Neoplasms

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Breast Neoplasms

Breast Diseases

Skin Diseases

Fibrinolytic Agents

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Snake venom protein C activator

ARV-471 administered orally QD continuously and Samuraciclib administered orally QD continuously on 28-day cycles

Daily oral dosages of ARV-471 continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days

vepdegestrant

Daily oral dosages of Samuraciclib continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days

Samuraciclib

Pfizer CT.gov Call Center

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.

Phase 1b will use an escalation/de-escalation approach to determine the RP2D of ARV-471 when administered in combination with samuraciclib. 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).

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 samuraciclib will be evaluated, at the doses selected as recommended dose for expansion (RDE(s)), in a DDI Assessment Cohort(s)

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 C)

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 AND OLDER WITH ER+ ADVANCED OR METASTATIC BREAST CANCER, SUB-STUDY C (ARV-471 IN COMBINATION WITH SAMURACICLIB)

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.

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).

Steady-state Area under the plasma concentration versus time curve (AUCtau) of ARV-471 with and without coadministration of samuraciclib

Steady-state Peak Plasma concentration ( Cmax) of ARV-471 with and without coadministration of 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.

Single dose AUC0-72 of samuraciclib with and without coadministration of ARV 471.

Single dose Cmax of samuraciclib with and without coadministration of ARV 471.

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.

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.

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

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.

To evaluate the plasma exposure of ARV-471 and samuraciclib when ARV-471 and samuraciclib are given in combination.

AUCtau of ARV-471 with and without co-administration of samuraciclib

Cmax of ARV-471 with and without co-administration of samuraciclib

To assess changes from baseline levels in plasma ctDNA with treatment and to evaluate potential predictability of their associations with clinical outcomes.

Participants classified on basis of pathological TP53 mutation detected or not detected.

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

Arvinas Estrogen Receptor, Inc.

Carrick Therapeutics Limited

Pfizer

Antineoplastic Agents

Letrozole

Estrogens

Mitogens

Palbociclib

Aromatase Inhibitors

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Protein Kinase Inhibitors

Participants will receive:

* ARV-471, orally, once daily, continuously, in a 28-day cycle, plus
* Palbociclib, orally, once daily for 21 consecutive days followed by 7 days off treatment in a 28 day cycle

Participants will receive:

* Letrozole, orally, once daily, continuously, in a 28-day cycle, plus
* Palbociclib, orally, once daily for 21 consecutive days followed by 7 days off treatment, in a 28-day cycle.

Pharmaceutical form: Tablets. Route of Administration: Oral

ARV-471 (PF-07850327)

Pharmaceutical form: Capsules. Route of Administration: Oral.

Pharmaceutical form: Capsules. Route of Administration: Orally

The purpose of this study is to understand the safety and effects of the study medicine ARV-471 (PF-07850327) given together with palbociclib in advanced breast cancer. In particular, the study will compare the combination of ARV-471 plus palbociclib to standard of care therapy (letrozole plus palbociclib). Both letrozole and palbociclib are medicines already used for treatment of breast cancer. ARV-471 is a new medicine under study.

This study is seeking participants who have breast cancer that:

* Have a locally advanced or metastatic disease and cannot be fully cured by surgery or radiation therapy. A metastatic disease is when disease has spread to other parts of the body.
* Is sensitive to hormonal therapy such as tamoxifen. This is called estrogen receptor positive disease.
* Have not received any prior medicine for advanced disease. Example medications include tamoxifen or letrozole or exemestane.

The study will have an open-label SLI (study lead-in) before initiation of Phase 3 trial. During SLI, two dose levels of palbociclib in combination with ARV-471 will be explored in parallel. Assignment to the palbociclib dose is by chance. Half of the participant will receive one dose and the other half another palbociclib dose. The purpose of SLI is to determine the recommended Phase 3 dose of palbociclib to be administered in combination with ARV-471.

In the Phase 3, half of the participants will take ARV-471 plus palbociclib while the other half will take letrozole plus palbociclib. In both SLI and Phase 3, participants will take the study medicines by mouth, with food, once a day. Participants will take the study medicines until breast cancer increase in size or side effects become too severe. Side effects refer to unwanted reactions to medications. Participants will visit the study clinic about once every 4 weeks.

The purpose of this study is to demonstrate that ARV-471 in combination with palbociclib provides superior clinical benefit compared to letrozole in combination with palbociclib in participants with ER(+)/HER2(-) aBC who have not received any prior systemic anti-cancer therapies for their locoregionally advanced or metastatic disease. The study will have a Study Lead-in (SLI) and a Phase 3. In the SLI, 50 participants (approximately 25 each arm) will be randomly assigned on a 1:1 basis to one of the two dose levels (DLs). In the randomized Phase 3, approximately 1130 eligible participants (approximately 565 each arm) will be randomized in a 1:1 ratio to the Experimental Arm (ie, ARV-471 plus palbociclib at RP3D determined in the SLI) or Control Arm (ie, letrozole plus palbociclib at the registered doses). Randomization will be stratified by menopausal status at study entry, visceral disease and de novo metastatic disease.

