Advanced Breast Cancer, Metastatic Breast Cancer
Conditions
Keywords
Antibody-drug Conjugate, Hydroxychloroquine, Advanced Breast Cancer, Metastatic Breast Cancer
Brief summary
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.
Detailed description
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.
Interventions
DRUGHydroxychloroquine
The dosage of hydroxychloroquine is determined based on the dose escalation study, and the appropriate administration method will be determined based on this result.
DRUGSacituzumab Govitecan
Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a chemotherapy drug, called govitecan. Sacituzumab is a form of targeted therapy because it attaches to specific molecules on the surface of cancer cells, known as Trop-2 receptors, and delivers govitecan to kill them.
DRUGTrastuzumab Deruxtecan
Trastuzumab-deruxtecan is a human HER2-directed antibody-drug conjugate (ADC) composed of humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, covalently linked to the membrane-permeable topoisomerase I inhibitor payload, DXd, an exatecan derivative, via a stable tetrapeptide-based linker, selectively cleaved within tumor cells.
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The research model consists of four arms： 1. arm A: SG. 2. arm B: HCQ+SG. 3. arm C: T-DXd . 4. arm D: HCQ+T-DXd.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of advanced breast cancer (female, 18 to 70 years old). 2. Pathological confirmed advanced breast cancer. 3. The patient is willing to receive SG or T-DXd treatment. 4. Failure of first-line treatment. 5. Have received no more than 3 chemotherapy schemes for metastatic breast cancer in the past. 6. ECOG physical condition score ≤ 2 points, estimated survival time of no less than 3 months. 7. At least one measurable lesion should be present in the imaging examination within 2 weeks prior to enrollment; Or simple bone metastasis lesions. 8. LVEF≥50%. 9. 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. 10. 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.
Exclusion criteria
1. Patients suffer from various factors such as difficulty swallowing and chronic diarrhea, which affect medication intake and absorption. 2. 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. 3. Patients who are known to be allergic to the active ingredients or other components of the investigational drug. 4. Received radiotherapy, chemotherapy, endocrine therapy within 4 weeks prior to enrollment, or is currently participating in any intervention drug clinical trials. 5. Pregnant or lactating women, women of childbearing age who refuse to take effective contraceptive measures during the study period. 6. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity, DLT | 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 |
| Adverse event, AE | 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. |
| Objective Response Rate, ORR | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate, DCR | 2 years | Proportion of patients with stable or shrinking tumor size--sum of the proportions of complete remission (CR), partial remission (PR) and stable disease (SD). |
| The rate of adverse events | up to 24 weeks after enrollment | The probability and severity of adverse reactions were analyzed up to 24 weeks after enrollment |
| Progression-Free Survival, PFS | 2 years | The time from the beginning of treatment to the progression or death of the patient |
| Exploration of biomarkers | the first week after the enrollment | Objective to explore the correlation between biomarkers and the ORR. The biomarkers will be test by nest-generation sequence, which include 520 genes and tumor mutation burden, like ERBB2/TP53/PIK3CA/ERBB4/CCND1 and so on. |
| Quality of life scale score, QoL | 1 year | The quality of life score of patients during treatment was analyzed(FACT-B). Performance Status Rating (PSR) was demonstrated for the FACT-B total score, which is the result of the following subscale scores: SWB (the Social / family Well-Being subscale) , EWB (the Emotional Well-Being subscale), AC (Additional Concerns subscale), PWB (the Physical Well-Being subscale), FWB (the Functional Well-Being subscale) |
| Overall Survival, OS | 4 years | The time from the start of randomization to death due to any cause. |
| Clinical Benefit Rate, CBR | 24 weeks after enrollment | Proportion of confirmed complete response, partial response, or stable disease ≥ 24 weeks. |
Countries
China
Contacts
Primary ContactJianli J Zhao, doctorate
Backup ContactErwei E Song, doctorate
Outcome results
None listed