dose or until the start of other anti-tumor therapy, whichever occurs first.]: The occurrence, incidence and severity of all adverse events (AEs).
• Serious Adverse Events (SAEs) [From the time of first dose of TQB3126 to 28 days after the last dose or until the start of other anti-tumor therapy, whichever occurs first.]: The occurrence, incidence and severity of all serious adverse events (SAEs).
• Abnormal Incidence of Laboratory Test Indicators [From the time of first dose of TQB3126 to 28 days after the last dose or until the start of other anti-tumor therapy, whichever occurs first.]: Incidence and severity of abnormal laboratory values.
• Objective Response Rate (ORR) [From the date of first dose until the date of first documented disease progression, assessed up to approximately 3 years.]: The proportion of subjects with a best overall response of complete response (CR) or partial response (PR) according to RECIST v1.1.
• Maximum Applicable Dose (MAD) [From the first dose of TQB3126 through completion of the Phase I dose-escalation assessment.]: MAD is the dose at which a dose-exposure plateau is reached, further dose escalation poses substantial safety risk, or available data indicate that a safe and effective optimal target dose has been identified.

Secondary outcomes

• Peak Concentration (Cmax) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Maximum observed plasma concentration of TQB3126.
• Time to Reach Maximum Plasma Concentration (Tmax) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Time to reach the maximum plasma concentration of TQB3126.
• Elimination Half-life (t1/2) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Elimination half-life of TQB3126 after oral dosing.
• Area Under the Plasma Concentration-time Curve From Time Zero to Time t (AUC0-t) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Area under the plasma concentration-time curve from time zero to the last measurable concentration.
• Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Area under the plasma concentration-time curve from time zero extrapolated to infinity.
• Apparent Clearance (CL/F) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Apparent total clearance of TQB3126 from plasma.
• Apparent Volume of Distribution (Vz/F) [Escalation: pre-dose+0.5,1,2,3,4,6,8,12,24,48,72,120 hours post single dose (Cycle0); pre-dose Cycle1 Day1. Expansion/combo: pre-dose+0.5-12 hours Cycle1 Day1; 24 hours Day2. All: pre-dose Day 7,14,21; pre-dose+0.5-12 hours Day 28; pre-dose Cycle2 Day1.]: Apparent volume of distribution of TQB3126 in plasma.
• Clinical Benefit Rate (CBR) [From the date of first dose until the date of first documented disease progression, assessed up to approximately 3 years.]: The proportion of subjects with a best overall response of complete response, partial response, or stable disease lasting a pre-specified minimum duration, per RECIST v1.1.
• Disease Control Rate (DCR) [From the date of first dose until the date of first documented disease progression, assessed up to approximately 3 years.]: The proportion of subjects with a best overall response of complete response, partial response, or stable disease, per RECIST v1.1.
• Duration of Response (DOR) [From the date of first dose until the date of first documented disease progression, assessed up to approximately 3 years.]: The time from the first documentation of complete or partial response to the first documentation of disease progression.
• Progression-Free Survival (PFS) [From the date of first dose until the date of first documented disease progression, assessed up to approximately 3 years.]: The time from the first dose to the first documentation of disease progression or death from any cause, whichever occurs first.
• Time to Response (TTR) [From the date of first dose until the date of first documented disease progression, assessed up to approximately 3 years.]: The time from the first dose to the first documentation of complete or partial response.

Other outcomes

• Relationship Between TQB3126 Exposure and Efficacy/Safety [PK/Holter: Cycle 0 (7-day washout), Cycles 1-2 (28 days each); efficacy: until disease progression; safety: first dose to 28 days after last dose or start of other anticancer therapy, whichever occurs first.]: Explore relationships between the pharmacokinetics of TQB3126 monotherapy or combination therapy and efficacy/safety in Phase I and Phase II. Holter electrocardiogram data are collected to support exploratory concentration-QTc (C-QTc) analyses. Holter is performed on Cycle 0 Day 1 and Cycle 1 Day 28 in dose escalation, and on Cycle 1 Day 1 and Cycle 1 Day 28 in dose expansion and combination-therapy participants undergoing PK sampling. Monitoring starts within 1 hour before dosing and continues through 24 hours after dosing; on Cycle 1 Day 28, it continues at least until 30 minutes before the predose blood collection on Cycle 2 Day 1.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. Subjects voluntarily participate in this study, sign the informed consent form, and demonstrate good treatment compliance.
2. Aged 18 to 75 years at the time of informed consent signature; Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; estimated survival expectancy of more than 3 months.
3. Histopathologically confirmed breast cancer.
4. Documented disease progression confirmed by clinical or imaging evidence during or after the most recent prior systemic therapy prior to the first study drug administration.
5. Have evaluable lesions per RECIST v1.1 criteria (measurable lesions; or bone-only metastases with at least one osteolytic or mixed lesion).
6. Adequate tissue samples shall be provided at screening for gene mutation testing to clarify genetic status.
7. Laboratory test results meet the criteria specified in the protocol (blood routine, liver and renal function, coagulation function, cardiac ultrasound Left Ventricular Ejection Fraction(LVEF) and other indicators are all within the protocol-specified ranges).
8. Subjects of childbearing potential must agree to use effective contraceptive measures throughout the study and for 6 months after study completion (the same requirement applies to male subjects); serum or urine pregnancy test result is negative within 7 days prior to enrollment.

