The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.
Clinical Trial Details
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Breast Cancer
Vepdegestrant (ARV-471)*
Vepdegestrant is an investigational compound. Its safety and efficacy have not been established. * Vepdegestrant is being co-developed with Arvinas.
CDK4 Inhibitor
PF-07220060 is an investigational compound. Its safety and efficacy have not been established.
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
Phase 1 /2
NCT06206837
Active enrolling
Locations
United States, Japan, Puerto Rico
Study design
Participant Group/Arm
EXPERIMENTAL: vepdegestrant in combination with PF-07220060
vepdegestrant administered orally once daily (QD) continuously and PF-07220060 administered orally twice daily (BID) continuously on 28-day cycles
Intervention/Treatment
DRUG: vepdegestrant
Daily oral dosages of vepdegestrant continuously, dose escalation/de-escalation in Phase 1b until recommended phase 2 dose (RP2D) determined, cycles lasting 28 days
DRUG: PF-07220060
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
Key eligibility criteria
Inclusion criteria
- Histological or cytological diagnosis of breast cancer. At time of enrollment this must not be amenable to surgical resection with curative intent (≥1% ER+ stained cells as per local practice on the most recent tumor biopsy HER2- tumor by IHC or in-situ hybridization per ASCO/CAP).
prior anticancer therapies: Phase 1b: at least 1 line of SOC for A/MBC; Prior fulvestrant allowed; ≤1 prior chemotherapy line (no antibody-drug conjugates permitted) for A/MBC setting allowed. Phase 2: At least one and maximum 2 lines of ET in A/MBC setting and most recent ET-based regimen for >6 months.
1, and only 1, prior CDK4/6 inhibitor-based regimen required. Up to 1 prior regimen of cytotoxic chemotherapy (no antibody-drug conjugates permitted) in the A/MBC setting; Prior fulvestrant allowed.
- Participant with only non-measurable lesion (Phase1b) or at least 1 measurable lesion as defined by RECIST v1.1. (Phase2) are eligible.
- ECOG PS = 0 or 1 (Phase1b) ; ≤2 (Phase2)
Exclusion criteria
- visceral crisis at risk of life-threatening complications in the short term.
- Any condition precluding an adeguate absorption of study interventions.
- newly diagnosed brain metastases, or symptomatic central nervous system (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 28 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 are excluded
- impaired cardiovascular function or clinically significant cardiovascular diseases.
- concurrent administration of medications, food, or herb supplements that are strong inhibitors/inducers of CYP3A or UGT2B7, moderate inducers of CYP34 (Phase1b only) 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
Key dates
Study start date
- February 2024
Estimated primary completion date
- February 2026
Key endpoints
Primary Outcome Measures
Outcome Measure
Phase 1b: Number of Participants With Dose Limiting Toxicities
Measure Description
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).
Time Frame
28 days
Outcome Measure
Phase 2: Percentage of Participants With Objective Response by investigator assessment
Measure Description
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
Secondary Outcome Measures:
Outcome Measure
Phase 1b and Phase 2: Evaluation of Safety of Vepdegestrant in combination with PF-07220060 (number of participants experiencing any AE, SAE, treatment-related AE and treatment-related SAE)
Measure Description
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.
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Safety of Vepdegestrant in combination with PF-07220060 (number of participants with lab abnormalities - Hematology and coagulation parameters)
Measure Description
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.
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Safety of Vepdegestrant in combination with PF-07220060 (number of participants with lab abnormalities - chemistry parameters)
Measure Description
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.
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Safety of Vepdegestrant in combination with PF-07220060 (number of participants with changes from baseline for ECG parameters)
Measure Description
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).
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Tolerability of Vepdegestrant in combination with PF-07220060 (number of participants experiencing any AE, SAE, treatment-related AE and treatment-related SAE)
Measure Description
"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."
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Tolerability of Vepdegestrant in combination with PF-07220060 (number of participants with lab abnormalities- Hematology and coagulation parameters)
Measure Description
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.