A Study of ARV-471 (PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Negative Advanced Breast Cancer

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)

It is defined as the number of participants with Grade 4 neutropenia AE (graded by NCI CTCAE v.5.0) with onset within the first 4 cycles divided by the number of participants.

It is defined as the number of participants reducing the dose of palbociclib and/or ARV-471 due to any cause occurring within the first 4 cycles divided by the number of participants.

It is defined as the number of participants discontinuing palbociclib and/or ARV-471 due to any cause occurring within the first 4 cycles divided by the number of participants.

Progression-free survival is defined as the time interval from the date of randomization to the date of first documented tumor progression determined by Blinded Independent Central Review (BICR) as per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or death due to any cause, whichever come first.

Objective response rate is defined as the proportion of participants who have a confirmed CR or PR, as best overall response determined by Investigators (SLI) or by BICR (Phase 3) as per RECIST version 1.1, from the date of randomization to the date of disease progression or death due to any cause, whichever occurs first.

Duration of response is defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined by Investigators (SLI) or by BICR (Phase 3) as per RECIST version 1.1 or death due to any cause, whichever occurs first.

Clinical benefit rate is defined as the proportion of participants who have a confirmed CR, PR at any time or SD or non CR/non PD for at least 24 weeks determined by Investigators (SLI) or by BICR (Phase 3) as per RECIST version 1.1, from the date of randomization until disease progression or death due to any cause, whichever occurs first.

Overall survival is defined as the time interval from the date of randomization to the date of documented death, due to any cause.

It is defined as the number of participants with TEAEs and SAEs divided by the number of participants. AEs and SAEs will be graded according to NCI CTCAE V5.0.

It is defined as the number of participants with laboratory abnormalities divided by the number of participants. Laboratory abnormalities will be graded according to NCI CTCAE V5.0.

It is defined as the number of participants with ECG abnormalities divided by the number of participants. ECG abnormalities will be graded according to NCI CTCAE V5.0.

Plasma concentrations of ARV-471 and palbociclib

Change from baseline between treatment comparison in Quality of Life using the EQ-5D 5L questionnaire.

Change from baseline between treatment comparison in Quality of Life using the EORTC QLQ-C30 questionnaire.

Change from baseline between treatment comparison in Quality of Life Using the EORTC QLQ-BR23 (Breast) questionnaire.

Menopause

Anastrozole

Antineoplastic Agents, Hormonal

ARV-471 taken once daily until surgical resection

Anastrozole 1mg taken once daily until surgical resection

ARV-471

Participants will have surgical resection approximately 5.5 months after starting treatment (C6D18 ± 14 days)

Surgical resection of breast tumor

This trial is a Phase 2 neoadjuvant study evaluating ARV-471 or anastrozole in post-menopausal women with ER+/HER2- localized breast cancer.

This is a Phase 2, open-label, randomized, non-comparative proof of concept study of ARV-471 or anastrozole in participants with ER+/HER2- breast cancer amenable to definitive surgical resection. The main goal of this study is to evaluate the biological activity of ARV-471 and anastrozole, respectively.

A Trial Using ARV-471 or Anastrozole in Post-Menopausal Women With Breast Cancer Prior to Surgery

An Open-label, Randomized, Non-comparative Phase 2 Study of ARV-471 or Anastrozole in Post-menopausal Women With ER+/HER2- Breast Cancer in the Neoadjuvant Setting

Percent change in Ki-67 expression between baseline and C1D15 tumor biopsies

Incidence of all adverse events, serious adverse events, and adverse events leading to study drug discontinuation

Pathologic stage at the time of surgical resection

pathologic complete response rate at the time of surgical resection

modified Pre-operative Endocrine Prognostic Index score at the time of surgical resection

radiographical response rate in the primary tumor during cycle 6

Best percentage change from baseline up to C6D1 in caliper measurement of the primary tumor

Arvinas Inc.

vepdegestrant administered orally once daily (QD) continuously and PF-07220060 administered orally twice daily (BID) continuously on 28-day cycles

Daily oral dosages of vepdegestrant continuously, dose escalation/de-escalation in Phase 1b until recommended phase 2 dose (RP2D) determined, cycles lasting 28 days

Daily oral dosages of PF-07220060 continuously, dose escalation/de-escalation in Phase 1b until recommended phase 2 dose (RP2D) determined, cycles lasting 28 days

PF-07220060

The purpose of this study is to learn about the safety and effects of giving vepdegestrant along with PF-07220060. 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.

