A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer

Phase 3Active Not RecruitingNCT05654623

Pfizer624 enrolled

Overview

A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer.

The purpose of this study is to learn about the safety and effects of the study medicine ARV-471 (PF-07850327, vepdegestrant) compared to fulvestrant (FUL) in participants with advanced breast cancer. Advanced breast cancer is difficult to cure or control with treatment. The cancer may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body, i.e. bones, lungs, brain, or liver. FUL is a medicine already used for treatment of breast cancer while ARV-471 is a new medicine. This study is seeking participants with breast cancer who: * have cancer that has come back in the place where it started or spread to nearby tissue, lymph nodes, or distant parts of the body. * cannot be fully cured by surgery or radiation therapy. Radiation therapy is the use of high-energy radiation such as x-rays, gamma rays and other sources to kill cancer cells and shrink tumors. * respond to hormonal or endocrine therapy (which target hormones and/or activity of hormone receptors) such as tamoxifen or aromatase inhibitors (this is called estrogen receptor positive disease) * have received one line of CDK4/6 inhibitor therapy (for example palbociclib, ribociclib or abemaciclib) in combination with endocrine therapy (for example letrozole) for advanced cancer. * are allowed up to one other endocrine therapy (for example exemestane) for advanced cancer. Half of the participants will be given ARV-471 while the other half of the participants will be given FUL. Participants who get ARV-471 will take ARV-471 by mouth with food, one time a day. During the first treatment cycle participants who will get FUL will be given FUL by shots into the muscles on Day 1 and again 2 weeks later. After the first month, FUL shots will be given on the first day of each new treatment cycle. One treatment cycle is 28 days. Participants will receive the study medicine until their breast cancer worsens or side effects become too severe. Participants will have visits at the study clinic about every 4 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

624

Conditions

Advanced Breast Cancer

Interventions

ARV-471DRUG

orally, once daily on a 28-day continuous dosing schedule

FulvestrantDRUG

intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adult participants with loco-regional recurrent or metastatic breast disease not amenable to surgical resection or radiation therapy * Confirmed diagnosis of ER+/HER2- breast cancer * Prior therapies for locoregional recurrent or metastatic disease must fulfill all the following criteria: * One line of CDK4/6 inhibitor therapy in combination with endocrine therapy. Only one line of CDK4/6 inhibitor is allowed in any setting. * ≤ 1 endocrine therapy in addition to CDK4/6 inhibitor with ET * 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. * Radiological progression during or after the last line of therapy. * Measurable disease evaluable per Response Evaluation Criterion in Solid Tumors (RECIST) v.1.1 or non-measurable bone-only disease * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Participants should be willing to provide blood and tumor tissue Exclusion Criteria: * Participants with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term * Prior treatment with: * ARV-471, fulvestrant, elacestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor for any setting * other investigational agents (including novel endocrine therapy any SERDs, SERCAs, CERANs) for any setting * prior chemotherapy for advanced/metastatic disease * Inadequate liver, kidney and bone marrow function * Active brain metastases * Participants with significant concomitant illness

Locations (312)

Outcomes

Primary Outcomes

Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1- All Randomized Participants

PFS assessed by BICR was defined as the time from the date of randomization to the date of the first documentation of objective progression of disease (PD) per RECIST v1.1, or death due to any cause, whichever occurred first. PD as per RECIST v1.1 was defined as at least a 20% increase in the sum of diameters of target measurable lesions above nadir (smallest sum observed considering baseline and all assessments prior to the timepoint under evaluation), with a minimum absolute increase of 5 millimeters (mm) relative to nadir or unequivocal progression of existing non-target lesions or the presence of new lesions. PFS was censored on the date of last adequate disease assessment for those who did not have a PFS event, discontinued the study treatment due to withdrawal of consent prior to an event, started a new anticancer therapy prior to an event, had an event after a gap of 2 or more missing disease assessments, or lost to follow-up. Kaplan-Meier method was used.