Exclusion Criteria:

1. Other malignant tumors within 5 years prior to first dose, except those cured by single surgical treatment with at least 5 years of disease-free survival, or cured differentiated thyroid cancer, cervical carcinoma in situ, non-melanoma skin cancer, or superficial bladder tumors.
2. Conditions affecting intravenous access or blood sampling, or multiple factors affecting oral drug administration/absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction).
3. Unresolved toxicity from prior therapy of Grade >1 (CTCAE v6.0), except Grade 2 alopecia, Grade 2 anemia, clinically insignificant laboratory abnormalities, or hypothyroidism stable on hormone replacement therapy.
4. Major surgery, significant traumatic injury within 4 weeks before first dose, anticipated need for major surgery during the study, or long-standing unhealed fracture.
5. Any bleeding event of Grade >=3 within 4 weeks before first dose.
6. Arterial/venous thrombotic events within 6 months before first dose (e.g., cerebrovascular accident, deep vein thrombosis, pulmonary embolism), excluding catheter-related or superficial venous thrombosis.
7. Active viral hepatitis that is poorly controlled (Hepatitis B Virus (HBV)/Hepatitis C Virus (HCV)-infected subjects meeting protocol-specified criteria may be enrolled).
8. Active syphilis infection requiring treatment.
9. Active tuberculosis, idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or radiation pneumonitis requiring treatment, or history of/current interstitial lung disease (ILD).
10. History of psychotropic substance abuse unable to be discontinued, mental disorders, epilepsy requiring treatment, or severe psychiatric/neurological disease.
11. Planned or prior allogeneic bone marrow or solid organ transplantation.
12. Decompensated cirrhosis (Child-Pugh Class B or C) or history of hepatic encephalopathy.
13. Significant cardiovascular disease, including New York Heart Association(NYHA) Class >II heart failure, clinically significant ventricular arrhythmia, unstable angina, myocardial infarction within 12 months, markedly prolonged QT interval corrected by Fridericia's formula (QTcF), or personal/family history of congenital long QT syndrome.
14. Poorly controlled hypertension (resting systolic BP >=160 mmHg or diastolic BP >=100 mmHg on at least 2 measurements >=24 hours apart).
15. Active or uncontrolled serious infection (Grade >=2).
16. Renal failure requiring hemodialysis or peritoneal dialysis; or history of/current nephrotic syndrome (except cured) or chronic nephritis.
17. History of immunodeficiency, including HIV infection or other acquired/congenital immunodeficiency diseases.
18. Poorly controlled autoimmune disease requiring immunosuppressants or systemic corticosteroids for immunosuppression, continued within 7 days before first dose (except low-dose corticosteroids).
19. Clinically significant endometrial abnormalities (including hyperplasia, dysfunctional uterine bleeding, etc.).
20. Tumor-related conditions/treatments: anti-cancer therapy within 3 weeks before first dose or still within the drug's washout period; prior local radiotherapy not meeting protocol-specified interval or target lesion requirements; use of National Medical Products Administration (NMPA)-approved proprietary Chinese medicine with anti-tumor indications within 1 week before first dose; imaging showing tumor invasion of major vessels with risk of fatal hemorrhage; uncontrolled pleural effusion/ascites/moderate-or-greater pericardial effusion requiring repeated drainage; known leptomeningeal metastasis or uncontrolled brain metastasis symptoms; severe skeletal-related events due to bone metastases.
21. Known hypersensitivity to the study drug or its excipients.
22. Participation in and use of another investigational anti-tumor drug within 4 weeks before first dose.
23. Any concomitant disease or condition that, in the investigator's judgment, seriously endangers subject safety or study compliance, or any other reason making the subject unsuitable for enrollment.