CTRI/2024/03/064777尚未招募3 期
A phase III, randomized, open-label study evaluating efficacy and safety of Giredestrant compared with Fulvestrant, both combined with a CDK4/6 inhibitor, in patients with estrogen receptor-positive, HER2-negative advanced breast cancer with resistance to prior adjuvant endocrine therapy
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 1,050
- 试验地点
- 8
- 主要终点
- To evaluate the efficacy of
研究概览
简要总结
The proposed Phase III study is designed to demonstrate a statistically significant and clinically meaningful progressionï€free survival (PFS) benefit of giredestrant compared with fulvestrant, each combined with the investigator’s choice of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)between palbociclib, abemaciclib and ribociclib, as first-line (1L) treatment of estrogen receptorpositive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC) resistant to adjuvant endocrine therapy (ET), a patient group considered to have a particularly high unmet need.
Available data support that giredestrant can provide meaningful clinical benefit to patients with ER+ HER2- aBC resistant to prior adjuvant ET. In the mBC setting, giredestrant demonstrated clinical efficacy in terms of clinical benefit rate (CBR), objective response rate (ORR) and duration of response (DOR) both as single agent (GO39932, WO42312/acelERA BC) and in combination with the CDK4/6i palbociclib (GO39932), as well as a favorable trend in PFS versus AI/fulvestrant which was more pronounced in patients with ESR1m tumors (WO42312/acelERA BC, Martin Jimenez et al. 2022).
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- Female
入选标准
- •Signed Informed Consent Form
- •Age more than or equal to 18 years.
- •Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent.
- •Documented ER plus tumor according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or ESMO guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines, defined as more than or equal to 1 percent of tumor cells stained positive, assessed locally based on the most recent tumor biopsy (or archived tumor sample)
- •Documented HER2 tumor according to ASCO/CAP or ESMO guidelines or any national guidelines with criteria conforming to ASCO/CAP or ESMO guidelines, assessed locally based on the most recent tumor biopsy (or archived tumor sample)
- •Confirmed ESR1 mutation status (mutation detected [ESR1m] vs.
- •no mutation detected [ESR1nmd]) in baseline ctDNA, as assessed through central lab testing of a blood sample freshly collected at screening, using the investigational FMI F1LCDx assay.
- •A valid central testing result using investigational F1LCDx is always required; in localities where FMI central testing is not available, samples will be submitted to an alternative, Sponsor-designated central laboratory.
- •Participants without a valid ESR1 mutation status central result (i.e., unknown ESR1 mutation status that cannot be classified as ESR1m or ESR1nmd) are not eligible.
- •Eligible ESR1 mutations are defined as short variants known to affect protein function occurring within amino acids 310 to
- •Consent to provide and confirmed availability of the most recently collected and representative tumor tissue specimen suitable for biomarker testing with associated pathology (i.e., archived formalin-fixed paraffin-embedded tissue block [preferred] or 15 to 20 slides containing unstained, freshly cut, serial sections).
- •Participants who have relapsed with prior standard adjuvant ET with an AI (i.e., anastrozole, letrozole, or exemestane) and/or a SERM (i.e., tamoxifenor toremifene), on-treatment after more than or equal to 12 months or off-treatment within 12 months of completion (i.e., treatment-free interval less than 12 months).
- •If neo/adjuvant ET included a CDK4/6i, relapse should have occurred more than or equal to 12 months since completion of CDK4/6i treatment.
- •No history of systemic anti-cancer therapy for locally advanced or metastatic disease.
- •Measurable disease as defined per RECIST v.1.1 or non-measurable bone-only disease which must be evaluable defined as having at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) which can be followed (soft tissue component not required).
- •Tumor lesions previously irradiated or subjected to other locoregional therapy will be deemed measurable only if disease progression at the treated site after completion of therapy is clearly documented.
- •Considered appropriate for treatment with ET (e.g., CDK4/6i in combination with fulvestrant) at time of entry into the study, recommended as per national or local treatment guidelines
- •Life expectancy of more than 6 months
- •ECOG Performance Status 0 to 1
- •Adequate organ function as defined by the following criteria: ANC more than or equal to 1.5x10 to the power of 9/L (1500/microL); Platelet count more than or equal to 100x10 to the power of 9/L (100,000/microL); Hemoglobin more than or equal to 90g/L (9g/dL).