Time frame: From date of randomization to date of first documentation of objective PD or death (any cause) or censoring date, whichever occurred first (up to 18.56 months and 19.38 months of treatment exposure for vepdegestrant and fulvestrant arms respectively)

PFS by BICR Assessment Per RECIST v1.1-Participants With ESR1 Mutation

PFS assessed by BICR was defined as the time from the date of randomization to the date of the first documentation of objective PD per RECIST v1.1, or death due to any cause, whichever occurred first. PD as per RECIST v1.1 was defined as at least a 20% increase in the sum of diameters of target measurable lesions above nadir (smallest sum observed considering baseline and all assessments prior to the timepoint under evaluation), with a minimum absolute increase of 5 mm relative to nadir or unequivocal progression of existing non-target lesions or the presence of new lesions. PFS was censored on the date of last adequate disease assessment for those who did not have a PFS event, discontinued the study treatment due to withdrawal of consent prior to an event, started a new anticancer therapy prior to an event, had an event after a gap of 2 or more missing disease assessments, or lost to follow-up. Kaplan-Meier method was used.

Data from ClinicalTrials.gov

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Secondary Outcomes

Overall Survival (OS)-All Randomized Participants

OS was defined as the time from date of randomization to date of death due to any cause. In case of no death, OS time would be censored on the date participant was last known to be alive.

Time frame: From date of randomization to the date of death due to any cause or censoring date

OS-Participants With ESR1 Mutation

OS was defined as the time from date of randomization to date of death due to any cause. In case of no death, OS time would be censored on the date participant was last known to be alive.

Time frame: From date of randomization to the date of death due to any cause or censoring date

Percentage of Participants With Objective Response (OR) by BICR Assessment- Participants With Measurable Disease at Baseline

OR was defined as the best overall response of confirmed complete response (CR) or partial response (PR) by BICR assessment as per RECIST v1.1 criteria. As per RECIST v1.1, CR was defined as complete disappearance of all target lesions, with the exception of nodal disease, complete disappearance of all non-target lesions and no new lesions. All nodes decreased to normal (short axis \<10 mm); all target lesions and disease sites were assessed. PR was defined as at least a 30% decrease from baseline in the sum of diameters of all target lesions, non-PD/not evaluated for the non-target lesions and no new lesions. The short diameter was used in the sum for nodal target lesions, while the longest diameter was used in the sum for non-nodal target lesions, all target lesions were assessed.

Time frame: From randomization until PD, death or start of new anticancer therapy, whichever occurred first (up to 18.56 months and 19.38 months of treatment exposure for vepdegestrant and fulvestrant arms respectively)

Clinical Benefit Rate (CBR) by BICR Assessment

CBR: percentage of participants with clinical benefit response. Clinical benefit response: confirmed CR or PR at any time, or stable disease (SD) \>=24 weeks per RECIST v1.1. CR: complete disappearance of all target lesions, of all non-target lesions and no new lesions; except for nodal disease, all nodes decreased to normal (short axis \<10 mm); all disease sites, all target lesions assessed. PR: \>=30% decrease from baseline in sum of diameters of all target lesions, non-PD/not evaluated for non-target lesions and no new lesions; all target lesions assessed. SD: did not qualify for CR, PR, PD. All target lesions assessed. PD per RECIST v1.1: at least 20% increased sum of diameters of target measurable lesions above nadir (smallest sum observed considering baseline and all assessments prior to timepoint under evaluation), with minimum absolute increase of 5mm relative to nadir or unequivocal progression of existing non-target lesions, or new lesions.

Time frame: From randomization until PD, death due to any cause or start of new anticancer therapy, whichever occurred first (up to 18.56 months and 19.38 months of treatment exposure for vepdegestrant and fulvestrant arms respectively)

Duration of Response (DOR) by BICR Assessment

DOR was defined as time from first documentation of objective tumor response (CR or PR) to first documentation of PD, or death due to any cause, whichever occurred first. CR: complete disappearance of all target lesions, of all non-target lesions and no new lesions; except for nodal disease, all nodes decreased to normal (short axis \<10 mm); all disease sites, all target lesions assessed. PR: \>=30% decrease from baseline in sum of diameters of all target lesions, non-PD/not evaluated for non-target lesions and no new lesions; all target lesions were assessed. The short diameter is used in the sum for nodal target lesions, while longest diameter is used in sum for non-nodal target lesions, all target lesions were assessed. DOR was analyzed in participants with an OR. PD: at least 20% increase in sum of diameters of target measurable lesions above nadir, with minimum absolute increase of 5 mm relative to nadir or unequivocal progression of existing non-target lesions, or new lesions.

