Brief Summary
This was a Phase 1/2 dose escalation and cohort expansion study and assessed the safety, tolerability and anti-tumor activity of ARV-471 alone and in combination with palbociclib (IBRANCE®) in participants with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) locally advanced or mBC, who had received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting.
Brief Title
A Phase 1/2 Trial of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Participants With ER+/HER2- Locally Advanced or Metastatic Breast Cancer
Categories
Completion Date
Completion Date Type
Actual
Conditions
BREAST CANCER
Eligibility Criteria
Inclusion Criteria:
Part A, Part B, and Part C:
* Participants at least 18 years of age at the time of signing the informed consent.
* Participants must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist.
* Participants must have measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
* Participants must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.)
* Women must be postmenopausal due to surgical or natural menopause.
Part A:
\- Participants must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting.
Part B:
* Participants must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting
* Participants must have received a CDK4/6 inhibitor
* Participants must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
Part C:
* Participants must have received at least one prior endocrine regimen.
* Participants must have received no more than two prior chemotherapy regimens for advanced disease.
Exclusion Criteria:
Part A, Part B, and Part C:
* Participants with known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug, have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable as judged by the Investigator.
* Receipt of prior anti-cancer or other investigational therapy within 14 days prior to the first administration of study drug.
* Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to \>25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.
Part A, Part B, and Part C:
* Participants at least 18 years of age at the time of signing the informed consent.
* Participants must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist.
* Participants must have measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
* Participants must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.)
* Women must be postmenopausal due to surgical or natural menopause.
Part A:
\- Participants must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting.
Part B:
* Participants must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting
* Participants must have received a CDK4/6 inhibitor
* Participants must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
Part C:
* Participants must have received at least one prior endocrine regimen.
* Participants must have received no more than two prior chemotherapy regimens for advanced disease.
Exclusion Criteria:
Part A, Part B, and Part C:
* Participants with known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug, have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable as judged by the Investigator.
* Receipt of prior anti-cancer or other investigational therapy within 14 days prior to the first administration of study drug.
* Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to \>25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.
Inclusion Criteria
Inclusion Criteria:
Part A, Part B, and Part C:
* Participants at least 18 years of age at the time of signing the informed consent.
* Participants must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist.
* Participants must have measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
* Participants must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.)
* Women must be postmenopausal due to surgical or natural menopause.
Part A:
\- Participants must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting.
Part B:
* Participants must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting
* Participants must have received a CDK4/6 inhibitor
* Participants must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
Part C:
* Participants must have received at least one prior endocrine regimen.
* Participants must have received no more than two prior chemotherapy regimens for advanced disease.
Part A, Part B, and Part C:
* Participants at least 18 years of age at the time of signing the informed consent.
* Participants must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist.
* Participants must have measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
* Participants must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.)
* Women must be postmenopausal due to surgical or natural menopause.
Part A:
\- Participants must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting.
Part B:
* Participants must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting
* Participants must have received a CDK4/6 inhibitor
* Participants must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
Part C:
* Participants must have received at least one prior endocrine regimen.
* Participants must have received no more than two prior chemotherapy regimens for advanced disease.
Gender
All
Gender Based
false
Keywords
Breast Cancer
Metastatic Breast Cancer
Malignant Neoplasm of the Breast
mBC
ER+/HER2-
Locally Advanced Breast Cancer
ARV-471
Vepdegestrant
Palbociclib
Ibrance
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT04072952
Org Class
Industry
Org Full Name
Arvinas Inc.
Org Study Id
ARV-471-mBC-101
Overall Status
Completed
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 1/2, Open Label, Dose Escalation, and Cohort Expansion Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Patients With Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Locally Advanced or Metastatic Breast Cancer, Who Have Received Prior Hormonal Therapy and Chemotherapy in the Locally Advanced/Metastatic Setting
Primary Outcomes
Outcome Description
DLT was defined as any adverse event (AE) or abnormal laboratory value which were related to vepdegestrant and assessed as unrelated to mBC, intercurrent illness, or concomitant medications occurring during the first 28 days of treatment that met at least 1 of the study specified criteria.
Outcome Measure
Part A: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment
Outcome Time Frame
Baseline (Day 1) up to C1D28
Outcome Description
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness was judged by investigator. Serious AE (SAE) was an AE resulted in any of the following outcomes: death, inpatient hospitalization or prolongation of existing hospitalization; was life-threatening experience (immediate risk of dying); resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was an AE occurring on/after the date of first dose of study medication and within 30 days of the last dose of study medication. TEAEs included both Serious TEAEs and non-serious TEAEs.
