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

• ClinicalTrials.gov Identifier: NCT05548127
• Recruitment Status: Recruiting
• First Posted: September 21, 2022
• Last Update Posted: April 18, 2024
• Sponsor: Pfizer
• Collaborator: Arvinas Estrogen Receptor, Inc.
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: August 25, 2022
• First Posted Date: September 21, 2022
• Last Update Posted Date: April 18, 2024
• Actual Study Start Date: February 23, 2023
• Estimated Primary Completion Date: December 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 5, 2024)

• Phase 1b: number of participants with dose limiting toxicities [ Time Frame: 28 days ]
  Dose Limiting Toxicities rate for ARV-471 in combination with abemaciclib, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1 [28 days]).
• Phase 2: percentage of participants with objective response by investigator assessment [ Time Frame: Up to approximately 1 year ]
  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.

Original Primary Outcome Measures (submitted: September 17, 2022)

• Phase 1b: Number of Participants With Dose Limiting Toxicities [ Time Frame: 28 days ]
  Dose Limiting Toxicities rate for ARV-471 in combination with Abemaciclib, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1 [28 days]).
• Phase 2: Percentage of Participants With Objective Response by investigator assessment [ Time Frame: Up to approximately 1 year ]
  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.

Current Secondary Outcome Measures (submitted: February 5, 2024)

• Phase 1b and Phase 2: number of participants experiencing any AE, SAE, Treatment Related SAE [ Time Frame: Up to 28 days after last dose of study treatment ]
  An adverse event (AE) were any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. Treatment-related AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) and coded using MedDRA were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling and grade 5=death.
• Phase 1b and Phase 2: number of participants with lab abnormalities - Hematology and coagulation parameters [ Time Frame: Up to 28 days after last dose of study treatment ]
  Blood samples were collected for the analysis of following hematology and coagulation parameters: hemoglobin [g/L], platelets, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils [10^9/L]; partial thromboplastin time prolonged, international normalized ratio increased, prothrombin time. Number of participants with hematological and coagulation abnormalities by grade as per CTCAE version 5.0 were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling and grade 5=death. For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.
• Phase 1b and Phase 2: number of participants with lab abnormalities - chemistry parameters [ Time Frame: Up to 28 days after last dose of study treatment ]
  Blood samples were collected for analysis of clinical chemistry parameters. These included: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, [international unit per liter (IU/L)] ; Lipase and amilase [IU/L] (limited to cycle1 only); Albumin, bilirubin, urea ,calcium, creatinine, glucose, magnesium, phosphate, uric acid, chloride, potassium and sodium [millimol per liter (mmol/L)]; eGFR [milliliter per minute (ml/min)]. Number of participants with blood chemistry abnormalities by grade as per CTCAE version 5.0 were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling and grade 5=death. For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.
• Phase 1b: percentage of participants with objective response by investigator assessment [ Time Frame: Up to approximately 1 year ]
  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.
• Phase 1b and Phase 2: duration of response by investigator assessment. [ Time Frame: Up to approximately 1 year ]
  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.
• Phase 1b and Phase2: Percentage of participants with Clinical Benefit Response by investigator assessment. [ Time Frame: Up to approximately 1 year ]
  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
• Phase 1b and Phase 2: Progression Free Survival by investigator assessment. [ Time Frame: Up to approximately 1 year ]
  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.
• Phase 2: Overall Survival [ Time Frame: Through study completion, up to approximately 3 year ]
  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
• Phase 2:ctDNA plasma quantitative changes from pre-treatment [ Time Frame: Day 1, 29 and 57 and End of Treatment (an average of 1 year) ]
  To assess changes from baseline levels in plasma circulating DNA (ctDNA) with treatment and to evaluate potential predictability of their associations with clinical outcome
• Phase 1b: Area Under the Curve from Time Zero to end of dosing interval Evaluation of abemaciclib with or without ARV-471 [ Time Frame: Phase 1b: pre-dose Day -1, 1, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 29 and 43 ]
  Exposure (AUCtau) of abemaciclib with and without co-administration of ARV-471
• Phase 1b: Maximum Observed Plasma Concentration (Cmax) of abemaciclib with or without ARV-471 [ Time Frame: Phase 1b: pre-dose Day -1, 1, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 29 and 43 ]
  Concentration (Cmax) of abemaciclib with and without co-administration of ARV-471
• Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of ARV-471 [ Time Frame: Phase 1b: pre-dose Day 1, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day 15; post dose Day 29 and 43. Phase 2: pre and post dose Day 15, 29 and 43; pre - dose Day 57, 113 and 169 ]
  Plasma concentration of ARV-471
• Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of abemaciclib [ Time Frame: Phase 1b: pre-dose Day -1, 1, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 29, 43 and 57 Phase 2: pre and post dose Day 15, 29 and 43; pre - dose Day 57, 113 and 169 ]
  Plasma concentration of abemaciclib

