A Study of BEBT-209 Plus Chemotherapy in Patients With Locally Advanced or Metastatic Triple-Negative Breast Cancer

A Randomized, Controlled, Open-label, Multi-center, Phase IIb/III Clinical Study to Evaluate BEBT-209 Plus Carboplatin and Gemcitabine Versus Carboplatin Plus Gemcitabine in Locally Advanced or Metastatic Triple-Negative Breast Cancer

Title: A Study to See if BEBT-209 Combined With Chemotherapy Works to Treat People With Triple-Negative Breast Cancer Researchers want to learn if a new drug called BEBT-209 works to treat people with a specific type of breast cancer. This cancer is called locally advanced or metastatic triple-negative breast cancer (TNBC).

The study has two parts. In the first part, researchers want to see if the new drug combination can shrink tumors. In the second part, researchers want to see if this treatment helps people live longer.

Researchers will put participants into two groups by chance. This is like flipping a coin.

Group 1: Participants get BEBT-209 plus two chemotherapy drugs. These drugs are Carboplatin and Gemcitabine.

Group 2: Participants get only the two chemotherapy drugs. Researchers will group people based on the treatments they had in the past.

Researchers will also check:

How long the treatment keeps the cancer from growing. This is called progression-free survival (PFS).

If the treatment is safe. Researchers will look for adverse events (AE), such as low blood cell counts.

How participants feel. This is called health-related quality of life (HRQoL). How the body uses the drug.

1. Study Overview This is a randomized, controlled, open-label, multi-center, Phase IIb/III study designed to systematically evaluate the efficacy and safety of BEBT-209 (a selective cyclin-dependent kinase 4/6 [CDK4/6] inhibitor) in combination with carboplatin and gemcitabine (CG) compared to CG alone. The study is conducted in patients with locally advanced or metastatic triple-negative breast cancer (TNBC).

2. The trial is structured into two stages:

   Phase IIb (Proof of Concept): Primarily focused on assessing the objective response rate (ORR) in approximately 60 participants.

   Phase III (Confirmatory): A pivotal stage focused on overall survival (OS) in approximately 386 participants.

3. Scientific Rationale:

   Triple-negative breast cancer remains a highly aggressive subtype with limited treatment options once initial therapies fail. BEBT-209 acts as a highly selective CDK4/6 inhibitor. By arresting the cell cycle at the G1 phase, BEBT-209 synchronizes tumor cells, making them more susceptible to chemotherapy-induced DNA damage. Preclinical and early-phase clinical data suggest that BEBT-209 not only enhances the sensitivity of TNBC cells to carboplatin and gemcitabine but also provides a myeloprotective effect, reducing chemotherapy-induced bone marrow suppression.

4. Study Design and Intervention:

   Eligible participants are randomly assigned in a 1:1 ratio to either the experimental group or the control group via a central randomization system.

   Experimental Group: Participants receive BEBT-209 (150 mg, four times per cycle on Day 1 [D1], Day 2 [D2], Day 8 [D8], and Day 9 [D9]) combined with carboplatin (area under the curve [AUC] × [creatinine clearance {CrCl} + 25]) and gemcitabine (1000 mg/m²). The AUC value is set to 2 mg/mL/min in this study.

   Control Group: Participants receive carboplatin (2 [mg/mL/min] × [CrCl {mL/min} + 25]) and gemcitabine (1000 mg/m²) on Day 1 (D1) and Day 8 (D8) of each 21-day cycle.

5. Stratification Factors:

   Phase IIb: Lines of prior therapy (1st-line vs. 2nd-line). Phase III: (1) Lines of prior systemic therapy; (2) Prior programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1, or PD-[L]1) inhibitor therapy (yes vs. no); (3) Prior TROP2 antibody-drug conjugate (ADC) therapy (yes vs. no).

6. Assessment and Follow-up:

Tumor response is evaluated every 6 weeks for the first three assessments, then every 9 weeks, and eventually every 12 weeks after one year, based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria.

Independent Review: An independent review committee (IRC) will perform a blinded central review of all imaging data to provide a baseline-independent assessment of ORR and progression-free survival (PFS).

Safety Monitoring: Safety is assessed through adverse events (AE), graded by Common Terminology Criteria for Adverse Events version 6.0 of the National Cancer Institute (NCI-CTCAE v6.0), physical exams, and laboratory monitoring. Special focus is placed on hematological toxicities (e.g., duration of severe neutropenia [DSN]).

Pharmacokinetics and Biomarkers:

A subset of participants in Phase IIb will undergo pharmacokinetics (PK) sampling. Exploratory analyses will investigate the relationship between biomarkers (e.g., PD-L1, BRCA1/2) and clinical outcomes.

Inclusion Criteria

Participants must meet all of the following criteria to be eligible for the study:

1. Age and gender: Female, aged 18 to 75 years (inclusive).
2. Informed consent: Voluntarily signed the written informed consent form (ICF).
3. Diagnosis: Pathologically confirmed hormone receptor (HR)-negative and human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic triple-negative breast cancer (TNBC).
4. HR-negative: <1% of nuclei stain positive for estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemistry (IHC). HER2-negative: IHC 0, 1+, or IHC 2+ with negative in situ hybridization (ISH).
5. Prior therapy: Must have received at least one but no more than two prior systemic therapies for unresectable locally advanced or metastatic disease. Progression within 12 months of completion of neoadjuvant/adjuvant therapy is considered one line of systemic therapy.
6. Measurable disease: At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
7. Performance status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with stable status within 2 weeks prior to screening (clinically insignificant decline).
8. Life expectancy: At least 12 weeks.
9. Organ function: Adequate organ and bone marrow function (no blood transfusion or growth factors within 2 weeks prior to screening):

(1)Absolute neutrophil count (ANC) ≥ 1,500/mm³; (2) Platelets ≥ 100,000/mm³; (3) Hemoglobin ≥ 9 g/dL; (4) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN) (or ≤ 5.0 × ULN with liver metastases); (5) Total bilirubin ≤ 1.5 × ULN (or ≤ 3 × ULN with liver metastases); (6) Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min (Cockcroft-Gault).

