Breast Cancer
Conditions
Keywords
Proteolysis Targeting Chimera (PROTAC), metastatic breast cancer
Brief summary
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.
Detailed description
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.
Interventions
DRUGvepdegestrant
Daily oral dosages of vepdegestrant continuously, dose escalation/de-escalation in Phase 1b until recommended phase 2 dose (RP2D) determined, cycles lasting 28 days
DRUGPF-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
Sponsors
Pfizer
Arvinas Estrogen Receptor, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs): Phase 1b | Cycle 1 (28 days) | Hematological DLT: neutropenic fever; Grade\>=3 thrombocytopenia associated with Grade\>=2(clinically significant)bleeding and Grade4 neutropenia/thrombocytopenia lasting \<7 days. Non-hematological: Grade\>=3 toxicities clinically significant,except those that were not been maximally treated;Grade 2 aspartate aminotransferase(AST), alanine aminotransferase(ALT)/alkaline phosphatase(ALP) levels at baseline as result of liver/bone metastasis,AST,ALT and ALP level\>8\*baseline/AST/ALT \>5\*baseline for\>=14 days; Hy's Law(concomitant ALT/AST elevation of \>=3\*upper limit of normal \[ULN\], total bilirubin elevation\>=2\*ULN without clear alternative etiology); Grade≥3 electrolyte abnormality with clinical sequelae; QTcF prolongation:any Grade\>=3 QT prolongation without clear alternative etiology;any adverse event (AE) attributed to Vepdegestrant and/or PF-07220060 resulting in failure to deliver 75% of doses for either/both agents and any death not clearly due to underlying disease/extraneous causes. |
| Percentage of Participants With Confirmed Objective Response (OR) by Derived Investigator Assessment: Phase 2 | From the date of first dose of study treatment combination until the first documentation of disease progression (PD), death or start of new anticancer therapy, whichever occurred first (maximum treatment exposure of 9.5 months for Phase 2) | OR was defined as best overall response (BOR) of confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors (RECIST) version (v) 1.1. CR was defined as complete disappearance of all target lesions, except for nodal disease, complete disappearance of all non-target lesions and no new lesions. All nodes, both target and non-target, must decrease to normal (short axis \<10 millimeter \[mm\]). PR was defined as at least a \>=30% decrease from baseline in the sum of diameters of all target lesions. The short diameter was used in the sum for nodal target lesions, while the longest diameter was used in the sum for non-nodal target lesions, all target lesions were assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Treatment Related TEAEs: Phase 1b | From the date of first dose of study treatment combination through study completion | AE: any untoward medical occurrence in clinical study participant, temporally associated with use of study treatment, whether or not considered related to study treatment. Serious adverse event (SAE): any untoward medical occurrence, at any dose met one or more of following criteria: death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or other important medical events. AEs includes both SAEs and all other AEs (non-SAEs). TEAEs will be those events with onset dates occurring during the on-treatment period. Relatedness to study drug judged by investigator. |
| Number of Participants With Laboratory Abnormalities: Phase 1b | From the date of first dose of study treatment combination through study completion | Laboratory parameters assessed: hemoglobin, platelets, white blood cells (WBC), absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), sodium, potassium, magnesium, chloride, total calcium, total bilirubin, urea or blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), uric acid, glucose (fasted), albumin, phosphorus, lipase and amylase. |
| Number of Participants With Electrocardiogram (ECG) Abnormalities: Phase 1b | From the date of first dose of study treatment combination through study completion | Twelve lead ECGs were measured with the participant in a supine position after at least 5 minutes. |
| Percentage of Participants With Confirmed OR by Derived Investigator Assessment: Phase 1b | From the date of first dose of study treatment combination through study completion | OR was defined as BOR of confirmed CR or PR according to RECIST v 1.1. CR was defined as complete disappearance of all target lesions, except for nodal disease, complete disappearance of all non-target lesions and no new lesions. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). PR was defined as at least a \>=30% decrease from baseline in the sum of diameters of all target lesions. The short diameter was used in the sum for nodal target lesions, while the longest diameter was used in the sum for non-nodal target lesions, all target lesions were assessed. |
| Duration of Response (DOR) by Derived Investigator Assessment: Phase 1b | From the date of first dose of study treatment combination through study completion | DoR: for participants with OR: time from first documentation of CR/PR to first documentation of PD/death. CR: complete disappearance of all target lesions (L), except nodal disease, complete disappearance of all non-target L and no new L. Both target and non-target nodes, must decrease to normal. PR: \>=30% decrease from baseline in sum of diameters of target L. Short diameter used in sum for nodal target L, longest diameter used in sum for non-nodal target L. PD: 20% increase in sum of diameter of target measurable L above smallest sum observed, minimum absolute increase of 5 mm for target L/unequivocal progression of pre-existing L for non-target L. DOR censored on date of last adequate disease assessment for participants who did not have DOR event, discontinued study treatment due to withdrawal of consent prior to event, started new anticancer therapy prior to event, had event after gap of \>2 missing disease assessments, or lost to follow-up. Kaplan-Meier method will be used. |