Original Secondary Outcome Measures (submitted: September 17, 2022)

• Phase 1b: Percentage of Participants With Objective Response by investigator assessment [ Time Frame: Up to approximately 1 year ]
  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.
• Phase 1b and Phase 2: Evaluation of Safety and Tolerability of ARV-471 in combination with Abemaciclib [ Time Frame: First study drug dose through a minimum of 28 Days After Last study drug administration ]
  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 abemaciclib. Laboratory test abnormalities as characterized by type, frequency, intensity (as graded by NCI CTCAE version 5.0), and timing.
• Phase 1b and Phase 2: Duration of Response by investigator assessment. [ Time Frame: Up to approximately 1 year ]
  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.
• Phase 1b and Phase2: Percentage of participants with Clinical Benefit Response by investigator assessment. [ Time Frame: Up to approximately 1 year ]
  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
• Phase 1b and Phase 2: Progression Free Survival by investigator assessment. [ Time Frame: Up to approximately 1 year ]
  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.
• Phase 1b and Phase 2: Plasma concentrations of ARV-471 and abemaciclib. [ Time Frame: At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days) ]
• Phase 2: Overall Survival [ Time Frame: Through study completion, up to approximately 3 year ]
  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
• Phase 2:ctDNA plasma quantitative changes from pre-treatment [ Time Frame: At predefined intervals throughout the treatment period, an average of 1 year ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study A)
• Official Title: TACTIVE-U: An Interventional Safety and Efficacy Phase 1b/2, Open-label Umbrella Study to Investigate Tolerability, pk, and Antitumor Activity of Vepdegestrant (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 A (ARV-471 in Combination With Abemaciclib)

Brief Summary

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 A:

All participants will receive ARV-471 and a medicine called abemaciclib. ARV-471 will be given by mouth, at home, 1 time a day. Abemaciclib will be given by mouth, at home, 2 times a day. We will examine the experiences of people receiving the study medicines. This will help us determine if the study medicines are safe and effective.

Participants will continue to take ARV-471 and abemaciclib 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: C4891006 is a sub-study from the Umbrella platform, TACTIVE-U, comprising multiple sub-studies that independently evaluate ARV-471 in participants with Estrogen Receptor Positive (ER+) Advanced or Metastatic Breast Cancer (A/MBC). ARV-471 will act as the backbone therapy given in combination with other anticancer agents thought to have clinical relevance in ER+ breast cancer.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

Phase 1b will use an escalation/de-escalation approach to determine the RP2D of ARV-471 when administered in combination with abemaciclib. The decision to de-escalate the starting dose levels 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]).

Phase 2 will further evaluate the preliminary antitumor activity and safety of the combination RP2D.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Breast Cancer

Intervention

• Drug: ARV-471
  Daily oral dosages of ARV-471 continuously, dose escalation/de-escalation in Phase 1b until the recommended phase 2 dose (RP2D) determined, cycles lasting 28 days
  Other Name: vepdegestrant, PF-07850327
• Drug: Abemaciclib
  Daily oral dosages of Abemaciclib continuously, cycles lasting 28 days

Study Arms

Experimental: ARV-471 in combination with Abemaciclib

ARV-471 administered orally once daily (QD) and Abemaciclib orally twice daily (BID) on 28-day cycle

Interventions:

• Drug: ARV-471
• Drug: Abemaciclib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 5, 2024): 40
• Original Estimated Enrollment (submitted: September 17, 2022): 35
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: December 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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: at least 1 and no more than 2 lines of prior therapies for advanced/metastatic disease; 1 line of any CDK4/6 inhibitor-based regimen is required (independent of the setting eg, adjuvant or advanced/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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

• Listed Location Countries: Canada, Italy, Spain, United States

Administrative Information

• NCT Number: NCT05548127
• Other Study ID Numbers: C4891006; 2022-502228-34-00 ( Registry Identifier: CTIS (EU) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Arvinas Estrogen Receptor, Inc.

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2024