Open, Controlled, Multicenter Phase I/II Clinical Study of Hydroxychloroquine in Combination With Antibody-drug Conjugate Versus Antibody-drug Conjugate for Advanced Breast Cancer.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Adverse event, AE
研究概览
简要总结
Advanced breast cancer is a special subtype of human breast cancer. Conventional guidelines recommend chemotherapy combined with other adjuvant therapies for this subtype of patients. However, the choice of treatment for these patients after treatment progress is a research hotspot in this field. Trastuzumab Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG) are new ADC drugs targeting HER2 or TROP-2 with high efficacy and low toxicity after the progress of first-line treatment. The autophagy agents hydroxychloroquine or chloroquine has become the only FDA (Food and Drug Administration) approved autophagy inhibitor, and hydroxychloroquine and antibody-drug conjugate(ADC) may have synergistic effects based on the previous work results of our research group.
Therefore,we envisage that Trastuzumab Deruxtecan(T-DXd) or Sacituzumab Govitecan (SG) combined with hydroxychloroquine(HCQ) in the treatment of advanced breast cancer in clinical practice has the advantages of improving efficacy and survival.
To this end, we intend to conduct a prospective,multi-center, phase I/II clinical trial to evaluate the efficacy and safety of T-DXd or SG in combination with HCQ in patients with advacned breast cancer.
详细描述
Breast cancer is the most prevalent malignant tumor in the world, and 30% of breast cancer patients will enter the advanced stage due to treatment failure. Most patients with advanced breast cancer have had distant organ metastasis, and the median progression free survival period is only 1-2 years.
In the past, advanced breast cancer patients faced the dilemma of poor survival due to the lack of precise targeted therapy. However, through a series of clinical studies, experts in the field of advanced breast cancer have successfully expanded the indications of ADC-based combination targeted therapy from the emergence of first generation ADC to the third generation ADC with "bystander effect", which has significantly prolonged the survival time of patients. Trastuzumab Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG) are new ADC drugs targeting HER2 or TROP-2 with high efficacy and low toxicity after the progress of first-line treatment.
Because both ADC and autophagy involve lysosomes, and the relationship between ADC and autophagy microenvironment has not been elucidated, the combination of autophagy regulators and ADC may be a treatment option that can benefit some patients more.The autophagy agents hydroxychloroquine or chloroquine has become the only FDA (Food and Drug Administration) approved autophagy inhibitor. And the synergistic effect of hydroxychloroquine and antibody-drug conjugate (ADC) has already been confirmed based on preliminary experiments of our research group. We envisage that Trastuzumab Deruxtecan (T-DXd) or Sacituzumab Govitecan (SG) combined with hydroxychloroquine(HCQ) in the treatment of advanced breast cancer in clinical practice has the advantages of improving efficacy and survival.
Therefore, we intend to further validate the efficacy and safety of the Autophagy inhibitor hydroxychloroquine(HCQ) in combination with the latest ADC drugs (T-DXd or SG) in a Phase I/II, randomized, controlled clinical study, in order to provide advanced breast cancer patients with a better choice of precision targeted therapy.
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 70 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of advanced breast cancer (female, 18 to 70 years old).
- •Pathological confirmed advanced breast cancer.
- •The patient is willing to receive SG or T-DXd treatment.
- •Failure of first-line treatment.
- •Have received no more than 3 chemotherapy schemes for metastatic breast cancer in the past.
- •ECOG physical condition score ≤ 2 points, estimated survival time of no less than 3 months.
- •At least one measurable lesion should be present in the imaging examination within 2 weeks prior to enrollment; Or simple bone metastasis lesions.
- •Previous treatment related toxicity must be relieved to NCI CTCAE (version 5.0) ≤ 1 degree, AST and ALT ≤ 2.5 times the upper limit of normal value, and total bilirubin ≤ 1.5 times the upper limit of normal value.
- •Adequate reserve of bone marrow function: white blood cell count ≥ 3.0 × 10^9/L, neutrophil count ≥ 1.5 × 10^9/L; Platelet count ≥ 100 × 10^9/L; Hemoglobin ≥ 90g/L; Serum creatinine ≤ 1.5 times the upper limit of normal value.
