2024-515349-41-00招募中2 期
SAFIR 03 - LibHERty: A ctDNA screening program in patients with HR+, HER2 low metastatic breast cancer for detection of high-risk relapse patients on any CDK4/6 inhibitor followed by a single arm phase II trial of trastuzumab-deruxtecan in patients with persistent ctDNA after 1 month of treatment with endocrine therapy combined with CDK4/6 inhibitor
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Unicancer
- 入组人数
- 600
- 试验地点
- 35
- 主要终点
- Primary endpoint: Progression-free survival is defined as the time from the first T-DXd administration to the first documented disease progression or death from any cause, whichever occurs first. The tumour assessments are conducted by investigators according to RECIST 1.1 every 6 weeks during the first 12 months of treatment phase, and every 9 weeks thereafter.
研究概览
简要总结
To assess whether early switch of standard treatment (at 8 weeks), from an endocrine therapy (AI or fulvestrant) plus CDK4/6 inh to trastuzumab deruxtecan (T-DXd) for a population expected to develop resistance to SOC treatment according to the Molecular Response is associated with an improved progression-free survival (PFS).
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Screening Phase_
- •Patient must have signed the written informed consent for screening phase prior to any trial specific procedures
- •Screening Phase_
- •Patient has a measurable or an evaluable disease according to RECIST v1.
- •Screening Phase_
- •Availability of an archived metastatic tumour sample (FFPE) for exploratory research. Bone metastasis are accepted if tissue is representative of tumour tissue (at least 10% tumour cellularity).
- •Screening Phase_
- •Patient must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
- •Screening Phase_
- •Registration in a National Health Care System (or equivalent).
- •Treatment Phase_
- •Patient must have signed the written informed consent for the treatment phase prior to any trial specific procedures.
- •Treatment Phase_
- •Patient must have discontinued CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) at least 7 days before enrolment, but no longer than 14 days
- •Treatment Phase_
- •Patients must present a no drop of ctDNA determined by a ctDNA assay after 4 weeks of standard of care treatment with a CDK4/6 inhibitor. A no-drop is defined by a Molecular Response (MR) ≥0.5 according to by MR calculation [Zhang 2020].
- •Treatment Phase_
- •Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status ≤
- •Treatment Phase_
- •Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days prior to enrolment.
- •Treatment Phase_
- •Participant has adequate bone marrow and organ function within 14 days before enrolment, defined as the following laboratory values: • Absolute neutrophil count (ANC) ≥ 1500/mm3, • platelet count ≥ 100,000/mm3, • haemoglobin ≥ 9.0 g/dl, • Serum creatinine ≤1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 30 mL/min, • Serum albumin ≥ 2.5 g/dL, • Total bilirubin ≤1.5 × ULN (<3 ULN if Gilbert’s disease), • In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN. If the participant has liver metastases, ALT and AST < 5 × ULN, he/she will be eligible for the study, • Adequate blood clotting function: defined as an international normalized ratio/prothrombin time ≤ 1.5 × ULN and either partial thromboplastin time or activated partial thromboplastin time within normal limits. Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to C1D
- •Screening Phase_
- •Patient is ≥18 years of age.
- •Treatment Phase_
- •Women of childbearing potential must have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) result within 3 days of enrolment.
- •Treatment Phase_
- •Men or women of childbearing potential must agree to the use of effective contraceptive for the study duration and for at least 7 months after the last dose of study treatment for women, and at least 4 months for men.
- •Treatment Phase_
- •Patient must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
- •Screening Phase_
- •Documented breast cancer that: • Is metastatic and eligible to biopsy for subsequent histological or cytological confirmation • Is HER2 low (HER2 1+, or 2+ and ISH negative) or HER2 ultra low (IHC 0 with incomplete and faint membrane staining in >0 and ≤ 10% of tumour cells) on the most recent tumour material available, as defined by the local pathologist under ASCO/CAP guidelines. • Is HR-positive (positive for estrogen receptor or progesterone receptor ≥ 10% of tumour cell nuclei are immunoreactive) in the metastatic setting.
- •Screening Phase_
- •Patient has either: • a metastatic relapse during or within 1 year after termination of the adjuvant endocrine therapy (AI resistant), or • a metastatic relapse located on either lung and/or liver, and/or other visceral location, occurring more than one year of completing adjuvant AI or a de-novo MBC (AI sensitive/naive).
- •Screening Phase_
- •For AI resistant population: patient has previously gone through the ctDNA screening part of the SAFIR 03 – SCREENING/ARRIBA study and fulfilled all the inclusion criteria and none of the exclusion criteria
- •Screening Phase_
- •Patient did not receive any therapy in the metastatic setting.
- •Screening Phase_
- •Patient is eligible for a first-line treatment with a marketed CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) in combination with either AI or fulvestrant, according to its marketing authorisation
- •Screening Phase_
- •Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status ≤
- •Screening Phase_
- •Patient has an adequate bone marrow and organ function.
排除标准
- •Screening Phase_
- •Patient is eligible to chemotherapy because of visceral crisis (severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease). Note : Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy.