- •The blood counts are to meet the specified criteria without transfusion or growth factor support, unless it is clear that the bone marrow function is adequate and that any aberration has a clear and correctable cause, and the correction undertaken.
- •AST and serum ALT less than or equal to 3xupper limit of normal (ULN); for participants with liver metastases: AST and ALT less than or equal to 5xULN.
- •Serum bilirubin less than or equal to 1.5xULN; for patients with Gilbert syndrome: less than or equal to 3xULN.
- •Estimated creatinine clearance more than or equal to 30 mL/min as calculated per institutional guidelines.
- •INR (or PT) less than 1.5x ULN and PTT (or aPTT) less than 1.5x ULN (except for participants receiving anticoagulation therapy).
- •For participants receiving warfarin, a stable INR between 2 and 3 is required.
- •For participants receiving heparin, PTT (or aPTT) between 1.5 and 2.5xULN (or patients va.
排除标准
- •Disease recurrence during the first 12 months of adjuvant ET.
- •Prior systemic therapy for metastatic breast cancer eg prior chemotherapy immunotherapy or biologic therapy for locally advanced unresectable or metastatic disease.
- •Prior treatment with a SERD eg fulvestrant novel oral proteolysis targeting chimera complete ER antagonist CERAN or novel SERM other than tamoxifen toremifene.
- •Treatment with any investigational therapy within 28 days prior to randomization or within 5 half lives of the investigational drugs whichever is longer.
- •Radiotherapy or any other anti cancer therapy within 2 weeks before randomization.
- •Participants who received prior radiotherapy to more than or equal to 25 percentage of bone marrow or hematopoietic stem cell or bone marrow transplantation are not eligible regardless of when.
- •Major surgical procedure or significant traumatic injury within 28 days prior to randomization.
- •Anticipation of need for a major surgical procedure during the course of the study.
- •Exposure to strong CYP3A4 inhibitors strong CYP3A4 inducers and moderate CYP3A inducers for participants who will receive abemaciclib only within 14 days or 5 drug elimination half lives whichever is longer prior to initiation of study treatment.
- •Advanced symptomatic, visceral spread that is at risk of life threatening complications in the short term including massive uncontrolled effusions pleural pericardial peritoneal or pulmonary lymphangitis appropriate for treatment with cytotoxic chemotherapy at time of entry into the study as per national or local treatment guidelines.
- •History of other malignancy within 5 years prior to screening except for cancers with very low risk of recurrence including but not limited to appropriately treated carcinoma in situ of the cervix non melanoma skin carcinoma papillary thyroid cancer treated with surgery or Stage I endometrial cancer.
- •Known active uncontrolled or symptomatic CNS metastases carcinomatous meningitis or leptomeningeal disease.
- •Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy eg radiotherapy surgery are clinically stable and have not been treated with anticonvulsants or corticosteroids within 2 weeks prior to randomization.
- •Active cardiac disease or history of cardiac dysfunction including any of the following History within 2 years of screening or presence of idiopathic symptomatic bradycardia or resting heart rate less than 50 bpm at screening.
- •Patients on stable dose of a beta blocker or calcium channel antagonist for preexisting baseline conditions eg hypertension may be eligible if resting heart rate is at least 50 bpm.
- •History of angina pectoris or symptomatic coronary heart disease within 12 months prior to study entry.
- •History of documented congestive heart failure New York Heart Association Class III to IV or cardiomyopathy.
- •QT interval based on mean value of triplicate ECGs corrected through use of Fridericias formula QTcF.
- •More than 470 ms for female participants intended to be treated with palbociclib or abemaciclib.
- •More than 450 ms for male participants intended to be treated with any CDK4 6i and for female participants intended to be treated with ribociclib.
- •History of long or short QT syndrome Brugada syndrome or known history of corrected QT interval prolongation or torsades de pointes.
- •Presence of an abnormal ECG that is clinically significant in the investigators opinion including complete left bundle branch block second or third degree heart block sick sinus syndrome.
- •Participants with first degree heart block may be eligible following consultation with a cardiologist and determination that no additional cardiac risks are present.
- •Participants with pacemakers to treat more severe heart blocks and other arrhythmias are eligible.