All the participants will receive vepdegestrant and PF-07220060. Both medicines will be taken 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 medicines are safe and effective. Participants will continue to take vepdegestrant and PF-07220060 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.

C4891026 is a prospective, open-label, multicenter, Phase 1b/2 study to evaluate the safety, antitumor activity, and pharmacokinetic (PK) of vepdegestrant in combination with PF-07220060 in the treatment of participants with Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Advanced or Metastatic Breast Cancer.

Phase 1b will use an escalation/de-escalation approach to determine the recommended phase 2 dose (RP2D) of vepdegestrant when administered in combination with PF-07220060. The decision to escalate the starting dose level of vepdegestrant will be using mTPI-2 decision criteria based on the number of dose limiting toxicity (DLT)-evaluable participants and the number of DLTs in those participants during the DLT observation period (Cycle 1).

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

A Study to Learn About Vepdegestrant When Given With PF-07220060 to People With Advanced or Metastatic Breast Cancer.

AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF VEPDEGESTRANT (ARV-471/PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH PF-07220060 IN PARTICIPANTS AGED 18 YEARS AND OLDER WITH ER+/HER2- ADVANCED OR METASTATIC BREAST CANCER

Dose Limiting Toxicities (DLTs) rate for Vepdegestrant in combination with PF-07220060, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1).

An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. A severe adverse event (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. A 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 CTCAE version 5.0 and coded using MedDRA were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling; and Grade 5=death.

Blood samples were collected for the analysis of the following hematology and coagulation parameters: hemoglobin \[g/L\], platelets, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils \[10\^9/L\]; partial thromboplastin time prolonged and prothrombin time \[seconds\]; international normalized ratio increased. Number of participants with hematological and coagulation abnormalities by grade as per Common Terminology Criteria for Adverse Events (CTCAE version 5.0) were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe; 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.

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 hematological and coagulation abnormalities by grade as per Common Terminology Criteria for Adverse Events (CTCAE version 5.0) were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling; Grade 5=death. For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.

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).

"An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. A severe adverse event (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. A 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 CTCAE version 5.0 and coded using MedDRA where reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=life-threatening or disabling; and Grade 5=death."

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 and prothrombin time \[seconds\]; international normalized ratio increased. Number of participants with hematological and coagulation abnormalities by grade as per Common Terminology Criteria for Adverse Events (CTCAE version 5.0) were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe; 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.

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 hematological and coagulation abnormalities by grade as per Common Terminology Criteria for Adverse Events (CTCAE version 5.0) were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe; 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.

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).

To evaluate the plasma exposure of vepdegestrant, ARV-473, and PF-07220060 when vepdegestrant and PF-07220060 are given in combination.

Steady-state Cmax (maximum observed serum concentration of drug \[Micrograms per milliliter\]) of vepdegestrant, ARV-473, and PF-07220060.

Steady-state Tmax (time taken (in hours) to reach the maximum serum drug concentration) of vepdegestrant, ARV-473, and PF-07220060.

Steady-state AUClast (Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) of vepdegestrant, ARV-473, and PF-07220060.

To assess changes from baseline levels in plasma circulating tumor DNA (ctDNA) with treatment and to evaluate potential predictability of their associations with clinical outcomes.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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 C)	NCT06125522	Breast Cancer	vepdegestrant Samuraciclib	18 Years -	Pfizer
A Study of ARV-471 (PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Negative Advanced Breast Cancer	NCT05909397	Breast Cancer	ARV-471 (PF-078... Palbociclib Letrozole Palbociclib	18 Years -	Pfizer
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 C)	NCT06125522	Breast Cancer	vepdegestrant Samuraciclib	18 Years -	Pfizer
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 C)	NCT06125522	Breast Cancer	vepdegestrant Samuraciclib	18 Years -	Pfizer
A Study of ARV-471 (PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Negative Advanced Breast Cancer	NCT05909397	Breast Cancer	ARV-471 (PF-078... Palbociclib Letrozole Palbociclib	18 Years -	Pfizer
A Trial Using ARV-471 or Anastrozole in Post-Menopausal Women With Breast Cancer Prior to Surgery	NCT05549505	Breast Cancer	ARV-471 Anastrozole Surgical resect...	18 Years -	Arvinas Inc.
A Study to Learn About Vepdegestrant When Given With PF-07220060 to People With Advanced or Metastatic Breast Cancer.	NCT06206837	Breast Cancer	vepdegestrant PF-07220060	18 Years -	Pfizer

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