A Proof of Concept Study to Evaluate Treatments' Efficacy by Monitoring Minimal Residual Disease Using ctDNA in HR-positive/HER2-negative Early Breast Cancer Population
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 976
- 试验地点
- 83
- 主要终点
- Evaluation of decrease or clearance in baseline ctDNA at three months after initiation of study treatment
研究概览
简要总结
This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease.
The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase).
After informed consent is obtained, a total of 976 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature).
At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy:
Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10)
If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.
详细描述
This is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment Study. Men and pre- and postmenopausal women aged ≥ 18 years with early stage HR-positive/HER2-negative BC at high risk of relapse, but with no evidence of locoregional, contralateral, or distant disease, who have undergone surgery, have received radiotherapy if indicated as per local guidelines and are on adjuvant treatment with endocrine therapy (ET) for at least two years and no more than seven years at the time of Study enrolment, with an additional three years of ET planned, and at least six months prior to enrolment on the same ET with aromatase inhibitors (AI) or tamoxifen (luteinizing hormone-releasing hormone [LHRH] agonist is mandatory for male and premenopausal participants receiving AI, as well as for premenopausal participants treated with tamoxifen, except in cases of bilateral oophorectomy).
Note: Premenopausal and male participants treated with tamoxifen alone are excluded.
After signing the ICF and confirmed eligibility, 976 participants will first enter the surveillance phase in which blood will be collected and analyzed to detect the presence or absence of ctDNA at predefined time points for longitudinal surveillance. ctDNA analysis will occur every three months from Study inclusion during the first year and every six months thereafter until end of surveillance phase, which is defined as ctDNA positive result, permanent discontinuation (or temporally discontinuation ≥ 90 days) of the adjuvant hormonal treatment, or the end of accrual of the treatment phase upon Steering Committee decision, whichever occurs first.
Surveillance phase participants should be followed up in line with standard practice every six months (± two weeks) to assess for disease recurrence.
Participants should continue to receive ET according to standard treatment (with tamoxifen or AI [letrozole, anastrozole, exemestane]); the use of LHRH agonist treatment is mandatory for male and premenopausal participants receiving either AI or tamoxifen , except in cases of bilateral oophorectomy. Changes in ET during the ctDNA surveillance period are generally not allowed, however, justified changes such as anastrozole and letrozole switch may be discussed with the Medical Monitor. Changes in LHRH agonist treatment may also be discussed with the Medical Monitor. Participants who permanently discontinue or temporally discontinued (≥ 90 days) standard ET during the surveillance phase are not eligible to enter the treatment phase of the Study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligibility criteria for surveillance phase:
- •Note: Participants who had not participated in the surveillance phase but have an additional positive ctDNA test will be eligible for direct-to-treatment phase entry if they fulfill all the matching eligibility requirements. Therefore, these participants will not need to meet all the eligibility criteria for the surveillance phase.
- •Inclusion criteria (surveillance phase):
- •Signed surveillance phase ICF prior to participation in any Study-related activities.
- •Male or female participants aged 18 years or older.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •Histologically proven primary HR-positive according to the updated American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.
- •Participants with high-risk early-stage BC according to at least one of the following criteria:
- •If no previous neoadjuvant chemotherapy:
- •i. pN2-N3, or ii. pN1 (including micrometastasis - pN1mi) if:
- •pT2 and high genomic risk, and/or histological grade III, and/or Ki 67 ≥ 30%. b. If participants have received previous neoadjuvant chemotherapy, they must have had residual invasive disease defined as at least one of the following: i. Residual invasive disease in lymph nodes (ypN+, including ypN1mi) ii. ypN0 with residual invasive disease in breast if:
- •cT2 and high genomic risk, and/or histological grade III, and/or Ki67 ≥ 30%. Note: Genomic risk using platforms such as Oncotype Dx, Prosigna or Mammaprint won't be assessed for the screening to participate in the Study. However, participants with the detailed scores assessed prior to Study inclusion, may be eligible.