10.Toxicity recovery: Prior anti-cancer therapy toxicities resolved to ≤ grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 6.0 (excluding alopecia or other stable toxicities deemed safe by the investigator).

11.Contraception: Negative serum pregnancy test within 7 days before treatment for women of childbearing potential. Agree to use highly effective contraception during the study and for 6 months after the last dose.

Note: The initial documentation of locally advanced or metastatic disease must be supported by biopsy, pathology, or imaging reports with specific dates. Systemic therapy includes systemic treatments for TNBC, such as chemotherapy, targeted therapy, and immunotherapy.

Exclusion Criteria

Participants meeting any of the following criteria will be excluded:

1. Prior treatment history: Prior treatment with gemcitabine.
2. Prior treatment with carboplatin for unresectable locally recurrent or metastatic breast cancer (unless completed in the (neo)adjuvant setting >6 months prior to first metastatic relapse).
3. Central nervous system (CNS) metastases: Known CNS metastases or leptomeningeal disease (including leptomeningeal metastases, spinal cord metastases, spinal cord compression, and unstable brain metastases). Participants with stable brain metastases (clinically/radiographically stable for at least 4 weeks) are eligible.
4. Pulmonary conditions: Clinically significant pulmonary diseases (e.g., pulmonary embolism within 3 months, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, significant pleural effusion) or autoimmune/inflammatory diseases with lung involvement. Current interstitial lung disease (ILD)/pneumonitis requiring systemic steroids, or active ILD/pneumonitis suggested by baseline imaging.
5. Effusion and cachexia: Uncontrolled moderate to large pleural, pericardial, or abdominal effusion requiring repeated drainage, or cachexia.
6. Transplantation: Prior history of hematopoietic stem cell or bone marrow transplantation.
7. Prohibited concomitant medications (within 7 days prior to first dose):

(1) Strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers; (2) Medications known to significantly prolong the QT interval or cause torsades de pointes (e.g., quinidine, disopyramide, procainamide, sotalol).

8.Washout periods for prior anti-tumor therapy: Radiotherapy or oral small-molecule targeted therapy within 14 days; cytotoxic chemotherapy within 21 days; systemic anti-tumor therapies (e.g., macromolecules, immune checkpoint inhibitors, antibody-drug conjugates (ADCs)) within 28 days; cell therapy within 3 months.

9.Hypersensitivity: Known or suspected hypersensitivity to BEBT-209, carboplatin, gemcitabine, or any of their excipients.

10.Cardiac abnormalities: Significant electrocardiogram (ECG) abnormalities: QTcF > 480 msec (based on the mean of triplicate ECGs if the first is >480 msec); History of long QT syndrome (personal or family); Clinically significant ventricular arrhythmia or current use of anti-arrhythmic drugs/implantable cardioverter-defibrillator (ICD).

11.Electrolyte imbalance: Uncontrolled electrolyte disturbances (e.g., hypocalcemia <1.0 mmol/L, hypokalemia <3.0 mmol/L, hypomagnesemia <0.5 mmol/L) that increase QTc prolongation risk (re-screening allowed after intervention).

12.Cardiovascular/cerebrovascular disease (within 6 months):

1. New York Heart Association (NYHA) Class III-IV congestive heart failure or uncontrolled heart failure/coronary artery disease;
2. Clinically significant arrhythmias (e.g., symptomatic atrial fibrillation/flutter) or NCI CTCAE v6.0 grade ≥ 3 arrhythmias;
3. Myocardial infarction, severe/unstable angina, stroke, transient ischemic attack (TIA), symptomatic pulmonary embolism, coronary artery bypass grafting (CABG), or percutaneous coronary intervention (PCI);
4. Refractory hypertension: systolic blood pressure (SBP) > 160 mmHg and/or diastolic blood pressure (DBP) > 100 mmHg despite ≥ 3 types of antihypertensive medications.

13.Gastrointestinal issues: Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, gastrectomy, or any malabsorption syndrome that may impair BEBT-209 absorption.

14.Active infections of clinical significance, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related diseases, and active syphilis infection.

Active hepatitis B is defined as positive hepatitis B surface antigen (HBsAg) or hepatitis B e antigen (HBeAg) with HBV DNA above the upper limit of normal (ULN) of the study center. Patients with HBV DNA quantification above the ULN are permitted to receive antiviral therapy prior to screening and may be enrolled once viral load decreases to within the normal range; however, anti-HBV therapy must be continued throughout the study period.

Active hepatitis C is defined as HCV RNA above the detection limit. Active syphilis infection is defined as positive treponemal antibody with positive nontreponemal test (rapid plasma reagin [RPR] or toluidine red unheated serum test [TRUST]).

15.Diabetes: Poorly controlled diabetes (hemoglobin A1c (HbA1c) ≥ 8.5%). 16.Other malignancies: Other progressive malignancies or malignancies treated within the past 5 years (excluding cured basal/squamous cell skin cancer or cervical carcinoma in situ).

17.Psychiatric/neurological conditions: Active suicidal ideation or behavior within 3 months; current neurological disorders ≥ NCI CTCAE v6.0 grade 2.

18.General exclusion: Any other severe medical, psychiatric, or laboratory abnormality that, in the investigator's opinion, increases participant risk or interferes with study results.