C4891001 - 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)
- Trial ID
- 2022-500544-38-00
- Protocol
- C4891001
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that **ARV-471** is superior to fulvestrant in prolonging progression-free survival (PFS) as assessed by blinded independent central review (BICR) in participants with estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer (aBC), including those with ESR1 mutation-positive breast cancer, who have previously received endocrine-based treatment for their advanced disease. This objective is clinically relevant as it aims to establish a more effective treatment option for patients with advanced breast cancer, potentially improving their disease management and outcomes.
Secondary objectives include:
- To demonstrate that ARV-471 is superior to fulvestrant in prolonging overall survival in all participants and those with ESR1 mutation-positive breast cancer.
- To compare measures of tumor control between treatment arms and evaluate the duration of response (DOR) by BICR assessment within each treatment arm.
- To evaluate safety and tolerability between the treatment arms.
- To characterize the effects of ARV-471 on QTc interval.
- To evaluate patient-reported outcomes between the two treatment arms.
- To determine plasma concentrations of ARV-471 and ARV-473 after repeated dosing of ARV-471.
- To assess changes from baseline levels in plasma circulating tumor DNA (ctDNA).
Participants
The clinical trial involves a total of **408 participants** diagnosed with **Advanced Breast Cancer**. The study population includes both male and female subjects aged 18 years and older, with a focus on those who have received prior endocrine-based treatment for their advanced disease. Participants were selected based on their ability to comply with all scheduled visits, treatment plans, laboratory tests, and lifestyle considerations. The trial includes individuals with histological or cytological confirmation of breast cancer, specifically those with ER(+) and HER2(-) tumors. Participants must have at least one measurable lesion as defined by RECIST version 1.1, or in the case of bone-only disease, non-measurable disease is acceptable. The trial does not include a vulnerable population, and participants are required to have an ECOG performance status of 0 or 1. The selection criteria ensure that the study population is representative of individuals with locoregional recurrent or metastatic disease not amenable to surgical resection or radiation therapy with curative intent.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, open-label, multicenter study designed to evaluate the efficacy of ARV-471 (PF-07850327) compared to **fulvestrant** in participants with **estrogen receptor-positive, HER2-negative advanced breast cancer**. The primary objective is to demonstrate the superiority of ARV-471 in prolonging progression-free survival (PFS) as assessed by blinded independent central review (BICR). The trial is expected to run until May 2028, with recruitment having commenced in May 2023.
Participants will be randomly assigned to receive either ARV-471, administered orally as a film-coated tablet, or fulvestrant, administered via intramuscular injection. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The expected duration of participant involvement is up to 36 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.
Inclusion criteria require participants to be 18 years or older, with histological or cytological confirmation of breast cancer and evidence of locoregional recurrent or metastatic disease. Participants must have received prior endocrine-based treatment and have at least one measurable lesion as defined by RECIST version 1.1. Exclusion criteria are not specified in the provided data. The primary endpoint is PFS, while secondary endpoints include overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and safety assessments. The trial will also evaluate quality of life and pharmacokinetic parameters.
Treatment
The clinical trial involves the administration of **PF-07850327**, a film-coated tablet developed by Pfizer Inc. This experimental medication is characterized by its chemical origin and is administered orally. The active substance in PF-07850327 is a complex chemical compound, specifically (3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione. The maximum daily dose for this medication is 200 mg, with a total maximum dose of 218,880 mg over a treatment period of up to 36 months. Participant compliance with the dosing schedule will be monitored throughout the trial.
In addition to the experimental treatment, the study includes a comparator treatment using **Fulvestrant**, a solution for injection provided by EVER Neuro Pharma GmbH and EVER Valinject GmbH. Fulvestrant is also of chemical origin and is administered via intramuscular injection. The formulation is available as a 250 mg injection solution in a pre-filled syringe. The maximum daily dose for Fulvestrant is 500 mg, with a total maximum dose of 18,500 mg over a treatment period of up to 36 months. The administration of Fulvestrant will follow a predefined schedule, and participant adherence to the treatment regimen will be closely monitored to ensure compliance.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from the date of randomization to the date of first documented disease progression, as determined by Blinded Independent Central Review (BICR) assessment per RECIST version 1.1, or death due to any cause, whichever occurs first. Secondary endpoints include **Overall Survival (OS)**, which is the time from the date of randomization to the date of death due to any cause, and **Objective Response Rate (OR)**, which includes confirmed Complete Response (CR) or Partial Response (PR) by BICR assessment. Additional secondary endpoints are **Clinical Benefit Rate (CBR)**, **Duration of Response (DOR)**, and the type, incidence, and severity of adverse events graded by NCI CTCAE v5.0.
