C4891002: A Phase 3, Randomized, Open-Label, Multicenter Study Of ARV-471 (PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib For The Treatment Of Participants With Estrogen Receptor Positive, HER2-Negative Breast Cancer Who Have Not Received Any Prior Systemic Anti-Cancer Treatment For Advanced Disease (VERITAC-3)
- Trial ID
- 2022-500545-24-00
- Protocol
- C4891002
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that **ARV-471** in combination with **palbociclib** is superior to letrozole plus palbociclib in prolonging progression-free survival (PFS) in participants with estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer who have not received any prior systemic anticancer therapy for their advanced disease. This is clinically relevant as it aims to improve the management and outcomes of patients with this specific subtype of breast cancer, potentially offering a more effective treatment option.
Secondary objectives include:
- Study Lead-in: To evaluate safety and tolerability of both dose levels.
- Study Lead-in: To evaluate measures of tumor control and duration of response in both dose levels.
- Study Lead-in: To evaluate the concentrations of ARV-471 and ARV-473.
- Study Lead-in: To evaluate the concentrations of palbociclib.
- Phase 3: To demonstrate that ARV-471 in combination with palbociclib is superior to letrozole in combination with palbociclib, in prolonging overall survival (OS).
- Phase 3: To compare measures of tumor control between treatment arms and evaluate duration of response within each treatment arm.
- Phase 3: To evaluate safety and tolerability of both treatment arms.
- Phase 3: To evaluate the concentrations of ARV-471 and ARV-473.
- Phase 3: To evaluate the concentrations of palbociclib.
- Phase 3: To evaluate patient-reported outcomes between the two treatment arms.
- Phase 3: To assess changes from baseline levels in plasma ctDNA.
Participants
The clinical trial involves a total of **33 participants** diagnosed with **ER+/HER2- Advanced Breast Cancer**. The study population includes both male and female participants aged 18 years or older, with no prior systemic anti-cancer therapy for their locoregionally advanced or metastatic disease. Participants were selected based on specific criteria, including histological or cytological confirmation of breast cancer with evidence of locoregionally advanced or metastatic disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. The trial does not involve a vulnerable population. Participants are required to provide a blood sample and a tumor sample collected at the time of diagnosis, with exceptions for those with bone-only disease. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
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) in combination with **palbociclib** compared to letrozole plus palbociclib in participants with **estrogen receptor-positive, HER2-negative advanced breast cancer**. The trial aims to demonstrate the superiority of ARV-471 with palbociclib in prolonging progression-free survival in participants who have not received any prior systemic anti-cancer treatment for their advanced disease. The study is expected to run until September 2030, with recruitment starting in September 2023.
Participants will be randomly assigned to one of the treatment arms and will receive the investigational products orally. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess overall outcomes. The screening visit will involve collecting a blood sample and a tumor sample, unless the participant has bone-only disease, in which case archival tissue may be used. Follow-up visits will occur at regular intervals to assess progression-free survival, overall survival, and other secondary endpoints such as objective response and clinical benefit response.
The expected duration of participant involvement is up to 29 days per treatment cycle, with the possibility of multiple cycles depending on individual response and tolerance. Participants may be withdrawn from the study early if they experience unacceptable adverse events, disease progression, or if they choose to discontinue participation. The primary endpoint of the study is progression-free survival, while secondary endpoints include overall survival, incidence of adverse events, and laboratory abnormalities. The study will also measure plasma concentrations of ARV-471 and palbociclib to evaluate pharmacokinetics.
Treatment
The clinical trial involves the administration of **PF-07850327**, an experimental medication formulated as a **film-coated tablet**. This investigational product is chemically synthesized and is intended for **oral use**. The active substance in PF-07850327 is (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 is 200 mg, with a total maximum dose of 162,400 mg over a treatment period of 29 days. The product is developed by Pfizer Inc. and is classified as an oncological anti-tumoral agent.
In addition to the experimental medication, the trial includes the administration of **IBRANCE** (palbociclib), which is available in two dosages: 100 mg and 75 mg **hard capsules**. Palbociclib is a chemically synthesized anti-tumoral agent, also administered orally. The 100 mg capsules have a maximum daily dose of 100 mg and a total maximum dose of 81,200 mg over 29 days, while the 75 mg capsules have a maximum daily dose of 75 mg and a total maximum dose of 60,900 mg over the same period. Both formulations are developed by Pfizer Europe MA EEIG and are used as comparator treatments in the study.