- •6. On adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned, and at least six months prior to enrolment on the same ET treatment with AI or tamoxifen (LHRH agonist is mandatory for male and premenopausal participants receiving AI or tamoxifen, except in cases of bilateral oophorectomy).
- •Note: Premenopausal and male participants treated with tamoxifen alone are excluded.
- •7. Prior treatment with cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) in the adjuvant setting will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial.
- •8. No prior treatment with selective estrogen receptor degraders (SERDs) will be allowed.
- •9. Availability and willingness to provide the most recently available (archival formalin-fixed paraffin-embedded [FFPE]) tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy) at the time of Study inclusion.
- •Note I: Participants with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC.
- •Note II: Participants with bilateral carcinoma of the breast may be included as long as at least one of the tumors meets the criteria established by the protocol and both are HR-positive and HER2-negative tumors.
- •10. Successful ctDNA assay designability, defined as the ability to generate a personalized, tumor-informed ctDNA assay based on sequencing of tumor tissue and matched germline DNA, enabling longitudinal ctDNA assessment.
- •11. Absence of metastatic disease by routine clinical assessment (computed tomography [CT] scan of the thorax and abdomen, and bone scan or positron emission tomography [PET] scan) confirmed no longer than three months prior to Study inclusion.
- •12. Participants must have had surgery for their primary BC with documented clear margins (as per local guidelines), and they must have received radiotherapy if indicated (as per local guidelines).
- •13. Participants must be able and willing to adhere to Study procedures.
排除标准
- •(surveillance phase):
- •Participants with pathological complete response (pCR) after neoadjuvant treatment.
- •Receiving or planning to receive any concurrent anti-cancer treatment for the current BC diagnosis, other than permitted adjuvant ET and/or bone-modifying agents (denosumab or biphosphonates).
- •Diagnosis of an alternative cancer in the five years prior to primary BC diagnosis, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ. Other stage I tumors will be discussed case by case prior to inclusion with the Medical Monitor of the Study.
- •Active or prior documented inflammatory bowel disease (i.e. Crohn's disease, ulcerative colitis, or a preexisting chronic condition resulting in baseline grade ≥ 1 diarrhea) that may significantly alter the absorption of oral drugs.
- •Active cardiac disease or history of cardiac dysfunction including any of the following:
- •a. History (within two years from screening) or presence of idiopathic bradycardia or resting heart rate < 50 beats per minute at screening.
- •b. History of angina pectoris or symptomatic coronary heart disease within 12 months prior to Study entry.
- •c. QT interval corrected through use of Fridericia's formula (QTcF) > 450 ms for women and > 470 ms for men by at least three electrocardiograms (ECGs) > 30 minutes apart.
- •d. History or presence of an abnormal ECG that is clinically significant in the investigator's opinion, e. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g. severe left ventricular systolic dysfunction, left ventricular hypertrophy cardiomyopathy, infiltrative cardiomyopathy, moderate-to-severe valve disease), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT syndrome within 12 months.
- •History of pneumonitis, interstitial lung disease (ILD), or pulmonary fibrosis.
- •Known history of Human Immunodeficiency Virus (HIV) infection.
- •Clinically significant liver disease consistent with Child-Pugh C, including current known infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), current alcohol abuse, or cirrhosis. Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- •Active bleeding diathesis venous thrombo-embolism, previous history of bleeding diathesis or chronic anti-coagulation treatment, or any indications or history of Disseminated Intravascular Coagulation (DIC) or Deep vein thrombosis (DVT). Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted.
- •Creatinine clearance < 30mL/min.
- •Participants with renal dysfunction who require dialysis.
- •Participant who has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks, contraindicate participation in the clinical trial or compromise compliance with the protocol.
- •Females who are known to be breastfeeding or pregnant as determined by a serum pregnancy test, Human chorionic gonadotropin (β-HCG), prior to the administration of any trial treatment (once during the treatment phase). Since β-HCG over expression can be also elevated in some tumor types, a positive result should be confirmed with a validated alternative test (e.g. ultrasound).
- •Female or male participants planning a pregnancy.