| Clinical Benefit Response (CBR) by Derived Investigator Assessment: Phase 1b | From the date of first dose of study treatment combination through study completion | CBR was defined as percentage of participants with BOR of confirmed CR or PR at any time, or stable disease (SD) \>=24 weeks as per RECIST v1.1. CR: complete disappearance of all target lesions, except for nodal disease, complete disappearance of all non-target lesions and no new lesions. All nodes, both target and non-target, must decrease to normal (short axis\<10 mm). PR: at least \>=30% decrease from baseline in sum of diameters of all target lesions. Short diameter was used in sum for nodal target lesions, while longest diameter was used in sum for non-nodal target lesions, all target lesions were assessed. SD: did not qualify for CR, PR, PD. All target lesions were assessed. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, minimum absolute increase of 5mm for target lesions/unequivocal progression of pre-existing lesions for non-target lesion. |
| Progression Free Survival (PFS) by Derived Investigator Assessment: Phase 1b | From the date of first dose of study treatment combination through study completion | PFS was 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 occurred first as per RECIST v1.1. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, minimum absolute increase of 5mm for target lesions/unequivocal progression of pre-existing lesions for non-target lesion. PFS was censored on the date of last adequate disease assessment for those who did not have a PFS event, discontinued the study treatment due to withdrawal of consent prior to an event, started a new anticancer therapy prior to an event, had an event after a gap of 2 or more missing disease assessments, or lost to follow-up. Kaplan-Meier method will be used. |
| Plasma Concentration of Vepdegestrant (ARV-471) and Its Epimer ARV-473: Phase 1b | Cycle 1, Day 8: Pre-dose; Cycle 1 Day 15: Pre-dose, 30 minutes, 1, 2, 4 ,6, 8 and 12 hours post-dose; Cycle 2 Days 1 and 15: Pre-dose, anytime between 4 to 8 hour post-dose; Cycles 3, 5, and 7, Day 1: Pre-dose | Plasma concentrations of ARV-471 and its epimer ARV-473 were reported in this outcome measure. |
| Plasma Concentration of PF-07220060: Phase 1b | Pre-dose (0 hour) of Day 8 of Cycle 1; pre-dose (0 hour), 0.5,1,2,4,6,8 and 12 hours post-dose of Day 15 of Cycle 1; Pre-dose (0 hour) and anytime between 4 to 8 hour post-dose of Day 1 and 15 of Cycle 2; Pre-dose (0 hour) of Day 1 of Cycle 3, 5 and 7 | — |
| Steady State Maximum Observed Plasma Concentration (Cmax,ss) of Vepdegestrant (ARV-471) and Its Epimer ARV-473: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | Cmax,ss was the steady-state maximum concentration of ARV-471 after multiple doses and was directly observed from data. ARV-473 is an epimer of ARV-471. |
| Cmax,ss of PF-07220060: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | — |
| Steady State Time to Maximum Plasma Concentration (Tmax,ss) of Vepdegestrant (ARV-471) and Its Epimer ARV-473: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | Tmax,ss was the steady-state time to maximum plasma concentration after multiple doses and was directly observed from data. ARV-473 is an epimer of ARV-471. ARV-473 is an epimer of ARV-471. |
| Tmax,ss of PF-07220060: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | Tmax,ss was the steady-state time to maximum plasma concentration after multiple doses and was directly observed from data. |
| Steady State Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast,ss) of Vepdegestrant (ARV-471) and Its Epimer ARV-473: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | AUClast,ss was defined as area under the plasma concentration time curve from time zero to the last measurable concentration as steady state. AUClast,ss was calculated using linear/log trapezoidal method. |
| AUClast,ss of PF-07220060: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | AUClast,ss was defined as area under the plasma concentration time curve from time zero to the last measurable concentration as steady state. AUClast,ss was calculated using linear/log trapezoidal method. |
| Apparent Total Clearance (CL/F) of Vepdegestrant (ARV-471): Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose administered divided by AUCinf. AUCinf was calculated as AUClast + (Clast/kel), where, AUClast= area under the concentration-time curve from time 0 to time of last measurable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| CL/F of PF-07220060: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose administered divided by AUCinf. AUCinf was calculated as AUClast + (Clast/kel), where, AUClast= area under the concentration-time curve from time 0 to time of last measurable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Apparent Volume of Distribution (Vz/F) of PF-07220060: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | Vz/F was calculated as Dose/(AUCinf \* kel). AUCinf was calculated as AUClast + (Clast/kel), where, AUClast= area under the concentration-time curve from time 0 to time of last measurable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Terminal Half-Life (t1/2) of PF-07220060: Phase 1b | Predose (0 hours), 0.5, 1, 2, 4, 6, 8, and 12 hours post dose on Cycle 1 Day 15 | T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| DOR by Derived Investigator Assessment: Phase 2 | From the date of first dose of study treatment combination through study completion | DOR: for participants with OR: time from first documentation of CR/PR to first documentation of PD/death. CR: complete disappearance of all target lesions (L), except nodal disease, complete disappearance of all non-target L and no new L. Both target and non-target nodes, must decrease to normal. PR: \>=30% decrease from baseline in sum of diameters of target L. Short diameter used in sum for nodal target L, longest diameter used in sum for non-nodal target L. PD: 20% increase in sum of diameter of target measurable L above smallest sum observed, minimum absolute increase of 5 mm for target L/unequivocal progression of pre-existing L for non-target L. DOR censored on date of last adequate disease assessment for participants who did not have DOR event, discontinued study treatment due to withdrawal of consent prior to event, started new anticancer therapy prior to event, had event after gap of \>2 missing disease assessments, or lost to follow-up. Kaplan-Meier method will be used. |