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Tolerability of Vepdegestrant in combination with PF-07220060 (number of participants with lab abnormalities - chemistry parameters)
Measure Description
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.
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b and Phase 2: Evaluation of Tolerability of Vepdegestrant in combination with PF-07220060 (number of participants with changes from baseline for ECG parameters)
Measure Description
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).
Time Frame
First study drug dose through a minimum of 28 Days After Last study drug administration
Outcome Measure
Phase 1b: To evaluate antitumor activity of Vepdegestrant in combination with PF-07220060
Measure Description
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
Outcome Measure
Phase 1b and Phase 2: Duration of Response by investigator assessment.
Measure Description
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
Outcome Measure
Phase 1b and Phase2: Percentage of participants with Clinical Benefit Response by investigator assessment.
Measure Description
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
Outcome Measure
Phase 1b and Phase 2: Progression Free Survival by investigator assessment.
Measure Description
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
Outcome Measure
Phase 1b and Phase 2: Plasma concentrations of Vepdegestrant, ARV-473 and PF-07220060 when given in combination.
Measure Description
To evaluate the plasma exposure of vepdegestrant, ARV-473, and PF-07220060 when vepdegestrant and PF-07220060 are given in combination.
Time Frame
Phase 1b: Pre-dose Day 8; Pre-, 0.5, 1, 2, 4, 6, 8, 12h post-dose Day 15; Pre- and 4-8h post-dose 29; Pre- and 4-8h post-dose Day 43; Pre-dose Days 57, 113 and 169. Phase 2: Pre- and 4-8h post-dose Days 15, 29 and 43; Pre-dose Days 57, 113 and 169
Outcome Measure
Phase 1b: Evaluation of the PK of Vepdegestrant and PF-07220060 when given in combination
Measure Description
Steady-state Cmax (maximum observed serum concentration of drug \[Micrograms per milliliter\]) of vepdegestrant, ARV-473, and PF-07220060.
Time Frame
Phase 1b (a cycle is 28 days): Pre-dose on Day 8 of Cycle 1; Pre-dose, 0.5, 1, 2, 4, 6, 8, 12h post-dose on Day 15 of Cycle 1; Pre-dose and 4-8h on Day 1 of Cycle 2; Pre-dose and 4-8h post-dose on Day 15 of Cycle 2; Pre-dose on Day 1 of Cycles 3, 5 and 7
Outcome Measure
Phase 1b: Evaluation of the PK of Vepdegestrant and PF-07220060 when given in combination
Measure Description
Steady-state Tmax (time taken (in hours) to reach the maximum serum drug concentration) of vepdegestrant, ARV-473, and PF-07220060.
Time Frame
Phase 1b (a cycle is 28 days): Pre-dose on Day 8 of Cycle 1; Pre-dose, 0.5, 1, 2, 4, 6, 8, 12h post-dose on Day 15 of Cycle 1; Pre-dose and 4-8h on Day 1 of Cycle 2; Pre-dose and 4-8h post-dose on Day 15 of Cycle 2; Pre-dose on Day 1 of Cycles 3, 5 and 7
Outcome Measure
Phase 1b: Evaluation of the PK of Vepdegestrant and PF-07220060 when given in combination
Measure Description
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.
Time Frame
Phase 1b (a cycle is 28 days): Pre-dose on Day 8 of Cycle 1; Pre-dose, 0.5, 1, 2, 4, 6, 8, 12h post-dose on Day 15 of Cycle 1; Pre-dose and 4-8h on Day 1 of Cycle 2; Pre-dose and 4-8h post-dose on Day 15 of Cycle 2; Pre-dose on Day 1 of Cycles 3, 5 and 7
Outcome Measure
Phase 2:ctDNA plasma quantitative changes from pre-treatment
Measure Description
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.
Time Frame
Phase 2 (each cycle is 28 days): Pre-dose on Day 1 of Cycles 1, 2 and 3 and after last treatment administration.
Number of participants
65
Collaborators and investigators
Sponsor: Pfizer
Collaborator: Arvinas Estrogen Receptor, Inc.