排除标准
- •Patients suffer from various factors such as difficulty swallowing and chronic diarrhea, which affect medication intake and absorption.
- •Individuals with severe heart disease or discomfort, expected inability to tolerate chemotherapy, including but not limited to: fatal arrhythmias or higher-level atrioventricular block, unstable angina, clinically significant valvular heart disease, electrocardiogram showing transmural myocardial infarction, and uncontrolled hypertension.
- •Patients who are known to be allergic to the active ingredients or other components of the investigational drug.
- •Received radiotherapy, chemotherapy, endocrine therapy within 4 weeks prior to enrollment, or is currently participating in any intervention drug clinical trials.
- •Pregnant or lactating women, women of childbearing age who refuse to take effective contraceptive measures during the study period.
- •The researchers believe that patients are not suitable to participate in any other circumstances of this study, which may interfere with the accompanying diseases or conditions of the study, or have any serious medical obstacles that may affect the safety of the subjects.
研究组 & 干预措施
Sacituzumab Govitecan
Sacituzumab Govitecan (SG) is given by intervenous route, 10 mg/kg on day 1 and day 8 of 21-day treatment cycles. Patient will receive treatment until disease progression, unacceptable toxicity, or decision to withdraw its participation.
干预措施: Sacituzumab Govitecan (Drug)
Hydroxychloroquine Combined With Sacituzumab Govitecan
The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result.
Sacituzumab Govitecan (SG) is given by intervenous route, 10 mg/kg on day 1 and day 8 of 21-day treatment cycles. Patient will receive treatment until disease progression, unacceptable toxicity, or decision to withdraw its participation.
干预措施: Hydroxychloroquine (Drug)
Hydroxychloroquine Combined With Sacituzumab Govitecan
The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result.
Sacituzumab Govitecan (SG) is given by intervenous route, 10 mg/kg on day 1 and day 8 of 21-day treatment cycles. Patient will receive treatment until disease progression, unacceptable toxicity, or decision to withdraw its participation.
干预措施: Sacituzumab Govitecan (Drug)
Trastuzumab Deruxtecan
Patients will receive T-DXd at 5.4 mg/kg administered as an intravenous (IV) infusion every three-weeks (Q3W) until disease progression, unacceptable toxicity, death, or discontinuation from the study.
干预措施: Trastuzumab Deruxtecan (Drug)
Hydroxychloroquine Combined With Trastuzumab Deruxtecan
The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result.
Patients will receive T-DXd at 5.4 mg/kg administered as an intravenous (IV) infusion every three-weeks (Q3W) until disease progression, unacceptable toxicity, death, or discontinuation from the study.
干预措施: Hydroxychloroquine (Drug)
Hydroxychloroquine Combined With Trastuzumab Deruxtecan
The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result.
Patients will receive T-DXd at 5.4 mg/kg administered as an intravenous (IV) infusion every three-weeks (Q3W) until disease progression, unacceptable toxicity, death, or discontinuation from the study.
干预措施: Trastuzumab Deruxtecan (Drug)
结局指标
主要结局
Adverse event, AE
时间窗: 2 years
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Dose Limiting Toxicity, DLT
时间窗: 3 weeks
A dose limiting toxicity（DLT）is defined as any of the following-related adverse event(AE) that occurs during the DLT period, graded according to the NCI Common Terminology Criteria for Adverse Events(CTCAE), Version 5.0
Objective Response Rate, ORR
时间窗: 2 years
the proportion of patients with a tumor volume reduction of ≥30% and a minimum timeframe according to accepted response evaluation criteria (e.g., RECIST version 1.1 in solid tumors), including cases of complete response (CR) and partial response (PR).
次要结局
- Progression-Free Survival, PFS(2 years)
- Overall Survival, OS(4 years)
- Clinical Benefit Rate, CBR(24 weeks after enrollment)
- Disease Control Rate, DCR(2 years)
- The rate of adverse events(up to 24 weeks after enrollment)
- Quality of life scale score, QoL(1 year)
- Exploration of biomarkers(the first week after the enrollment)
研究者
Jianli Zhao
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University