| Percentage of Participants With CBR by Derived Investigator Assessment: Phase 2 | From the date of first dose of study treatment combination through study completion | CBR was defined as percentage of participants with BOR of confirmed CR or PR at any time, or stable disease (SD) \>=24 weeks as per RECIST v1.1. CR: complete disappearance of all target lesions, except for nodal disease, complete disappearance of all non-target lesions and no new lesions. All nodes, both target and non-target, must decrease to normal (short axis\<10 mm). PR: at least \>=30% decrease from baseline in sum of diameters of all target lesions. Short diameter was used in sum for nodal target lesions, while longest diameter was used in sum for non-nodal target lesions, all target lesions were assessed. SD: did not qualify for CR, PR, PD. All target lesions were assessed. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, minimum absolute increase of 5mm for target lesions/unequivocal progression of pre-existing lesions for non-target lesion. |
| PFS by Derived Investigator Assessment: Phase 2 | From the date of first dose of study treatment combination through study completion | PFS was 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 occurred first as per RECIST v1.1. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, minimum absolute increase of 5mm for target lesions/unequivocal progression of pre-existing lesions for non-target lesion. PFS was censored on the date of last adequate disease assessment for those who did not have a PFS event, discontinued the study treatment due to withdrawal of consent prior to an event, started a new anticancer therapy prior to an event, had an event after a gap of 2 or more missing disease assessments, or lost to follow-up. Kaplan-Meier method will be used. |
| Overall Survival (OS): Phase 2 | From the date of first dose of study treatment combination through study completion | OS was defined as the time from the date of first dose of study treatment combination to the date of death due to any cause. Participants last known to be alive were censored at the date of last contact. Kaplan-Meier method will be used. |
| Number of Participants With TEAEs, TESAEs and Treatment Related TEAEs: Phase 2 | From the date of first dose of study treatment combination through study completion | AE: any untoward medical occurrence in clinical study participant, temporally associated with use of study treatment, whether or not considered related to study treatment. SAE: any untoward medical occurrence, at any dose met one or more of following criteria: death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or other important medical events. AEs includes both SAEs and all other AEs (non-SAEs). TEAEs will be those events with onset dates occurring during the on-treatment period. Relatedness to study drug judged by investigator. |
| Number of Participants With ECG Abnormalities: Phase 2 | From the date of first dose of study treatment combination through study completion | Twelve lead ECGs were measured with the participant in a supine position after at least 5 minutes. |
| Number of Participants With Laboratory Abnormalities: Phase 2 | From the date of first dose of study treatment combination through study completion | Laboratory parameters assessed included hemoglobin, platelets, WBC, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils, absolute basophils, ALT, AST, ALP, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, urea or BUN, creatinine, eGFR, uric acid, glucose (fasted), albumin, phosphorus, lipase and amylase. |
| Plasma Concentration of Vepdegestrant (ARV-471) and Its Epimer ARV-473: Phase 2 | Cycle 1, Day 15 and Cycle 2 Days 1 and 15: Pre-dose, anytime between 4 to 8 hour post-dose; Cycles 3, 5, and 7, Day 1: Pre-dose | Plasma concentrations of ARV-471 and its epimer ARV-473 were reported in this outcome measure. |
| Plasma Concentration of PF-07220060: Phase 2 | Cycle 1, Day 15 and Cycle 2 Days 1 and 15: Pre-dose, anytime between 4 to 8 hours post-dose; Cycles 3, 5, and 7, Day 1: Pre-dose | Plasma concentrations of ARV-471 and its epimer ARV-473 were reported in this outcome measure. |
| Change From Baseline in Circulating Tumor Deoxyribonucleic Acid (ctDNA) Plasma Level: Phase 2 | Baseline and up to End of Treatment | — |
Countries
Belgium, Canada, China, France, Japan, Puerto Rico, Spain, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Participant flow
Pre-assignment details
Results are reported at primary completion date. Remaining results will be reported on completion of analysis at study completion date later.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 59.7 Years STANDARD_DEVIATION 11.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 69 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 9 | 0 / 7 | 2 / 27 | 2 / 27 |
| other Total, other adverse events | 9 / 9 | 7 / 7 | 27 / 27 | 27 / 27 |
| serious Total, serious adverse events | 4 / 9 | 1 / 7 | 3 / 27 | 5 / 27 |
Outcome results
None listed