Additionally, a 50 mg **capsule** formulation of palbociclib is included in the trial. This formulation is also chemically synthesized and administered orally, with a maximum daily dose of 50 mg and a total maximum dose of 40,600 mg over 29 days. This product is developed by Pfizer Inc. and serves as an anti-tumoral agent in the study.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy of PF-07850327 in combination with palbociclib compared to letrozole plus palbociclib in prolonging progression-free survival in participants with estrogen receptor-positive, HER2-negative breast cancer.
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 v1.1, or death due to any cause, whichever occurs first. This endpoint is critical in evaluating the effectiveness of ARV-471 in combination with palbociclib compared to letrozole plus palbociclib in participants with estrogen receptor-positive, HER2-negative advanced breast cancer.
Secondary efficacy endpoints include **overall survival (OS)**, which is the time from the date of randomization to the date of death due to any cause. Additional secondary endpoints involve objective response, clinical benefit response, and duration of response as determined by BICR assessment per RECIST v1.1. The trial will also monitor the incidence of adverse events (AEs) and serious adverse events (SAEs), laboratory abnormalities, and ECG abnormalities. Plasma concentrations of ARV-471, its epimer ARV-473, and palbociclib will be measured to assess pharmacokinetics. Patient-reported outcomes will be evaluated using the EuroQol EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-BR23 instruments. Additionally, changes in circulating tumor DNA (ctDNA) plasma levels from pretreatment will be analyzed to explore potential predictive associations with clinical outcomes.
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.• Pre-peri menopausal female and male participants must agree on LHRH use. • WOCBP participants and male participants must agree on contraception.
- Phase 3 ONLY. Participants must provide a blood sample AND a tumor sample collected at the time of diagnosis of locally advanced/metastatic disease. If not available, a de novo biopsy is required. The sole exception is those patients with bone only disease for whom archival tumor sample at initial diagnosis is acceptable.
- Histological or cytological confirmation of BC with evidence of locoregionally advanced or metastatic disease, not amenable to surgical resection or radiation therapy with curative intent. •Documented ER(+), defined as ER(+) ≥1% stained cells on the most recent tumor biopsy, ie, at diagnosis of recurrence or metastatic disease (Allison et al, 2020). The sole exception is those patients 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 guideline (Wolff et al, 2018). •Participants who have bilateral BCs which are both ER(+)/HER2(-) are eligible.
- No prior systemic anti-cancer therapy for their locoregionally advanced or metastatic disease.
- At least 1 measurable lesion as defined by RECIST v1.1. Bone only disease: participants with only non-measurable lesions are eligible.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.
- Participants must be adults with ER+/HER2- A/MBC, who have not been previously treated with prior therapies for advanced/metastatic disease. Participants must have at least 1 measurable lesion as per RECIST v1.1, or for those with bone only disease, those with only non-measurable lesions are eligible.
Exclusion Criteria
- Prior treatments: CDK4/6i, vepdegestrant, fulvestrant, elacestrant and other investigational agents (including novel ET, any SERDs, SERCAs, CERANs) in any setting.
- Lack of adequate bone marrow, liver and kidney function.
- Impaired cardiovascular function or clinically significant cardiovascular diseases.
- Refractory nausea and vomiting, chronic GI disease, GI ulcer, GI bleeding, inability to swallow the formulated product or previous significant gastric (total or partial), bowel resection that would preclude adequate absorption of study interventions.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Hungary | Not Recruiting | 25 Sept 2023 | 3 |
 Italy | Not Recruiting | 25 Sept 2023 | 3 |
 Slovakia | Not Recruiting | 25 Sept 2023 | 2 |
 Spain | Not Recruiting | 25 Sept 2023 | 9 |
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 USE | 200 | 29 | PRD9906032 |
palbociclib | Comparator | CAPSULE | ORAL | 50 | 29 | PRD10869005 |
IBRANCE 100 mg hard capsules | Comparator | HARD CAPSULES | ORAL | 100 | 29 | PRD6503933 |
IBRANCE 75 mg hard capsules | Comparator | HARD CAPSULES | ORAL USE | 75 | 29 | PRD6503936 |