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 B)

• ClinicalTrials.gov Identifier: NCT05573555
• Recruitment Status: Recruiting
• First Posted: October 10, 2022
• Last Update Posted: May 6, 2024
• Sponsor: Pfizer
• Collaborator: Arvinas Estrogen Receptor, Inc.
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: October 5, 2022
• First Posted Date: October 10, 2022
• Last Update Posted Date: May 6, 2024
• Actual Study Start Date: March 1, 2023
• Estimated Primary Completion Date: December 14, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 6, 2024)

• Phase 1b: Number of Participants With Dose Limiting Toxicities [ Time Frame: Cycle 1 (28 days) ]
  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]).
• 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.
• Drug Drug Interaction cohort: Area Under the Curve from Time Zero to end of dosing interval Evaluation of ribociclib with and without co-administration of ARV-471 [ Time Frame: pre-dose Day -1, 1, 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 8, 29 and 43 ]
  Exposure (AUCtau) of ribociclib with and without co-administration of ARV-471
• Drug Drug Interaction cohort: Maximum Plasma Concentration (Cmax) of ribociclib with and without co-administration of ARV-471 [ Time Frame: pre-dose Day -1, 1, 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 8, 29 and 43 ]
  Concentration (Cmax) of ribociclib with and without co-administration of ARV-471

Original Primary Outcome Measures (submitted: October 5, 2022)

• Phase 1b: Number of Participants With Dose Limiting Toxicities [ Time Frame: 28 days ]
  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]).
• 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: March 6, 2024)

• Phase 1b, Drug Drug Interaction cohort 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, Drug Drug Interaction cohort 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 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, Drug Drug Interaction cohort 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.
• Drug Drug Interaction cohort: number of participants with changes from baseline for ECG parameters [ Time Frame: Up to 28 days after last dose of study treatment ]
  The following ECG parameters were analyzed and changes from baseline were assessed: heart rate, PR interval, QT interval, QRS interval and QT interval corrected using Fridericia's formula (QTcF).
• 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 1b: Maximum Observed Plasma Concentration (Cmax) of ARV-471 with and without co-administration of ribociclib [ Time Frame: Phase 1b: pre-dose Day -1, 1, 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 8, 29 and 43 ]
  Concentration (Cmax) of ARV-471 with and without co-administration of ribociclib
• Phase 1b Area Under the Curve from Time Zero to end of dosing interval Evaluation of ARV-471 with and without co-administration of ribociclib [ Time Frame: Phase 1b: pre-dose Day -1, 1, 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 8, 29 and 43 ]
  Exposure (AUCtau) of ARV-471 with and without co-administration of ribociclib
• Phase 1b and Phase 2: Maximum Observed Plasma Concentration (Cmax) of ARV-471 [ Time Frame: Phase 1b: pre-dose Day 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 8, 29 and 43 Phase 2: pre and post dose Day 8, 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 ARV-473 [ Time Frame: Phase 1b: pre-dose Day -1, 1, 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day -1 and 15; post dose Day 8, 29 and 43 Phase 2: pre and post dose Day 8, 15, 29 and 43; pre - dose Day 57, 113 and 169 ]
  Plasma concentration of ARV-473
• Phase 1b and Phase 2: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of ribociclib [ Time Frame: Phase 1b: pre-dose Day -1, 1, 8, 15, 29, 43, 57, 113, 169; 1, 2, 4, 6, 8 hours post dose on Day 15; post dose Day 8, 29 and 43 Phase 2: pre and post dose Day 8, 15, 29 and 43; pre - dose Day 57, 113 and 169 ]
  Plasma concentration of ribociclib
• 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, up to cycle 3 (each cycle is 28 days) and end of treatment ]
  To assess changes from baseline levels in plasma ctDNA with treatment and to evaluate potential predictability of their associations with clinical outcomes.

Original Secondary Outcome Measures (submitted: October 5, 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: Evaluation of effect of ribociclib on PK of ARV471 [ Time Frame: At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days) ]
  AUCtau and Cmax of ARV-471 with and without co-administration of ribociclib
• Phase 1b and Phase 2: Evaluation of Safety and Tolerability of ARV-471 in combination with Ribociclib [ 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 ribociclib. 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 ribociclib. [ Time Frame: At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days) ]
  To evaluate the plasma exposure of ARV-471 and ribociclib when ARV-471 and ribociclib are given in combination.
• 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, up to cycle 3 (each cycle is 28 days) and end of treatment ]
  To assess changes from baseline levels in plasma ctDNA with treatment and to evaluate potential predictability of their associations with clinical outcomes.

• 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 B)
• 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 B (ARV-471 IN COMBINATION WITH RIBOCICLIB)

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 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: 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.
• 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 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).

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.

In addition, the potential drug-drug interaction (DDI) between ARV-471 and ribociclib will be evaluated, at the doses selected for the ph2 portion, in a DDI Assessment Cohort(s)

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 RP2D determined, cycles lasting 28 days
• Drug: Ribociclib
  Daily oral dosages of ribociclib consecutively for 21 days followed by 7 days off treatment, cycles lasting 28 days

Study Arms

Experimental: ARV-471 in combination with Ribociclib

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

Interventions:

• Drug: ARV-471
• Drug: Ribociclib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 6, 2024): 47
• Original Estimated Enrollment (submitted: October 5, 2022): 35
• Estimated Study Completion Date: December 14, 2026
• Estimated Primary Completion Date: December 14, 2026 (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, and only 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

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: NCT05573555
• Other Study ID Numbers: C4891023; 2022-502231-19-00 ( 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: May 2024