Outcome Measure
Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-Related TEAEs
Outcome Time Frame
From start of study treatment up to 30 days after end of study treatment (up to approximately 4 years and 6 months)
Outcome Description
CBR: percentage of participants with summation of complete response (CR), partial response (PR) or stable disease (SD) of 24 weeks duration or longer. CR: disappearance of all target lesions (TLs) and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the longest diameter (LD) of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.
Outcome Measure
Part B: Clinical Benefit Rate (CBR)
Outcome Time Frame
From start of study treatment until disease progression or death due to any cause (up to approximately 2 years and 11 months)
Outcome Description
DLT was defined as any AE or abnormal laboratory value which were related to vepdegestrant and assessed as unrelated to mBC, intercurrent illness, or concomitant medications occurring during the first 28 days of treatment that met at least 1 of the study specified criteria.
Outcome Measure
Part C: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment
Outcome Time Frame
Baseline (Day 1) up to C1D28
Outcome Description
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness was judged by investigator. SAE was an AE resulted in any of the following outcomes: death, inpatient hospitalization or prolongation of existing hospitalization; was life-threatening experience (immediate risk of dying); resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was an AE occurring on/after the date of first dose of study medication and within 30 days of the last dose of study medication. TEAEs included both Serious TEAEs and non-serious TEAEs.
Outcome Measure
Part C: Number of Participants With TEAEs, Serious TEAEs and Treatment-Related TEAEs
Outcome Time Frame
From start of study treatment up to 30 days after end of study treatment (up to approximately 3 years and 9 months)
Outcome Description
MTD is the highest dose of a drug that can be given to participants without causing unacceptable DLTs, as determined during a clinical study.
Outcome Measure
Part C: Maximum Tolerated Dose (MTD)
Outcome Time Frame
Baseline (Day 1) up to C1D28
Secondary Ids
Secondary Id
C4891019
Secondary Outcomes
Outcome Description
AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1.
Outcome Measure
Part A: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of Vepdegestrant and Its Epimer ARV-473
Outcome Description
AUClast was defined as area under the concentration-time curve from time 0 through the last quantifiable concentration (AUClast). Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Area Under the Concentration-time Curve From Time 0 Through the Last Measurable Concentration (AUClast) of Vepdegestrant and Its Epimer ARV-473
Outcome Description
Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Maximum Observed Plasma Concentration (Cmax) of Vepdegestrant and Its Epimer ARV-473
Outcome Description
Cmin was defined as the minimum observed plasma concentration. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15
Outcome Measure
Part A: Minimum Observed Plasma Concentration (Cmin) of Vepdegestrant and Its Epimer ARV- 473
Outcome Description
CL/F was defined as the apparent oral plasma clearance of vepdegestrant. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15
Outcome Measure
Part A: Apparent Oral Plasma Clearance (CL/F) of Vepdegestrant
Outcome Description
Tmax was defined as the time of maximum observed plasma concentration. Based on predefined reporting convention in the SAP, summary statistics describing variability (median) was not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Time of Maximum Observed Plasma Concentration (Tmax) of Vepdegestrant and Its Epimer ARV- 473
Outcome Description
Rac was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Accumulation Ratio for AUC0-tau (Rac [AUCtau]) of Vepdegestrant and Its Epimer ARV- 473
Outcome Description
Rac was calculated as the ratio of Day 15/Day 1 based on Cmax. Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Accumulation Ratio for Cmax (Rac [Cmax]) of Vepdegestrant and Its Epimer ARV- 473
Outcome Description
Effective half-life based on accumulation ratio of RAUC(0-tau). Accumulation ratio was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Effective Half-life Based on Accumulation Ratio of RAUC(0-tau) of Vepdegestrant and Its Epimer ARV-473
Outcome Description
The epimer ARV-473 to parent ratio based on Cmax was reported. Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Epimer (ARV-473) to Parent (Vepdegestrant) Ratio for Cmax (MRCmax).
Outcome Description
The epimer ARV-473 to parent ratio based on AUCtau was reported. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1
Outcome Measure
Part A: Epimer (ARV-473) to Parent (Vepdegestrant) Ratio for AUCtau (MRAUCtau)
Outcome Description
ORR was defined as the percentage of participants with best overall response (BOR) of CR and PR as per Response Evaluation Criteria in Solid Tumours (RECIST version \[v\] 1.1). BOR: best response was recorded from start of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR was defined as \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Only participants with measurable disease at baseline were included in the analysis of ORR.