- •Treatment Phase_
- •Uncontrolled or significant cardiovascular disease, including any of the following: • History of myocardial infarction within 6 months before enrolment, • History of symptomatic congestive heart failure (New York Heart Association Class II to IV), • Patient with a corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) based on average of the screening triplicate12-lead ECG. • Patients with known troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrolment to rule out MI
- •Treatment Phase_
- •Clinically severe pulmonary compromise resulting from current pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjögren’s, sarcoidosis, etc.), or prior pneumonectomy.
- •Screening Phase_
- •Patient has a breast cancer amenable for resection or radiation therapy with curative intent.
- •Treatment Phase_
- •Patient has spinal cord compression or clinically active central nervous system metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
- •Treatment Phase_
- •Major surgery within 4 weeks before study enrolment.
- •Treatment Phase_
- •Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to enrolment, or who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 25% of the bone marrow was irradiated
- •Treatment Phase_
- •Patient using drugs that could have pharmacokinetics interaction with investigational drugs. Concomitant use of strong CYP3A4 inhibitors or OATP 1B inhibitors should be avoided. If concomitant use of strong CYP3A4 or OATP 1B inhibitors is unavoidable, consider delaying T-DXd treatment until the inhibitors have cleared from the circulation (approximately 3 elimination half-lives of the inhibitors) when possible. If a strong CYP3A4 inhibitor or an OATP 1B inhibitor is co-administered and T-DXd treatment cannot be delayed, patients should be closely monitored for adverse reactions.
- •Treatment Phase_
- •Patient receiving drug that may cause QTc prolongations or cardiac arrhythmia. Pimozide (Orap®) and cisapride (Prepulsid®) are strictly contraindicated: they are associated with a major risk of ventricular rhythm disorder.
- •Treatment Phase_
- •Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP.
- •Treatment Phase_
- •Participation in a therapeutic clinical study within 4 weeks before enrolment.
- •Screening Phase_
- •Social, familial, or geographic factors that would interfere with study participation or follow-up.
- •Treatment Phase_
- •Patient is currently pregnant, breastfeeding, or planning to become pregnant
- •Treatment Phase_
- •Patient has substance abuse history or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the patient’s participation in the clinical study or evaluation of the clinical study results.
- •Treatment Phase_
- •Person deprived of their liberty or under protective custody or guardianship.
- •Screening Phase_
- •Prior exposure to ADC or CDK4/6 inhibitors (in metastatic setting). CDK4/6 inhibitors given in adjuvant setting must be stopped for at least 12 months prior screening
- •Treatment Phase_
- •Social, familial, or geographic factors that would interfere with study participation or follow-up.
- •Screening Phase_
- •Patient who has initiated the CDK4/6 inhibitor treatment.
- •Screening Phase_
- •Patient is unable to swallow tablets.
- •Screening Phase_
- •Patient has a history of (non-infectious) ILD/pneumonitis requiring steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at baseline
- •Screening Phase_
- •Patient has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
- •Screening Phase_
- •Patient has a history of severe hypersensitivity reactions to other monoclonal antibodies.
- •Treatment Phase_
- •AI resistant patients who are eligible to SAFIR 03 - ARRIBA trial (i.e. PIK3CA mutated patients), until SAFIR 03 - ARRIBA study closure or study steering committee’s decision.
- •Screening Phase_
- •Person deprived of their liberty or under protective custody or guardianship.
- •Treatment Phase_21.Patient is eligible to chemotherapy because of visceral crisis (severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease). Note : Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy
- •Treatment Phase_
- 另有 11 项未显示
结局指标
主要结局
Primary endpoint: Progression-free survival is defined as the time from the first T-DXd administration to the first documented disease progression or death from any cause, whichever occurs first. The tumour assessments are conducted by investigators according to RECIST 1.1 every 6 weeks during the first 12 months of treatment phase, and every 9 weeks thereafter.
Primary endpoint: Progression-free survival is defined as the time from the first T-DXd administration to the first documented disease progression or death from any cause, whichever occurs first. The tumour assessments are conducted by investigators according to RECIST 1.1 every 6 weeks during the first 12 months of treatment phase, and every 9 weeks thereafter.
次要结局
- Overall survival (OS): defined as the time from the first T-DXd administration to death due to any cause. Patients still alive at the cut-off time (including lost to follow-up) will be censored at the last known alive date.
- Objective response Rate (ORR): ORR will be assessed by the investigators using RECIST v1.1 and is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) up to 6 months after the first administration of treatment.
- Duration of response (DoR) is defined as the time interval from the date of first documentation of confirmed CR or PR to the date of first documented disease progression or death, from any cause whichever occurs first. Patients without progression at the cut-off date will be censored at the last assessment date
- Clinical Benefit Rate (CBR): CBR will be assessed by the investigators using RECIST v1.1 and is defined as the proportion of patients with at least a confirmed complete response (CR) or partial response (PR) up to 6 months after the first administration of treatment or a stable disease for 6 months or more after the first administration of treatment.
- Time to Response (TTR): TTR is defined, for patients with an objective response according to RECIST v1.1, as the time from the first T-DXd administration to the first documentation of objective response which is subsequently confirmed.
- The assessment of the incidences of adverse events, graded by NCI CTC-AE v5.
研究者
Nourredine AIT RAHMOUNE
Scientific
Unicancer
研究点 (35)
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