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
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- BeBetter Med Inc
- Enrollment
- 446
- Locations
- 2
- Primary Endpoint
- Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (Phase IIb)
Overview
Brief Summary
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.
Detailed Description
- 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).
- 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Participants must meet all of the following criteria to be eligible for the study:
- •Age and gender: Female, aged 18 to 75 years (inclusive).
- •Informed consent: Voluntarily signed the written informed consent form (ICF).
- •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).
- •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).
- •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.
- •Measurable disease: At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
- •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).
- •Life expectancy: At least 12 weeks.
- •Organ function: Adequate organ and bone marrow function (no blood transfusion or growth factors within 2 weeks prior to screening):
Exclusion Criteria
- •Participants meeting any of the following criteria will be excluded:
- •Prior treatment history: Prior treatment with gemcitabine.
- •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).
- •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.
- •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.
- •Effusion and cachexia: Uncontrolled moderate to large pleural, pericardial, or abdominal effusion requiring repeated drainage, or cachexia.
- •Transplantation: Prior history of hematopoietic stem cell or bone marrow transplantation.
- •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.
Arms & Interventions
BEBT-209 plus CG
This is a phase IIb/III study. Participants in this arm will receive BEBT-209 150 mg orally on Days 1, 2, 8, and 9 of each 21-day cycle, administered as follows:
Days 1 and 8: BEBT-209 administered at least 30 minutes before dinner Days 2 and 9 (chemotherapy days): BEBT-209 administered at least 30 minutes before breakfast, followed by carboplatin (2 [mg/mL/min] × [CrCl (mL/min) + 25]) and gemcitabine (1000 mg/m²) intravenously; the interval between BEBT-209 dosing and chemotherapy initiation is 4 hours ± 0.5 hours.
Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.
Intervention: BEBT-209 capsules (Drug)
Carboplatin plus Gemcitabine(CG)
Participants in this arm will receive carboplatin (2 [mg/mL/min] × [CrCl (mL/min) + 25]) and gemcitabine (1000 mg/m²) in 21-day cycles. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.
Intervention: Carboplatin Injection (Drug)
Carboplatin plus Gemcitabine(CG)
Participants in this arm will receive carboplatin (2 [mg/mL/min] × [CrCl (mL/min) + 25]) and gemcitabine (1000 mg/m²) in 21-day cycles. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.
Intervention: Gemcitabine Hydrochloride for Injection (Drug)
BEBT-209 plus CG
This is a phase IIb/III study. Participants in this arm will receive BEBT-209 150 mg orally on Days 1, 2, 8, and 9 of each 21-day cycle, administered as follows:
Days 1 and 8: BEBT-209 administered at least 30 minutes before dinner Days 2 and 9 (chemotherapy days): BEBT-209 administered at least 30 minutes before breakfast, followed by carboplatin (2 [mg/mL/min] × [CrCl (mL/min) + 25]) and gemcitabine (1000 mg/m²) intravenously; the interval between BEBT-209 dosing and chemotherapy initiation is 4 hours ± 0.5 hours.
Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.
Intervention: Carboplatin Injection (Drug)
BEBT-209 plus CG
This is a phase IIb/III study. Participants in this arm will receive BEBT-209 150 mg orally on Days 1, 2, 8, and 9 of each 21-day cycle, administered as follows:
Days 1 and 8: BEBT-209 administered at least 30 minutes before dinner Days 2 and 9 (chemotherapy days): BEBT-209 administered at least 30 minutes before breakfast, followed by carboplatin (2 [mg/mL/min] × [CrCl (mL/min) + 25]) and gemcitabine (1000 mg/m²) intravenously; the interval between BEBT-209 dosing and chemotherapy initiation is 4 hours ± 0.5 hours.
Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent.
Intervention: Gemcitabine Hydrochloride for Injection (Drug)
Outcomes
Primary Outcomes
Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (Phase IIb)
Time Frame: From randomization until disease progression or end of treatment or death (up to 24 months).
Percentage of participants achieving complete response (CR) or partial response (PR) per RECIST v1.1. This is the primary endpoint for the Phase IIb and will be assessed by both independent review committee (IRC) and investigator (INV).
Overall Survival (OS) (Phase III)
Time Frame: From randomization until death (up to 48 months).
Defined as the time from the date of randomization to the date of death due to any cause. This is the primary endpoint for the Phase III.
Secondary Outcomes
- Objective Response Rate (ORR) per RECIST v1.1 (Phase III)(From randomization until disease progression or end of treatment or death (up to 24 months).)
- Progression-Free Survival (PFS) per RECIST v1.1 (Phase IIb and Phase III)(From randomization until disease progression or end of treatment or death (up to 24 months).)
- Disease Control Rate (DCR) per RECIST v1.1 (Phase IIb and Phase III)(From randomization until disease progression or end of treatment or death (up to 24 months).)
- Duration of Response (DoR) per RECIST v1.1 (Phase IIb and Phase III)(From the date of the first documented objective response (CR or PR) until the first documented disease progression or death (up to 24 months).)
- Overall Survival (OS) (Phase IIb)(From randomization until death (up to 48 months).)
- Change from Baseline in Health-Related Quality of Life (HRQoL) (Phase IIb and Phase III)(Baseline, then at each chemotherapy visit (every 21-day cycle), at the end of treatment, and every 3 months during follow-up until death or withdrawal (up to 24 months).)
- Adverse Events (AE) and Serious Adverse Events (SAE) (Phase IIb and Phase III)(From signing of informed consent until 30 days after the last dose.)
- Maximum Plasma Concentration (Cmax) of BEBT-209 and its major Metabolites(C1D1 (pre-dose, 1h, 2h, 4h, 6h post-dose) and C1D2 (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Time to reach Cmax (Tmax) of BEBT-209 and its major metabolites(C1D1 (pre-dose, 1h, 2h, 4h, 6h post-dose) and C1D2 (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Terminal Elimination Half-life (t1/2) of BEBT-209 and its major metabolites(C1D1 (pre-dose, 1h, 2h, 4h, 6h post-dose) and C1D2 (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Area Under the Concentration-Time Curve (AUC) of BEBT-209 and its major Metabolites(Cycle 1 Day 1 (C1D1 ) (pre-dose, 1h, 2h, 4h, 6h post-dose) and Cycle 1 Day 2 (C1D2) (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Steady-state Maximum Concentration (Cmin,ss) of BEBT-209 and its major metabolites(C1D8 (pre-dose).)
- Steady-state Maximum Concentration (Cmax,ss) of BEBT-209 and its main metabolites(C1D8 (pre-dose, 1h, 2h, 4h, 6h post-dose) and C1D9 (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Average Steady-state Plasma Concentration (Cav,ss) of BEBT-209 and its major metabolites(C1D8 (pre-dose, 1h, 2h, 4h, 6h post-dose) and C1D9 (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Steady-state Elimination Half-life (t1/2,ss) of BEBT-209 and its metabolites(C1D8 (pre-dose, 1h, 2h, 4h, 6h post-dose) and C1D9 (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Area Under the Concentration-Time Curve steady-state (AUCss) of BEBT-209 and its Metabolites(Cycle 1 Day8 (C1D8) (pre-dose, 1h, 2h, 4h, 6h post-dose) and Cycle 1 Day 9 (C1D9 ) (1, 2, 4, 8, 12, 24, 36h post-dose).)
- Biomarker Analysis (Phase IIb and Phase III)(Baseline and at disease progression (up to 36 months))