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Snake venom protein C activator

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

vepdegestrant

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

Pfizer CT.gov Call Center

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

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

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.

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).

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 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.

Spots Global Cancer Trial Database for proteolysis targeting chimera (protac)