Fludzoparib" and Anti-angiogenic, HRD-positive/HER2-negative Advanced Breast Cancer
Conditions
Brief summary
This study develops a new therapeutic approach for HER2-negative advanced breast cancer patients without precise treatment targets. The trial aims at extending the combination target therapy involving PARP inhibitors and anti-angiogenesis from only BRCA mutation carriers to all patients with homologous recombination repair defects (HRD-positive). The phase III randomized clinical study will investigate the effectiveness of the combination therapy of PARP inhibitor fludzoparib and anti-angiogenic apatinib in treating HRD-positive/HER2-negative advanced breast cancers.
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. 80% of these patients have HER2-negative subtype breast cancer, which has not yet been found the similar target as HER2, with the median survival time of only 6-20 months. In the past, ovarian 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 ovarian cancer have successfully expanded the indications of PARP inhibitor-based combination targeted therapy from the small population of BRCA mutation(20%) to the large population of HRD-positive (Homologous recombination deficiency) (50%), which has significantly prolonged the survival time of patients. Because causes other than BRCA mutations can also cause tumor cells to be HRD and thus sensitive to PARP inhibitors, so that HRD-positive patients are likely to benefit. The HRD-positive profile of nearly 50% of the patients could be a potential beneficiary of PARP inhibitor-based targeted therapy. The synergistic effect of PARP inhibitor and anti-angiogenic combination therapy has already been confirmed in preliminary cellular experiments and clinical studies related to ovarian cancer. Further cell-based experiments and preclinical studies have also confirmed the feasibility of the combination targeted therapy in the HRD-positive/HER2-negative subtype of breast cancer. Therefore, we intend to further validate the efficacy and safety of the PARP inhibitor fluazoparib in combination with the antiangiogenic abatinib in a Phase III, randomized, controlled clinical study, in order to provide HRD-positive/HER2-negative breast cancer patients with a better choice of precision targeted therapy.
Interventions
DRUGFluzoparib
Fluzoparib capsules appropriate dose oral, each treatment cycle defined as 3 weeks (21 days).
DRUGApatinib Mesylate
Apatinib Mesylate oral; each treatment cycle defined as 3 weeks (21 days).
DRUGCapecitabine tablets
Capecitabine tablets, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
For the first three courses: reasonable dosage with reference to guidelines. After 3 courses of medication, it is recommended to increase the dose of vinorelbine tartrate once a week. Each treatment cycle defined as 3 weeks (21 days).
Eribulin, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
DRUGGemcitabine Hydrochloride
Gemcitabine, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
Paclitaxel-albumin, reasonable dosage with reference to guidelines, each treatment cycle defined as 3 weeks (21 days).
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
The subjects must meet all of the following conditions: Adult female patients (aged 18 to 70 years) with metastatic breast cancer diagnosed by pathology or imaging; 2) Pathological confirmation of HER2 negative (definition: immunohistochemical result is 0 or + or ++ and in situ hybridization result is negative); 3) The patient's HRD test was positive (definition: BRCA1/2 mutation, or HRD score greater than or equal to 42 points); 4) HR+/HER2- patients who have received endocrine therapy during the metastasis stage; 5) Having received no more than two lines of chemotherapy (or ADC) regimens for metastatic breast cancer in the past; 6) Evaluation of anti-tumor treatment (including chemotherapy /HER2-ADC/TROP2-ADC) for 6-8 cycles to achieve clinical benefit (CR or PR) or SD for 24 weeks or more; 7) ECOG physical condition score ≤2 points, and the expected survival period is no less than 3 months; 8) At least one measurable lesion was found in the imaging examination within 2 weeks before enrollment. Or simple bone metastasis lesion; 9) At the time of enrollment, the previous treatment-related toxicity must be remitted to NCI CTCAE (Version 5.0) ≤1 degree (except for alopecia or other toxicities that the investigator deems to pose no risk to the patient's safety). 10\) Adequate bone marrow functional reserve: 1. White blood cell count (WBC) ≥3.0×10\^9 / L 2. Neutrophil count (ANC) ≥1.5×10\^9 / L 3. Platelet count (PLT) ≥70×10\^9 / L 11) Liver, kidney and heart function tests are basically normal (based on the normal values in the laboratories of each research center) : a. Total bilirubin (TBIL) ≤3× upper limit of normal (ULN) b. Alanine aminotransferase and aspartate aminotransferase (ALT/AST) ≤2.5×ULN (≤5 ×ULN for patients with liver metastasis) c. Serum creatinine ≤1.5×ULN or creatinine clearance rate (Ccr) ≥60 ml/min; d.Left ventricular ejection fraction (LVEF) ≥ 55%, e. QTcF(Fridericia correction) ≤ 470 ms. 12) Be able to understand the research process, voluntarily participate in this research, and sign the informed consent form.
Exclusion criteria
If a subject experiences any of the following situations, they will not be eligible to participate in this study: 1. Patients with HR+/ HER2-MBC who have not received endocrine therapy before; 2. Has not received any treatment for metastatic breast cancer; 3. Received more than two chemotherapy regimens for metastatic breast cancer; 4. Patients who are known to be allergic to the active ingredient or other ingredients of the investigational drug. 5. Pregnant or lactating women, and women of childbearing age who refused to take effective contraceptive measures during the study period. 6. Those with severe heart disease or discomfort, expected to be unable to tolerate chemotherapy, including but not limited to: fatal arrhythmia or higher-grade atrioventricular block, unstable angina pectoris, clinically significant valvular heart disease, electrocardiogram showing transmural myocardial infarction, uncontrollable hypertension; 7. Any other circumstances where the researcher deems the patient unsuitable for participation in this study, any concomitant diseases or conditions that may interfere with participation in the study, or any serious medical conditions that may affect the safety of the subjects (such as uncontrollable heart disease, hypertension, active or uncontrollable infection, active hepatitis B virus infection).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival，PFS（Independent Review Committee） | 2 years | The time from the beginning of treatment to the progression or death of the patient |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| Clinical Benefit Rate，CBR | 2 years | Proportion of confirmed complete response, partial response, or stable disease ≥ 24 weeks. |
| 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) |
| Progression Free Survival，PFS（Investigator） | 2 years | The time from the beginning of treatment to the progression or death of the patient |
| the rate of adverse events | 2 years | The probability and severity of adverse reactions, and the extent and incidence of AEs were assessed according to CTCAE. |
| Quality of life scale score，QoL | 2 years | The function or quality of a patient's physical, psychological, and social adaptability is also known as quality, which is assessed according to the EROTC C30 scale. |
| Overall survival time ，OS | 2 years | The time from the start of randomization to death due to any cause. |
Countries
China
Contacts
Primary ContactZhao Jianli
Outcome results
None listed