Patient-reported outcomes will be evaluated using validated instruments such as the EORTC QLQ-C30, EORTC QLQ-BR23, EuroQol EQ-5D-5L, and the Brief Pain Inventory-Short Form (BPI-SF). Plasma concentrations of ARV-471 and its epimer ARV-473 will be measured, along with ctDNA plasma quantitative changes from baseline to assess their associations with clinical outcomes. The schedule for these assessments will be aligned with the trial protocol, ensuring systematic data collection and analysis throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations) at screening. a. 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. b. Pre/ peri-menopausal female and male participants must agree to initiate or continue to use an LHRH agonist as per Table 2 and Section 6.9.1. c. IOCBP female and male participants must agree to use contraception. Refer to Appendix 4 for further details.
- 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. a. 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 and participants in whom the collection of a biopsy is clinically contraindicated for whom ER(+) using archival tissue at initial diagnosis is acceptable. b. Documented HER2(-) tumor by either IHC or in-situ hybridization per ASCO/CAP guidelines on the most recent tumor biopsy and as per above in inclusion criterion a. (Wolff et al, 2018). 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. unless the participants has bone only disease or in whom the collection of a biopsy is clinicallt contraindicated. In these cases, an archival tumor tissue at initial diagnosis is acceptable. Refer to Section 8.7.1 for details.
- Prior therapies for locoregional recurrent or metastatic disease must fulfill all the following criteria: Note: Progression during or within 12 months from the end of adjuvant therapy is counted as a line of therapy in advanced/metastatic setting a. One line of CDK4/6 inhibitor therapy in combination with ET. Only one line of CDK4/6 inhibitor is allowed in any setting. b. ≤1 endocrine therapy in addition to CDK4/6 inhibitor with ET. c. Most recent endocrine treatment duration must have been given for ≥6 months prior to disease progression. This may be the endocrine treatment component of the CDK4/6 inhibitor line of therapy. d. Radiological progression during or after the last line of therapy
- At least one measurable lesion as defined by RECIST version 1.1. Bone only disease: participants with only non-measurable disease are eligible. Refer to Section 8.2.1.
- ECOG PS ≤1
Exclusion Criteria
- 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 (Appendix 12 of the protocol).
- 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. • 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. • QTcF interval >470 msec on screening ECG. • 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 (see Section 6.9 and Appendix 10 of the protocol for the list of prohibited medications). 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, elacestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor, other investigational agents (including novel endocrine therapy any SERDs, SERCAs, CERANs) for any setting b. 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. • 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 as outlined in Appendix 7 of the protocol.
- Known active infection including SARS-CoV-2 infection, HBV, HCV, and HIV 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 25 May 2023 | 9 |
 Belgium | Not Recruiting | 25 May 2023 | 12 |
 Bulgaria | Not Recruiting | 25 May 2023 | 12 |
 Czechia | Not Recruiting | 25 May 2023 | 5 |
 Finland | Not Recruiting | 25 May 2023 | 8 |
 France | Not Recruiting | 25 May 2023 | 59 |
 Germany | Not Recruiting | 25 May 2023 | 13 |
 Greece | Not Recruiting | 25 May 2023 | 9 |
 Hungary | Not Recruiting | 25 May 2023 | 12 |
 Italy | Not Recruiting | 25 May 2023 | 23 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PF-07850327 round | Test | FILM-COATED TABLET | ORAL | 200 | 36 | PRD9906032 |
Fulvestrant EVER Pharma, 250 mg/ 5 ml, roztwór do wstrzykiwań w ampułko-strzykawce | Comparator | ROZTWÓR DO WSTRZYKIWAŃ W AMPUŁKO-STRZYKAWCE | INTRAMUSCULAR INJECTION | 500 | 36 | PRD7501679 |
Fulvestrant EVER Pharma 250 mg Injektionslösung in einer Fertigspritze | Comparator | INJEKTIONSLÖSUNG IN EINER FERTIGSPRITZE | INTRAMUSCULAR INJECTION | 500 | 36 | PRD6824954 |