A Phase 3, Randomized, Open-Label, Multicenter Trial of ARV-471 (PF-07850327) vs Fulvestrant in Participants with Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer Whose Disease Progressed After Prior Endocrine Based Treatment for Advanced Disease (VERITAC-2)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- Pfizer Inc
- 入组人数
- 560
- 试验地点
- 14
- 主要终点
- To demonstrate that ARV-471 is superior to fulvestrant in prolonging PFS by BICR assessment in participants with
研究概览
简要总结
In nonclinical studies, ARV-471 has demonstrated robust ER degradation, superior activity against clinically relevant ER mutated forms (eg,Y537S and D538G), and improved TGI as single agent compared to fulvestrant in ER wild type and ESR1 mutant patient-derived xenograft models as administered as single agent. In the FIH study, ARV-471 administered orally QD as a single agent appears to be safe and well tolerated across total daily doses of 30 mg to 700 mg with preliminary evidence of efficacy in participants pretreated with CDK4/6 inhibitor plus endocrine therapy. These results support the hypothesis that ARV-471 may represent an important therapeutic approach in patients with ER(+)/HER2(-) advanced breast disease.
This is an international Phase 3 multicenter, randomized, open-label, parallel-group study aimed to demonstrate that ARV-471 is superior to fulvestrant in prolonging the PFS (by BICR assessment) in participants with ER(+)/HER2(-) aBC who have progressed after prior endocrine treatment-based regimen(s)for advanced disease. Approximately 560 participants (of which approximately 280 are participants with ESR1 mutation) will be randomly assigned to Arm A (ARV-471, PF-07850327) or Arm B (fulvestrant).
Participants will be randomly assigned on a 1:1 basis to: • Arm A: (Investigational Arm; n ≈ 280). Participants will receive ARV-471 200 mg orally, once daily on a 28-day continuous dosing schedule. • Arm B: (Comparator Arm; n ≈ 280). Participants will receive fulvestrant 500 mg, intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle).
Participants will be stratified by ESR1 mutational status (Mutant, Yes/No) and visceral disease (Yes/No). Visceral refers to lung, liver, brain, pleural, and peritoneal involvement.
Pre- and peri-menopausal female and male participants must receive therapy with an LHRH agonist starting on Cycle 1 Day 1 (if not already on treatment) and continued during the study.
The study includes a QTc sub-study in approximately 80 participants in Arm A enrolled at selected sites which will evaluate the effect of ARV-471 on QTc interval via triplicate ECGs (central reading) time-matched with PK draws.
An E-DMC will be established to review aggregate safety data to monitor safety and tolerability by treatment arm.
A Global Steering Committee will be established at the program level for ARV-471. It will be responsible for providing scientific advice and medical input on the ongoing and future clinical development plans for ARV-471 in ER(+) breast cancer, including for this study.
Participants will undergo efficacy assessments. Efficacy analyses will be performed using BICR tumor assessments as the primary data source. All radiographic images as well as other information will be collected and objectively verified by BICR as described in the Study Imaging Manual.
It is anticipated that the final PFS analysis will occur at approximately 310 PFS events in all participants population and 165 PFS events in the ESR1 mutant subgroup population. The final OS analysis will occur at approximately 396 OS events in all participants population and 194 OS events in ESR1 mutant subgroup population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening.
- •Female participants under 60 years of age, with cessation of regular menses for 12 consecutive months and with no other alternative medical cause, must have a FSH level within the post-menopausal level, as per local laboratory reference range.
- •Pre/ peri-menopausal female and male participants must agree to initiate or continue to use an LHRH agonist.
- •WOCBP female and male participants must agree to use contraception.
- •2.Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
- •Histological or cytological confirmation of breast cancer with evidence of locoregional recurrent or metastatic disease which is not amenable to surgical resection or radiation therapy with curative intent.
- •Documented ER(+) tumor, defined as ER(+) ≥10% stained cells by an assay consistent with local standards, on the most recent tumor biopsy, ie, at diagnosis of recurrence or metastatic disease (Allison et al, 2020).
- •The sole exception is those participants with bone only disease for whom ER(+) using archival tissue at initial diagnosis is acceptable.
- •Documented HER2(-) tumor by either IHC or in-situ hybridization per ASCO/CAP guidelines c.
- •Participants who have bilateral breast cancers which are both ER(+)/HER2(-) are eligible d.
- •Participants must provide a blood sample AND a tumor sample collected at the time of diagnosis of locoregional recurrent or metastatic disease.
- •If not available, a de novo biopsy is required.
- •Participants with bone lesions only: archival tumor tissue at initial diagnosis is acceptable
- •Prior therapies for locoregional recurrent or metastatic disease must fulfill all the following criteria: a.
- •One line of CDK4/6 inhibitor therapy in combination with ET b.
- •â‰¤1 endocrine therapy in addition to CDK4/6 inhibitor with ET c.
- •Radiological progression during or after the last line of therapy Note: A neoadjuvant/adjuvant treatment is counted as a line for locoregional recurrent or metastatic disease if relapse occurs on or within 12 months after last dose.