Time frame: From first documentation of objective tumor response until confirmed PD or death, whichever occurred first (up to 18.56 months and 19.38 months of treatment exposure for vepdegestrant and fulvestrant arms respectively)

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs, Grade 3 or 4 and Grade 5 TEAEs as Assessed by NCI CTCAE v5.0

Adverse event (AE): any untoward medical occurrence in clinical study participant, temporally associated with use of study treatment, whether or not considered related to study treatment. AEs included both SAEs and all other (non-SAEs) AEs. SAE: any untoward medical occurrence, at any dose met one or more of following criteria: death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or other important medical events. TEAEs: AEs that occur on or after first dose of study treatment up to 28 days after last dose of study treatment. Relatedness to study drug were judged by investigator. As per National Cancer Institute Common Terminology Criteria for AE (NCI CTCAE) severity of AEs were graded as following, Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening; urgent treatment indicated, Grade 5: death related to AE.

Time frame: From the first dose of study treatment up to 28 days after last dose of study treatment

Number of Participants With Grade Shift From Baseline to Maximum Post-Baseline in Hematology Parameters Assessed by NCI CTCAE v5.0

Hematological parameters including neutrophil count decreased, white blood cell decreased, anemia, platelet count decreased, hemoglobin increased and leukocytosis were assessed. Baseline was defined as the last assessment on or prior to the date of the first dose of study treatment. As per NCI CTCAE v5.0, severity was graded as, Grade 1: mild, Grade 2: moderate, Grade 3: severe and Grade 4: life-threatening; urgent treatment indicated. Grade 0: Non-missing laboratory value that fell outside the grading range for the corresponding laboratory parameter. Categories with at least 1 non-zero values showing any shift in Grade from baseline to post-baseline were reported.

Time frame: From baseline up to 28 days after last dose of study treatment (up to 19.56 months and 20.38 months for vepdegestrant and fulvestrant arms respectively)

Number of Participants With Grade Shift From Baseline to Maximum Post-Baseline in Serum Chemistry Laboratory Abnormalities Assessed by NCI CTCAE v5.0

Serum chemistry parameters including alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, creatinine increased, hypercalcemia, hyperkalemia, hypermagnesemia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia were assessed. Baseline was defined as the last assessment on or prior to the date of the first dose of study treatment. As per NCI CTCAE v5.0 severity was graded as, Grade 1: mild, Grade 2: moderate, Grade 3: severe and Grade 4: life-threatening; urgent treatment indicated. Grade 0: Non-missing laboratory value that falls outside the grading range for the corresponding laboratory parameter. Categories with at least 1 non-zero values showing any shift in Grade from baseline to post-baseline were reported.

Time frame: From baseline up to 28 days after last dose of study treatment (up to 19.56 months and 20.38 months for vepdegestrant and fulvestrant arms respectively)

Number of Participants According to Categorization of Electrocardiogram (ECG) Parameters

Twelve lead ECGs were collected using an automated ECG machine that calculated heart rate and measured corrected QT (QTc interval, QT interval, PR interval and QRS complex). Criteria for heart rate was as follows, \<= 50 beats/minute (min), \>=100 beats/min, increase from baseline \>= 20 beats/min, decrease from baseline \>= 20 beats/min. Criteria for PR interval was \>= 220 millisecond (msec). Criteria for QRS interval was \>= 120 msec. Criteria for QT interval was as follows, \<=450 msec, \> 450 to \<= 480 msec, \>480 to \<=500 msec, \>500 msec, increase from baseline \<= 30 msec, increase from baseline \> 30 to \<= 60 msec. Criteria for QTCF interval was as follows, \<=450 msec, \> 450 to \<= 480 msec, \> 480 to \<= 500 msec, \> 500 msec, increase from baseline \<= 30 msec, increase from baseline \> 30 to \<= 60 msec, increase from baseline \> 60 msec. Baseline was defined as the last assessment on or prior to the date of the first dose of study treatment.

Time frame: From baseline up to 28 days after last dose of study treatment (up to 19.56 months and 20.38 months for vepdegestrant and fulvestrant arms respectively)

Number of Participants According to Categorization of QT Interval Corrected Using Fridericia's Formula (QTcF) Results-QTc Substudy Analysis Set

Criteria for QTcF interval for single beat were as follows, \<= 450 msec, \> 450 to \<= 480 msec, \> 480 to \<=500 msec, \> 500 msec, increase from baseline \<= 30 msec, increase from baseline \> 30 to \<= 60 msec, increase from baseline \> 60 msec. Baseline was defined as the last assessment on or prior to the date of the first dose of study treatment.

