An Open-label, Multicenter, Phase Ib/II Clinical Study to Evaluate the Safety and Efficacy of Multiple Combination Therapies With FWD1802 in Subjects With ER-positive/HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 196
- 试验地点
- 1
- 主要终点
- Phase Ib- Dose-Limiting Toxicity (DLT).
研究概览
简要总结
This is a Study to Evaluate the Efficacy and Safety of Multiple Combination Therapies with FWD1802 in Subjects with ER-positive/HER2-negative Unresectable Locally Advanced or Metastatic Breast Cancer
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Subjects consent to provide blood samples for centralized laboratory testing of ESR1 mutation status and other biomarkers.
- •Histologically or cytologically confirmed ER-positive/HER2-negative locally advanced or metastatic breast cancer
- •Subjects must meet at least one of the following criteria: postmenopausal or prior bilateral oophorectomy, or postmenopausal or Premenopausal/perimenopausal women must agree to receive and maintain approved luteinizing hormone-releasing hormone (LHRH) agonist therapy during study treatment
- •Prior Therapy Requirements:Subjects must meet all of the following criteria:
- •Progression during/after, intolerance to, ineligibility for, or refusal of standard therapy
- •Endocrine therapy history:
- •Recurrence during or within 1 year after completing ≥2 years of adjuvant endocrine therapy;OR progression after ≥1 line of endocrine therapy for advanced breast cancer(ABC) with ≥6 months of maintenance therapy (no restriction on the number of prior endocrine therapy lines).
- •≤2 prior lines of chemotherapy for ABC
- •No prior SERD (selective estrogen receptor degrader) therapy except fulvestrant
- •Everolimus combination arm: Prior CDK4/6 inhibitor therapy requiredf) CDK4/6 inhibitor combination arm:Permitted ≤1 line of prior non-investigational CDK4/6 inhibitor therapy;If only received adjuvant CDK4/6 inhibitor therapy, recurrence must occur >12 months after treatment completion Note: Antibody-drug conjugates (ADCs) are classified as chemotherapy in this study.
- •Phase Ib: At least one evaluable lesion per RECIST v1.1, allowed subjects with osteolytic bone lesion(s) confirmed by CT/MRI.Phase II: At least one measurable lesion per RECIST v1.
- •Subject must have sufficient organ and bone marrow functions at screening.
排除标准
- •Leptomeningeal metastasis (carcinomatous meningitis)；Spinal cord compression；Symptomatic or clinically unstable central nervous system (CNS) metastases；
- •History or any persistent chronic gastrointestinal disorders or other conditions of impaired absorption that may interfere with oral absorption of the investigational drug
- •Symptomatic visceral metastases , or clinically symptomatic and unstable effusions;Pleural effusion;Ascites;Pericardial effusion or Pulmonary lymphangitis carcinomatosa. Prior intracavitary infusion therapy should have more than 14 days of stabilization,
- •Prior therapy with any selective estrogen receptor degrader (SERD) or similar agents other than fulvestrant
- •Inadequate washout period for prior anticancer therapies.
- •Type 1 diabetes mellitus; Type 2 diabetes mellitus with poor glycemic control at screening(applies only to the everolimus combination arm).
- •Subjects will be excluded if they meet any of the following:
- •Interstitial lung disease or drug-induced ILD history, OR evidence of active pneumonitis on chest CT scan within 4 weeks prior to first study treatment.
- •Severe pulmonary disease at screening, including but not limited to:Severe asthma;Severe chronic obstructive pulmonary disease (COPD) Idiopathic
- •Uncontrolled hypertension despite antihypertensive therapy, defined as:Systolic blood pressure (SBP) >150 mmHg OR Diastolic blood pressure (DBP) >95 mmHg.
- •Active cardiac disease or history of cardiac dysfunction
研究组 & 干预措施
FWD1802 in combination with Palbociclib (CDK4/6 inhibitor) with or without LHRH agonist；
干预措施: FWD1802 (Drug)
FWD1802 in combination with Palbociclib (CDK4/6 inhibitor) with or without LHRH agonist；
干预措施: Palbociclib 125mg (Drug)
FWD1802 in combination with Ribociclib (CDK4/6 inhibitor) with or without LHRH agonist
干预措施: FWD1802 (Drug)
FWD1802 in combination with Ribociclib (CDK4/6 inhibitor) with or without LHRH agonist
干预措施: Ribociclib 200Mg Oral Tablet (Drug)
FWD1802 in combination with Abemaciclib (CDK4/6 inhibitor) with or without LHRH agonist
干预措施: FWD1802 (Drug)
FWD1802 in combination with Abemaciclib (CDK4/6 inhibitor) with or without LHRH agonist
干预措施: Abemaciclib 150 MG (Drug)
FWD1802 in combination with Everolimus (mTOR inhibitor) with or without LHRH agonist
干预措施: FWD1802 (Drug)
FWD1802 in combination with Everolimus (mTOR inhibitor) with or without LHRH agonist
干预措施: Everolimus 10 mg (Drug)
结局指标
主要结局
Phase Ib- Dose-Limiting Toxicity (DLT).
时间窗: Approximately 1.5 years
Phase Ib- Maximum Tolerated Dose (MTD).
时间窗: Approximately 1.5 years
Phase Ib- Recommended Phase II Dose (RP2D).
时间窗: Approximately 1.5 years
Incidence of Treatment-Emergent Adverse Events (TEAEs)
时间窗: Approximately 2 years
Number and proportion of participants experiencing any treatment-emergent adverse event during the study period. Assessment criteria: Events will be categorized as "related" or "unrelated" to study drug based on investigator's causality assessment. Reporting format: Frequency counts and percentages stratified by severity grade (Grade 1-5 as per NCI-CTCAE v5.0).
Severity Grading of Adverse Events
时间窗: Approximately 2 years
Maximum severity grade of treatment-emergent adverse events experienced by participants. Assessment tool: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Reporting format: Proportion of participants with events in each severity category (Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening; Grade 5=death).
Clinically Significant Abnormalities in 12-Lead ECG Parameters
时间窗: Approximately 2 years
Number of participants with clinically significant changes in electrocardiogram parameters from baseline. Assessed parameters: QTc interval, PR interval, QRS duration, heart rate.
Vital Sign Abnormalities
时间窗: Approximately 2 years
Proportion of participants with clinically significant deviations in vital signs: Parameters: Systolic/diastolic blood pressure (mmHg), heart rate (bpm), respiratory rate (breaths/min), body temperature (°C).
Serious Adverse Events (SAEs) Incidence
时间窗: Approximately 2 years
Phase II- Investigator-assessed Objective Response Rate (ORR) based on RECIST v1.1.
时间窗: Approximately 2 years
次要结局
- Phase Ib- PK Assessment-Cmax(Approximately 1.5 years)
- Phase Ib- PK Assessment-AUC0-t(Approximately 1.5 years)
- Phase Ib- PK Assessment-AUC0-inf(Approximately 1.5 years)
- Phase Ib- PK Assessment-t1/2(Approximately 1.5 years)
- Efficacy Assessment-ORR(Approximately 2 years)
- Efficacy Assessment-CBR(Approximately 2 years)
- Efficacy Assessment-DOR(Approximately 2 years)
- Efficacy Assessment-DCR(Approximately 1.5 years)
- Phase Ib- PK Assessment-Tmax(Approximately 1.5 years)
- Efficacy Assessment-PFS(Approximately 2 years)
- Efficacy Assessment-OS(Approximately 2 years)
- Pharmacokinetic (PK) Parameters:Plasma Concentration at Each Sampling Time Point.(Approximately 2 years)