The purpose of this study is to learn about the safety and effects of the study medicine called vepdegestrant. The safety and effects of vepdegestrant will be see when given with other medicines. Vepdegestrant is studied to see if it can be a possible treatment for advanced metastatic breast cancer. This type of cancer would have spread from where it started (breast) to other parts of the body and would be tough to treat. The study is seeking for participants who have breast cancer that: * is hard to treat (advanced) and may have spread to other organs (metastatic). is sensitive to hormonal therapy (it is called estrogen receptor positive). * is no longer responding to treatments taken before starting this study. This study is divided into separate sub-studies. For Sub-Study C: All the participants will receive vepdegestrant and a medicine called samuraciclib. Vepdegestrant and samuraciclib will be taken once in a day by mouth. The medicines will be taken at home. The experience of people receiving the study medicines will be studied. This will help see if the study medicine is safe and effective. Participant will continue to take vepdegestrant and samuraciclib 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.
C4891024 is a prospective, open-label, multicenter, Phase 1b/2 sub-study to evaluate the safety, antitumor activity, and PK of ARV-471 with samuraciclib 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 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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
11
Daily oral dosages of ARV-471 continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days
Daily oral dosages of Samuraciclib continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days
Highlands Oncology Group
Fayetteville, Arkansas, United States
Highlands Oncology Group
Rogers, Arkansas, United States
Highlands Oncology Group
Springdale, Arkansas, United States
Clinical and Translational Research Unit (CTRU)
Palo Alto, California, United States
Stanford Cancer Center
Palo Alto, California, United States
UCHealth Poudre Valley Hospital
Fort Collins, Colorado, United States
UCHealth Harmony
Fort Collins, Colorado, United States
UCHealth Greeley Hospital
Greeley, Colorado, United States
UCHealth - Medical Center of the Rockies
Loveland, Colorado, United States
Memorial Hospital East
Shiloh, Illinois, United States
...and 11 more locations
Phase 1b: Number of Participants With Dose Limiting Toxicities
Dose Limiting Toxicities rate for ARV-471 in combination with Samuraciclib, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1).
Time frame: 28 days
Drug Drug Interaction: To evaluate the effect of samuraciclib on PK of ARV 471.
Steady-state Area under the plasma concentration versus time curve (AUCtau) of ARV-471 with and without coadministration of samuraciclib
Time frame: From the start of Lead-in period (maximum 13 days) to the end of cycle 1 (at least 28 days)
Drug Drug Interaction: To evaluate the effect of samuraciclib on PK of ARV 471.
Steady-state Peak Plasma concentration ( Cmax) of ARV-471 with and without coadministration of samuraciclib
Time frame: From the start of Lead-in period (maximum 13 days) to the end of cycle 1 (at least 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.
Time frame: Up to approximately 1 year
Drug Drug Interaction: • To evaluate the effect of ARV 471 on PK of samuraciclib.
Single dose AUC0-72 of samuraciclib with and without coadministration of ARV 471.
Time frame: From the start of Lead-in period (maximum 13 days) to the end of cycle 1 (at least 28 days))
Drug Drug Interaction: • To evaluate the effect of ARV 471 on PK of samuraciclib.
Single dose Cmax of samuraciclib with and without coadministration of ARV 471.
Time frame: From the start of Lead-in period (maximum 13 days) to the end of cycle 1 (at least 28 days))
Phase 1b, Drug drug interaction and Phase 2: Evaluation of Safety and Tolerability of ARV-471 in combination with Samuraciclib
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 samuraciclib. Laboratory test abnormalities as characterized by type, frequency, intensity (as graded by NCI CTCAE version 5.0), and timing. Changes from baseline for the ECG parameters heart rate, QTcF, PR interval, and QRS complex will be summarized by treatment and time. The frequency of uncorrected QT values above 500 ms will be tabulated.
Time frame: First study drug dose through a minimum of 28 Days After Last study drug administration
Phase 1b: To evaluate antitumor activity of ARV-471 in combination with samuraciclib
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.
Time frame: Up to approximately 1 year
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.
Time frame: 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
Time frame: 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.
Time frame: Up to approximately 1 year
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Phase 1b and Phase 2: Plasma concentrations of ARV-471 and samuraciclib.
To evaluate the plasma exposure of ARV-471 and samuraciclib when ARV-471 and samuraciclib are given in combination.
Time frame: At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days)
Phase 1b: Evaluation of effect of samuraciclib on PK of ARV-471
AUCtau of ARV-471 with and without co-administration of samuraciclib
Time frame: At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days)
Phase 1b: Evaluation of effect of samuraciclib on PK of ARV-471
Cmax of ARV-471 with and without co-administration of samuraciclib
Time frame: At predefined intervals throughout the treatment period, up to cycle 7 (each cycle is 28 days)
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.
Time frame: At predefined intervals throughout the treatment period, up to cycle 3 (each cycle is 28 days) and end of treatment
Phase 2: To evaluate the correlation between TP53 mutation status and antitumor activity
Participants classified on basis of pathological TP53 mutation detected or not detected.
Time frame: Screening
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
Time frame: Through study completion, up to approximately 3 year