- •Participation in another interventional clinical trial within 28 days prior to screening or concurrent participation in another interventional clinical trial.
- •Eligibility criteria for participant entry into the treatment phase:
- •Inclusion criteria (treatment phase):
- •A. Inclusion criteria for direct-to-treatment-phase entry:
- •Participants who have not participated in the molecular surveillance phase but have a positive ctDNA test (conducted under other circumstances) will be considered eligible to enter to the treatment phase directly if they fulfill all the inclusion criteria listed below:
- •Signed treatment phase ICF prior to participation in any Study-related activities.
- •Male or female participants aged 18 years or older.
- •Histologically proven primary HR-positive according to the updated ASCO/CAP 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.
- •Availability and willingness to provide the most recently available (archival FFPE) tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy) at the time of Study inclusion.
- •Note I: Participants with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC.
- •Note II: Participants with bilateral carcinoma of the breast may be included as long as at least one of the tumors meets the criteria established by the protocol and both are HR-positive and HER2-negative tumors.
- •5. Successful ctDNA assay designability, defined as the ability to generate a personalized, tumor-informed ctDNA assay based on sequencing of tumor tissue and matched germline DNA, enabling longitudinal ctDNA assessment.
- •6. Confirmation of ctDNA positivity by the Study test. Note: Only participants who are confirmed as ctDNA-positive by the SignateraTM Genome test will be eligible to enter the treatment phase. External ctDNA results may be used to identify potential candidates, but eligibility will be based solely on the ctDNA status determined by the SignateraTM Genome test.
- •7. Participants must have had surgery for their primary BC with documented clear margins (as per local guidelines), and they must have received radiotherapy if indicated (as per local guidelines).
- •8. Fulfillment of all general treatment phase eligibility criteria listed below.
- •9. No participation in another interventional clinical trial within 28 days prior to screening or concurrent participation in another interventional clinical trial.
- •B. Inclusion criteria for all participants to treatment phase entry:
- •Participants will be considered eligible to enter to the treatment phase if they fulfill all the eligibility criteria listed below:
- •I. General inclusion criteria for all Study arms:
- •1. Signed treatment phase ICF prior to participation in any Study treatment phase-related activities.
- •2. ctDNA positivity with no evidence of locoregional or contralateral clinical or radiologic recurrence by standard assessments (breast staging scans, e.g.: mammogram, breast ultrasound, breast magnetic resonance imaging [MRI]).
- •3. ECOG performance status 0 or
- •On adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned. Participants must have received the same ET treatment with AI or tamoxifen during at least the last six months. A temporary discontinuation of < 90 days during the surveillance phase is allowed.
- •5. Receiving LHRH agonist therapy alongside the same ET treatment for at least 90 days prior to initiation of one of the available Study treatments if male or premenopausal female participant.
- •6. Prior treatment with CDK4/6i in the adjuvant setting will be allowed in the case of an interval of at least 12 months between the last CDK4/6i dose and Study inclusion in the trial.
- •7. No prior treatment with SERDs will be allowed.
- •Female of reproductive potential and male participants with female partners of childbearing potential, must remain abstinent and truly abstain from sexual activity (refrains from heterosexual intercourse) or use locally recognized adequate methods of contraception (described as that with a failure rate < 1%) for the duration of trial treatment. In addition, participants must follow these guidelines for a certain period of time after the last dose of trial treatment, specified in the protocol depending on which treatment arm the participant is allocated in.
- •During this period of time, female and male participants must as well refrain from donating eggs or sperm.
- •Note: Female participants will be deemed not of childbearing potential if they are postmenopausal or have had irreversible sterilization. Well-defined premenopausal status refers to women who have not reached the postmenopausal state because they are not permanently infertile due to prior bilateral oophorectomy, age ≥ 60 years or age < 60 years with amenorrhea for ≥ 12 months and estradiol and follicle-stimulating hormone (FSH) levels in the postmenopausal range.