Outcome Time Frame
From start of study treatment until disease progression or death due to any cause (up to approximately 4 years and 6 months)
Outcome Measure
Part A: Overall Response Rate (ORR) by Investigator Per RECIST v1.1
Outcome Description
CBR: percentage of participants with summation of CR, PR or SD of 24 weeks duration or longer. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.
Outcome Time Frame
From start of study treatment until disease progression or death due to any cause (up to approximately 4 years and 6 months)
Outcome Measure
Part A: Clinical Benefit Rate (CBR)
Outcome Description
DCR: percentage of participants with CR, PR or SD. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. DCR was based on confirmed responses. Confirmed responses were at least 4 weeks after the criteria for response were first met.
Outcome Time Frame
From start of study treatment up to progressive disease or death (up to approximately 4 years and 6 months)
Outcome Measure
Part A: Disease Control Rate (DCR)
Outcome Description
PFS: time from first dose of the study drug until date of documented radiological PD based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Kaplan-Meier (KM) estimate was used for analysis.
Outcome Time Frame
From start of study treatment up to progressive disease or death (up to approximately 4 years and 6 months)
Outcome Measure
Part A: Progression-Free Survival (PFS) Per RECIST v1.1
Outcome Description
DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of PD or death, whichever occurred first per RECIST version v 1.1. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.
Outcome Time Frame
From the date of first documented confirmed CR/PR to the date of PD or death due to any cause (up to approximately 4 years and 6 months)
Outcome Measure
Part A: Duration of Response
Outcome Description
ORR was defined as the percentage of participants with BOR of CR and PR as per RECIST version \[v\] 1.1. BOR: best response was recorded from start of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR was defined as \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Only participants with measurable disease at baseline were included in the analysis of ORR.
Outcome Time Frame
From start of study treatment until disease progression or death due to any cause (up to approximately 2 years and 11 months)
Outcome Measure
Part B: Overall Response Rate (ORR) by Investigator Per RECIST v1.1
Outcome Description
PFS: time from first dose of the study drug until date of documented radiological PD based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.
Outcome Time Frame
From start of study treatment up to progressive disease or death (up to approximately 2 years and 11 months)
Outcome Measure
Part B: Progression-Free Survival (PFS) Per RECIST v1.1
Outcome Description
DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of PD or death, whichever occurred first per RECIST version v 1.1. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.
Outcome Time Frame
From the date of first documented confirmed CR/PR to the date of PD or death due to any cause (up to approximately 2 years and 11 months)
Outcome Measure
Part B: Duration of Response
Outcome Description
OS was defined as the time from first dose of the study drug until the documented date of death from any cause. KM estimate was used for analysis.
Outcome Time Frame
From start of study treatment up to death (up to approximately 2 years and 11 months)
Outcome Measure
Part B: Overall Survival
Outcome Description
An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness was judged by investigator. SAE was an AE resulted in any of the following outcomes: death, inpatient hospitalization or prolongation of existing hospitalization; was life-threatening experience (immediate risk of dying); resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was an AE occurring on/after the date of first dose of study medication and within 30 days of the last dose of study medication. TEAEs included both Serious TEAEs and non-serious TEAEs.
Outcome Time Frame
From start of study treatment up to 30 days after end of study treatment (up to approximately 2 years and 11 months)
Outcome Measure
Part B: Number of Participants With TEAEs, Serious TEAEs and Treatment-Related TEAEs
Outcome Description
Pre-dose Plasma concentrations of vepdegestrant and ARV-473 was reported. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Predose on C1D15 and C1D28 to C26D28
Outcome Measure
Part B: Pre-dose Concentrations of Vepdegestrant and Its Epimer ARV-473
Outcome Description
AUCtau was calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant \& ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant \& ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for drug-drug interaction (DDI) evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D8, C1D21/C2D15 for palbociclib 100 mg arms.
Outcome Measure
Part C: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D8, C1D21/C2D15 for palbociclib 100 mg arms.
Outcome Measure
Part C: Area Under the Concentration-time Curve From Time 0 Through the Last Measurable Concentration (AUClast) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D8, C1D21/C2D15 for palbociclib 100 mg arms.
Outcome Measure
Part C: Maximum Observed Plasma Concentration (Cmax) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
Cmin was defined as the minimum observed plasma concentration. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15 for arms with palbociclib 125 mg. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D8, C1D21/C2D15 for arm with palbociclib 100 mg.
Outcome Measure
Part C: Minimum Observed Plasma Concentration (Cmin) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
As planned for Part C, PK data of vepdegestrant and palbociclib for arms administered with 125 mg palbociclib was reported for C1D15. PK data of vepdegestrant data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15 for arms with palbociclib 125 mg. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D8, C1D21/C2D15 for arm with palbociclib 100 mg.