- •Participants with history of well controlled atrial fibrillation are eligible.
- •History within 12 months of screening or presence of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as significant structural heart disease eg severe left ventricular systolic dysfunction restrictive cardiomyopathy, hypertrophic cardiomyopathy infiltrative cardiomyopathy moderate to severe valve disease or family history of long QT syndrome.
- •Clinically significant history of liver disease consistent with Child Pugh Class B or C including active viral infection or other hepatitis eg hepatitis B virus HBV or hepatitis C virus HCV current alcohol abuse or cirrhosis or positive test for viral hepatitis.
- •Known HIV infection.
- •Screening HIV test should be performed as allowed per local regulations.
- •Serious infection requiring oral or IV antibiotics or other clinically significant infection within 14 days prior to randomization.
- •Participants who fully recovered from serious or clinically significant infections at least 14 days prior to randomization are eligible.
- •Active inflammatory bowel disease, chronic diarrhea short bowel syndrome or major upper gastrointestinal GI surgery including gastric resection potentially affecting enteral absorption or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea.
- •Malabsorption syndrome or other condition that would interfere with enteral absorption.
- •Inability or unwillingness to swallow pills or receive IM injections.
- •Any serious medical condition or abnormality in clinical laboratory tests that in the investigators judgment precludes the individuals safe participation in and completion of the study.
- •For pre or perimenopausal female or male participants known hypersensitivity to LHRH agonists or any of their excipients.
- •Pregnancy or breastfeeding or intention of becoming pregnant during the study or within 98 days after the final dose of study treatment based on local prescribing information for fulvestrant patients may be advised to use an effective means of contraception for up to 2 years after the last dose of fulvestrant.
- •Female participants of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
结局指标
主要结局
To evaluate the efficacy of
时间窗: PFS, defined as time from randomization to first | occurrence of Progressive disease, as determined by the investigator according to RECIST v1.1, or death from any cause during the study whichever occurs first.
giredestrant compared with
时间窗: PFS, defined as time from randomization to first | occurrence of Progressive disease, as determined by the investigator according to RECIST v1.1, or death from any cause during the study whichever occurs first.
fulvestrant (both combined with CDK4/6i) in the ESR1m subgroup and FAS
时间窗: PFS, defined as time from randomization to first | occurrence of Progressive disease, as determined by the investigator according to RECIST v1.1, or death from any cause during the study whichever occurs first.
次要结局
- To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the ESR1nmd subgroup(Progression free survival, defined as time from randomization to first occurrence of progressive disease, as determined by the)
- To evaluate efficacy of giredestrant compared with fulvestrant (both combined with CDK4 or 6i) in the in ESR1m & ESR1nmd, subgroups & in the FAS(Overall Survival (OS), defined as the time from randomization to)
- To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the ESR1m, ESR1nmd subgroups & in the FAS(Confirmed objective response rate is the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions more than or equal to 4 weeks apart)
- To evaluate the safety of giredestrant compared with fulvestrant in the FAS, and in the choice of CDK4/6i subgroups(Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0. Change from baseline in selected vital signs and in clinical laboratory test results)
- To evaluate efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the in ESR1m & ESR1nmd, subgroups & in the FAS(Clinical Benefit Rate is from the first occurrence of a documented objective response to PD, as determined by the investigator according to RECIST v1.1)
- To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with(CDK4/6i) in the ESR1m & ESR1nmd subgroups & in the FAS)
- To evaluate the efficacy of giredestrant compared with(fulvestrant (both combined with CDK4/6i) in the ESR1m &)
- To evaluate the efficacy of(giredestrant compared with)
- To evaluate the efficacy of giredestrant compared with fulvestrant (both combined with CDK4/6i) in the ESR1m & ESR1nmd subgroups & in the FAS(Time to confirmed deterioration in physical functioning, role functioning & global health status or QoL, from randomization to the first documentation of a more than or equal to 10 point decrease from baseline in the EORTC QLQ C30 linearly transformed PF scale score, RF scale score or GHS or QoL scale score, respectively, held for two consecutive timepoints, or a more than or equal to 10 point decrease followed by death attributable to cancer progression with 28 days from the last assessment.)
研究者
研究点 (8)
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