- •9. Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤ 1 as determined by the National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v.5.0) (except for alopecia, or other toxicities not considered a safety risk for the participant at investigator's discretion). Adverse events (AEs) of current ET treatment are not included.
- •10. Adequate hematologic and organ function within 14 days before the first Study treatment on Day 1 of Cycle 1, defined by the following:
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研究组 & 干预措施
Arm B: Experimental Arm with giredestrant
Giredestrant: 30 mg will be taken orally (PO) once a day (QD) on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
干预措施: Giredestrant (Drug)
Arm C: Experimental Arm with giredestrant + abemaciclib
Giredestrant: 30 mg will be taken PO QD on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
Abemaciclib 150 mg will be taken PO twice daily (BID) (two intakes for a total daily dose of 300 mg) during each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
Note: Participants who have previously received adjuvant abemaciclib at a reduced dose (100 mg BID or 50 mg BID) due to toxicity may initiate study treatment at the same reduced dose level, at the investigator's discretion. Dose re-escalation is not permitted.
干预措施: Giredestrant (Drug)
Arm C: Experimental Arm with giredestrant + abemaciclib
Giredestrant: 30 mg will be taken PO QD on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
Abemaciclib 150 mg will be taken PO twice daily (BID) (two intakes for a total daily dose of 300 mg) during each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
Note: Participants who have previously received adjuvant abemaciclib at a reduced dose (100 mg BID or 50 mg BID) due to toxicity may initiate study treatment at the same reduced dose level, at the investigator's discretion. Dose re-escalation is not permitted.
干预措施: Abemaciclib (Drug)
Arm D: Experimental Arm with giredestrant + inavolisib
Giredestrant: 30 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
Inavolisib: 9 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
干预措施: Inavolisib (Drug)
Arm A: Control Arm
Participants assigned to this arm will continue receiving the same standard ET that was prescribed during the surveillance phase for a period of 90 days. This will be done in accordance with standard clinical practice and until the analysis of the primary endpoint. After this 90-day period, participants will be eligible to receive one of the other three predefined treatments (giredestrant, giredestrant plus abemaciclib or giredestrant plus inavolisib if a detectable PIK3CA mutation is present and the participant also meets all additional eligibility criteria for Arm D). as determined by the investigator´s choice. No changes to the prescribed ET are permitted during the 90-day period.
干预措施: Standard ET followed by change in treatment (Drug)
Arm D: Experimental Arm with giredestrant + inavolisib
Giredestrant: 30 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
Inavolisib: 9 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).
干预措施: Giredestrant (Drug)
结局指标
主要结局
Evaluation of decrease or clearance in baseline ctDNA at three months after initiation of study treatment
时间窗: Treatment phase (three months after Study treatment initiation)
To evaluate the efficacy - in terms of rate of participants with a 90% decrease or clearance in baseline ctDNA at three months - of the different arms
次要结局
- Proportion of participants with at least a 90% decrease in baseline ctDNA at six, nine, and 12 months after initiation of study treatment.(Treatment phase (at six, nine, and 12 months after study treatment initiation))
- Proportion of participants with at least a 90% decrease in baseline ctDNA at three months maintained at six months and 12 months after initiation of study treatment.(Treatment phase (at six and 12 months after study treatment initiation))
- Proportion of participants with 50% and 70% decrease in baseline ctDNA at three, six, nine, and 12 months after initiation of study treatment.(Treatment phase (at three, six, nine, and 12 months after study treatment initiation))
- Best percentage of ctDNA decrease relative to baseline at six, nine, and 12 months after initiation of study treatment.(Treatment phase (up to five years))
- Total ctDNA detection and breakdown by incidence at first ctDNA test versus incidence at subsequent ctDNA tests.(Surveillance phase (up to two years after study start date))
- Time to rising ctDNA defined as time to first ctDNA increase compared to baseline(Treatment phase (up to five years after study treatment initiation))
- Duration of at least a 90% decrease in baseline ctDNA after initiation of study treatment.(Treatment phase (up to five years after study treatment initiation))
- Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v5.0.(Treatment phase (up to five years after study treatment initiation))