Outcome Measure
Part C: Apparent Oral Plasma Clearance (CL/F) of Vepdegestrant and Palbociclib
Outcome Description
Tmax was defined as the time of maximum observed plasma concentration. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D8, C1D21/C2D15 for palbociclib 100 mg arms.
Outcome Measure
Part C: Time of Maximum Observed Plasma Concentration (Tmax) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
Rac was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. As prespecified, participants in the Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg Arm were not assessed. Based on the predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms.
Outcome Measure
Part C: Accumulation Ratio for AUC0-tau (Rac [AUCtau]) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
Rac was calculated as the ratio of Day 15/Day 1 based on Cmax. Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. As prespecified, participants in the Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg Arm were not assessed. Based on the predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms.
Outcome Measure
Part C: Accumulation Ratio for Cmax (Rac [Cmax]) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
Effective half-life based on accumulation ratio of RAUC(0-tau). Accumulation ratio was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. Based on the predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12, 24 hours post dose on C1D15 for arms with palbociclib 125 mg (each cycle is of 28 days)
Outcome Measure
Part C: Effective Half-life Based on Accumulation Ratio of RAUC(0-tau) (Effective T1/2) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib
Outcome Description
Epimer ARV-473 to parent ratio based on Cmax was reported. Cmax was defined as the maximum observed plasma concentration obtained from the observed concentration versus time data. As planned for Part C, PK data of vepdegestrant, ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1/C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21/C2D15. As per protocol, in 100 mg palbociclib administered arm, intensive PK sample collection not done on C1D21 was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D21/C2D15 for palbociclib 100 mg arms.
Outcome Measure
Part C: Epimer (ARV-473) to Parent (Vepdegestrant) Compound Molar Ratio for Cmax (MRCmax)
Outcome Description
Epimer ARV-473 to parent ratio based on AUCtau was reported. AUCtau was calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.
Outcome Time Frame
Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D1 and C1D15, and an additional sample at 24 hours post dose on C1D1 for palbociclib 125 mg arms. Pre-dose, 1, 2, 4, 6, 8 hours post dose on C1D21/C2D15 for palbociclib 100 mg arms.
Outcome Measure
Part C: Epimer (ARV-473) to Parent (Vepdegestrant) Compound Molar Ratio for AUCtau (MRAUCtau)
Outcome Description
ORR was defined as the percentage of participants with BOR of CR and PR as per RECIST version \[v\] 1.1. BOR: best response was recorded from start of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR was defined as \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Only participants with measurable disease at baseline were included in the analysis of ORR.
Outcome Time Frame
From start of study treatment until disease progression or death due to any cause (up to approximately 3 years and 9 months)
Outcome Measure
Part C: Overall Response Rate (ORR) by Investigator Per RECIST v1.1
Outcome Description
CBR: percentage of participants with summation of CR, PR or SD of 24 weeks duration or longer. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.
Outcome Time Frame
From start of study treatment until disease progression or death due to any cause (up to approximately 3 years and 9 months)
Outcome Measure
Part C: Clinical Benefit Rate (CBR)
Outcome Description
PFS: time from first dose of the study drug until date of documented radiological PD based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.
Outcome Time Frame
From start of study treatment up to progressive disease or death (up to approximately 3 years and 9 months)
Outcome Measure
Part C: Progression-Free Survival (PFS) Per RECIST v1.1
Outcome Description
OS was defined as the time from first dose of the study drug until the documented date of death from any cause. KM estimate was used for analysis.
Outcome Time Frame
From start of study treatment up to death (up to approximately 3 years and 9 months)
Outcome Measure
Part C: Overall Survival
Outcome Description
DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of PD or death, whichever occurred first per RECIST version v 1.1. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: \>30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: \>20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.
Outcome Time Frame
From the date of first documented confirmed CR/PR to the date of PD or death due to any cause (up to approximately 3 years and 9 months)
Outcome Measure
Part C: Duration of Response
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jesus Anampa Mesias
Investigator Email
janampa@montefiore.org
Investigator Phone
718-920-4826/718-405-8505/646-757-0997
Categories Mesh Debug
Breast Cancer --- BREAST NEOPLASMS
Cancer --- NEOPLASMS BY SITE
Cancer --- NEOPLASMS
MeSH Terms
BREAST NEOPLASMS
NEOPLASMS BY SITE
NEOPLASMS
BREAST DISEASES
SKIN DISEASES
SKIN AND CONNECTIVE TISSUE DISEASES
PALBOCICLIB