TACTIVE-U: A Study to Learn About the Study Medicine (Called ARV-471) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study B)

Study Overview
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Brief Summary
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The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called ARV-471) when given together with other medicines for the potential treatment of advanced or metastatic breast cancer. This study is seeking participants who have breast cancer that: is advanced, may have spread to other organs (metastatic) and cannot be fully treated by surgery or radiation therapy is sensitive to hormonal therapy (it is called estrogen receptor positive); and is no longer responding to previous treatments This study is divided into separate sub-studies. For Sub-Study B: All participants will receive ARV-471 and a medicine called ribociclib. ARV-471 and ribociclib will be given at the same time by mouth, at home, 1 time a day. The experiences of people receiving the study medicine will be examined. This will help determine if the study medicine is safe and effective. Participants will continue to take ARV-471 and ribociclib until their cancer is no longer responding, or side effects become too severe. They will have visits at the study clinic about every 4 weeks.

Detailed Description
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C4891023 is a prospective, open-label, multicenter, Phase 1b/2 sub-study to evaluate the safety, antitumor activity, and PK of ARV-471 with ribociclib in the treatment of participants with A/MBC. The sub-study is part of Umbrella platform, TACTIVE-U, comprising multiple sub-studies that independently evaluate ARV-471 in participants with with Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Advanced or Metastatic Breast Cancer. ARV-471 will act as the backbone therapy given in combination with other anticancer agents thought to have clinical relevance in ER+ breast cancer.

Official Title
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TACTIVE-U: AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL UMBRELLA STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF ARV-471 (PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH OTHER ANTICANCER TREATMENTS IN PARTICIPANTS AGED 18 YEARS AND OVER WITH ER+ ADVANCED OR METASTATIC BREAST CANCER, SUB-STUDY B (ARV-471 IN COMBINATION WITH RIBOCICLIB)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: ARV-471
* Drug: Ribociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histological or cytological diagnosis of ER+ and HER2- advanced/metastatic breast cancer that is not amendable to surgical resection with curative intent (≥1% ER+ stained cells on the most recent tumor biopsy). prior anticancer therapies: up to 2 lines of prior therapies for advanced/metastatic disease; 1 line of any CDK4/6 inhibitor-based regimen is required (in any setting eg adjuvant, metastatic) at least 1 measurable lesion as defined by RECIST v1.1. ECOG PS ≤1. Exclusion Criteria: visceral crisis at risk of life-threatening complications in the short term known history of drug-induced pneumonitis or other significant symptomatic deterioration of lung functions. newly diagnosed brain metastases, 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, clinically stable and discontinued anti-seizure medications and corticosteroids for at least 14 days prior to enrollment in the of study. history of any other tumor malignancies within the past 3 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. inflammatory breast cancer impaired cardiovascular function or clinically significant cardiovascular diseases concurrent administration of medications, food, or herb supplements that are strong inhibitors and strong/moderate inducers of CYP3A and drugs known to predispose to Torsade de Pointes or QT interval prolongation. renal impairment, not adequate liver function and/or bone marrow function known active infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1b will use an escalation/de-escalation approach to determine the RP2D of ARV-471 when administered in combination with ribociclib. The decision to escalate the starting dose level of ARV-471 will be using mTPI-2 decision criteria based on the number of DLT-evaluable participants and the number of DLTs in those participants during the DLT observation period (Cycle 1 [first 28 days]). During Phase 1b, a 7 days lead-in period will be conducted with ARV-471 as monotherapy. Phase 2 will further evaluate the preliminary antitumor activity and safety of the combination RP2D.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARV-471 in combination with Ribociclib<br>ARV-471 administered orally QD continuously and Ribociclib administered orally QD consecutively for 21 days followed by 7 days off treatment on 28-day cycles | Drug: ARV-471<br>* Daily oral dosages of ARV-471 continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days<br>Drug: Ribociclib<br>* Daily oral dosages of ribociclib consecutively for 21 days followed by 7 days off treatment, cycles lasting 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose Limiting Toxicities | Dose Limiting Toxicities rate for ARV-471 in combination with Ribociclib, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1 [28 days]). | 28 days | 
| Phase 2: Percentage of Participants With Objective Response by investigator assessment | Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. as determined by investigator assessment. | Up to approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Percentage of Participants With Objective Response by investigator assessment | Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. as determined by investigator assessment. | Up to approximately 1 year | 
| Phase 1b: Evaluation of effect of ribociclib on PK of ARV-471 | AUCtau and Cmax of ARV-471 with and without co-administration of ribociclib | At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days) | 
| Phase 1b and Phase 2: Evaluation of Safety and Tolerability of ARV-471 in combination with Ribociclib | AEs as characterized by type, frequency, intensity as graded by NCI CTCAE version 5.0, timing, seriousness, and relationship to ARV-471 in combination with ribociclib. Laboratory test abnormalities as characterized by type, frequency, intensity (as graded by NCI CTCAE version 5.0), and timing. | First study drug dose through a minimum of 28 Days After Last study drug administration | 
| Phase 1b and Phase 2: Duration of Response by investigator assessment. | Duration of Response (DoR) is defined for participants with confirmed OR (CR or PR) as the time from the first documentation of OR to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. | Up to approximately 1 year | 
| Phase 1b and Phase2: Percentage of participants with Clinical Benefit Response by investigator assessment. | Clinical Benefit Response (CBR) is defined as the proportion of participants with Best Overall Response of confirmed CR or PR at any time, or Stable Disease (SD) ≥24 weeks | Up to approximately 1 year | 
| Phase 1b and Phase 2: Progression Free Survival by investigator assessment. | Progression Free Survival (PFS) is defined as the time from the date of first dose of study interventions to the date of first documentation of PD or death due to any cause, whichever occurs first. | Up to approximately 1 year | 
| Phase 1b and Phase 2: Plasma concentrations of ARV-471 and ribociclib. | To evaluate the plasma exposure of ARV-471 and ribociclib when ARV-471 and ribociclib are given in combination. | At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days) | 
| Phase 2: Overall Survival | Overall Survival (OS) is defined as the time from the date of first dose of study interventions to the date of death due to any cause | Through study completion, up to approximately 3 year | 
| Phase 2:ctDNA plasma quantitative changes from pre-treatment | To assess changes from baseline levels in plasma ctDNA with treatment and to evaluate potential predictability of their associations with clinical outcomes. | At predefined intervals throughout the treatment period, up to cycle 3 (each cycle is 28 days) and end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TACTIVE-U; Umbrella study; PROTAC; metastatic breast cancer