- •At least one measurable lesion as defined by RECIST version 1.
- •Bone only disease: participants with only non-measurable disease are eligible
- •ECOG PS ≤1.
排除标准
- •History of any other solid tumor malignancies within the past three years, except for the following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated in situ carcinoma of the cervix.
- •For all other solid tumors, must have been curatively treated and with no evidence of disease for >3 years.
- •Participants with inflammatory breast cancer are excluded.
- •Participants with newly diagnosed brain metastasis or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
- •Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, stereotactic surgery) and clinically stable (including participants with residual CNS symptoms/deficits) off enzyme-inducing anticonvulsants and steroids for at least 14 days prior to randomization
- •Major surgery or radiotherapy or prior endocrine therapy, CDK4/6 inhibitor, or other anticancer treatments within 14 days of randomization (28 days or 5 half-lives, whichever is shorter, for anticancer therapy containing an antibody- based agent, approved or investigational).
- •Participants who received prior radiotherapy to ≥ 25% of bone marrow are not eligible independent of when it was received
- •Participants in visceral crisis at risk of immediately life-threatening complications in the short term, including participants with massive uncontrolled effusions (pleural, pericardial, and peritoneal), pulmonary lymphangitis, or liver involvement > 50%.
- •Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as: • Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism or other clinically significant episode of thromboembolic disease, congenital long QT syndrome, Torsade de Pointes, clinically important arrhythmias, left anterior hemiblock (bifascicular block), ongoing cardiac dysrhythmias of NCI-CTCAE Grade ≥2, atrial fibrillation of any grade.
- •â€¢ Participants with cardiac rhythm device/ pacemaker (QTc Sub-study).
- •For all the other participants with cardiac rhythm device/pacemaker eligibility must be discussed in detail with the sponsor medical monitor.
- •â€¢ QTcF interval >470 msec on screening ECG.
- •â€¢ Symptomatic cardiac valve disease.
- •Participants with mitral valve prolapse which is asymptomatic or not associated with clinically significant sequelae (eg, mitral regurgitation) are eligible.
- •Refractory nausea and vomiting, chronic GI disease, GI ulcer, GI bleeding, inability to swallow the formulated product, or previous significant gastric (total or partial) or bowel resection that would preclude adequate absorption of study drug
- •Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
- •Concurrent administration of medications, food or herb supplements that are strong inhibitors and inducers of CYP3A and drugs known to predispose to Torsade de Pointes or QT interval prolongation.
- •Prior use of strong CYP3A inhibitors must be stopped 7 days and strong inducers of CYP3A must be stopped 14 days before randomization.
- •Prior treatment with: a) ARV-471, fulvestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor, other investigational novel endocrine therapy (ie, SERD, SERCA, CERAN) for any setting b) prior CDK4/6 inhibitor treatment in the neoadjuvant/adjuvant setting c) prior chemotherapy for advanced/metastatic disease.
- •Participation in other studies involving investigational drug(s) within 28 days prior to randomization.
- •If in the FU Phase, the participant is eligible provided at least 5 half-lives have elapsed from the last dose.
- •Any unresolved toxicities from prior surgeries or therapies Grade >1 (Grade > 2 for peripheral neuropathy) by NCI-CTCAE Version 5.0 at the time of randomization except for alopecia
- •Hepatic dysfunction defined as: • Total bilirubin >1.5 x ULN unless the participant has documented Gilbert’s syndrome (in this case total bilirubin ≥3 x ULN); • AST and ALT >3 x ULN; >5.0 x ULN if liver metastases present; • Alkaline phosphatase >2.5 x ULN; >5 x ULN in case of bone metastasis.
- •â€¢ aPTT >1.25 x ULN and INR >1.25 unless the participant is receiving anticoagulation, then aPTT and INR should be within the therapeutic range of the intended use.
- •Hematologic abnormalities defined as: • ANC <1500/mm3 or <1.5 x 109/L; • Platelets <100,000/mm3 or < 100 x109/L; • Hemoglobin <9 g/dL.
- •One transfusion allowed ≤2 weeks before randomization.
- •Renal impairment defined as an eGFR <45 mL/min/1.73m2 as calculated using the 2021 CKD-EPI Equations
- •Known active infection including SARS-CoV-2 infection, HBV, HCV, andHIV or AIDS-related illness (screening for chronic conditions is not required).
- •Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
结局指标
主要结局
To demonstrate that ARV-471 is superior to fulvestrant in prolonging PFS by BICR assessment in participants with
时间窗: ≤18 weeks
ER(+)/HER2(-) aBC (all participants and participants with ESR1 mutation-positive BC) who have received prior endocrine-based treatment for their advanced disease by PFS which defined as the time from the date of randomization to the date
时间窗: ≤18 weeks
of first documented disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause,
时间窗: ≤18 weeks
whichever occurs first
时间窗: ≤18 weeks
次要结局
- 1) To demonstrate that ARV-471 is superior to fulvestrant in prolonging OS(2) Overall response rate (ORR) in participants)