Time frame: Baseline and from the first dose of study treatment up to the end of treatment (EOT) i.e., 28 days after last dose of study treatment (approximately up to 19.56 months)

Change From Baseline in European Organization for the Research and Treatment of Cancer and Quality of Life Questionnaire (EORTC QLQ-C30) Score

The EORTC QLQ-C30 contains 30 items and is composed of 5 multi-item functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning), 3 multi-item symptom scales (fatigue, pain and nausea/vomiting), 6 single item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and one global quality of life scale. This questionnaire contained 30 questions organized into 5 multi-item functional scales, 3 multi-item symptom scales, 6 single item symptom scales, and one global quality of life scale. All the scales and single-item measures range in score from 0 to 100. Higher scores on the functional scales represent higher levels of functioning. Higher scores on the global health status/quality of life scale represent higher health status/quality of life. Higher scores on symptom scales/items represent a greater presence of symptoms.

Time frame: From baseline up to 28 days after last dose of study treatment

Change From Baseline in European Organization for the Research and Treatment of Cancer and Quality of Life Questionnaire-Breast Cancer Specific (EORTC QLQ-BR23) Score

The EORTC QLQ-BR23 was a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consisted of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side-effects, breast symptoms, arm symptoms, upset by hair loss). Each item was rated by choosing 1 of 4 possible responses that record the level of intensity (1= not at all, 2= a little, 3= quite a bit, and 4= very much) within each scale. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning. For symptom-oriented scales, higher scores represented greater symptom severity.

Time frame: From baseline up to 28 days after last dose of study treatment

Change From Baseline in EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Index and Visual Analogue Scale (VAS) Scores

The EQ-5D-5L was a 5-item participant-completed questionnaire designed to assess health status in terms of a single index value or utility score. There were 2 components, a Health State Profile where participants rated their level of problems (1=none, 2=slight, 3=moderate, 4=severe, 5=extreme/unable) in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and a visual analogue scale (VAS) in which participants rated their overall health status from 0 (worst imaginable) to 100 (best imaginable). Responses to 5 dimensions comprised health state/ single utility index value. E.g. if a participant responds "no problems" for each 5 dimensions, then health state was coded as "11111" with a predefined index value to it. Every health state (coded as combination of responses) had a unique predefined utility index value assigned to it per US value sets, Overall index scores ranged from 0 to 1, with lower scores representing a higher level of dysfunction.

Time frame: From baseline up to 28 days after last dose of study treatment

Change From Baseline in Pain Severity and Pain Interference as Assessed by Brief Pain Inventory Short Form (BPI-SF) Score

The BPI-SF consisted of items to measure participant perceptions of pain severity (item 3), assess degree of interference of pain on daily functioning, body diagrams on which participants indicate location of pain, record pain medication usage, VAS assessed degree of pain relief in last 24 hours (item 9a). Items in pain severity scale evaluated pain "at its worst", "at its least", and "on average" over previous 24 hours, as well as "pain now" (at time of assessment). Participants responded on 10- point numerical rating scale, where 0 = "no pain" and 10 = "pain as bad as you can imagine". Pain interference scale asked participants to rate how their pain interferes with "enjoyment of life", "general activity", "walking ability", "mood", "sleep", "normal work" and "relations with other people." Responses for interference scale were also based on 10-points scale, where 0 = "does not interfere" and 10 = "interferes completely". Higher scores=high levels of pain, impact attributed to pain.

Time frame: From baseline up to 28 days after last dose of study treatment

Plasma Concentration of ARV-471 and Its Epimer ARV-473

Plasma concentrations of ARV-471 and its epimer ARV-473 were reported in this outcome measure.

Time frame: Anytime between -4 to 0 hours on Day 1 of Cycle 2, Cycle 3, Cycle 5 and Cycle 7 and anytime between 5 to 7 hours on Day 1 of Cycle 2 and Cycle 3

Change in Plasma Circulating Tumor DNA (ctDNA) From Baseline

Quantitative change in plasma ctDNA levels from baseline to each protocol specified time point (up to EOT), as assessed using a validated assay.

Time frame: Baseline and up to EOT