Breast Cancer
Conditions
Keywords
Breast Cancer, Metastatic Breast Cancer, Malignant Neoplasm of the Breast, mBC, ER+/HER2-, Locally Advanced Breast Cancer, ARV-471, Vepdegestrant, Palbociclib, Ibrance
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.
Interventions
DRUGVepdegestrant
Vepdegestrant administered QD for 28-day cycles
DRUGPalbociclib
Daily oral dosages of vepdegestrant for 28 days in combination with palbociclib for 21 days
Sponsors
Arvinas Estrogen Receptor, Inc.
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subsequent dose level is determined by the Cohort Review Committee after the initial starting dose cohort and each subsequent dose cohort completes the first 28 days of treatment Dose escalation followed by expansion at a Recommended Phase 2 Dose (RP2D) including a combination cohort with palbociclib (IBRANCE®)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment | Baseline (Day 1) up to C1D28 | 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. |
| Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-Related TEAEs | From start of study treatment up to 30 days after end of study treatment (up to approximately 4 years and 6 months) | 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. |
| Part B: Clinical Benefit Rate (CBR) | From start of study treatment until disease progression or death due to any cause (up to approximately 2 years and 11 months) | 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. |
| Part C: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment | Baseline (Day 1) up to C1D28 | 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. |
| Part C: Number of Participants With TEAEs, Serious TEAEs and Treatment-Related TEAEs | From start of study treatment up to 30 days after end of study treatment (up to approximately 3 years and 9 months) | 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. |
| Part C: Maximum Tolerated Dose (MTD) | Baseline (Day 1) up to C1D28 | MTD is the highest dose of a drug that can be given to participants without causing unacceptable DLTs, as determined during a clinical study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of Vepdegestrant and Its Epimer ARV-473 | 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. | 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. |
| Part A: Area Under the Concentration-time Curve From Time 0 Through the Last Measurable Concentration (AUClast) of Vepdegestrant and Its Epimer ARV-473 | 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 | 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. |
| Part A: Maximum Observed Plasma Concentration (Cmax) of Vepdegestrant and Its Epimer ARV-473 | 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 | 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. |
| Part A: Minimum Observed Plasma Concentration (Cmin) of Vepdegestrant and Its Epimer ARV- 473 | Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15 | 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. |
| Part A: Apparent Oral Plasma Clearance (CL/F) of Vepdegestrant | Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15 | 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. |
| Part A: Time of Maximum Observed Plasma Concentration (Tmax) of Vepdegestrant and Its Epimer ARV- 473 | 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 | 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. |
| Part A: Accumulation Ratio for AUC0-tau (Rac [AUCtau]) of Vepdegestrant and Its Epimer ARV- 473 | 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 | 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. |
| Part A: Accumulation Ratio for Cmax (Rac [Cmax]) of Vepdegestrant and Its Epimer ARV- 473 | 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 | 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. |
| Part A: Effective Half-life Based on Accumulation Ratio of RAUC(0-tau) of Vepdegestrant and Its Epimer ARV-473 | 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 | 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. |
| Part A: Epimer (ARV-473) to Parent (Vepdegestrant) Ratio for Cmax (MRCmax). | 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 | 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. |
| Part A: Epimer (ARV-473) to Parent (Vepdegestrant) Ratio for AUCtau (MRAUCtau) | 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 | 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. |
| Part A: Overall Response Rate (ORR) by Investigator Per RECIST v1.1 | From start of study treatment until disease progression or death due to any cause (up to approximately 4 years and 6 months) | 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. |
| Part A: Clinical Benefit Rate (CBR) | From start of study treatment until disease progression or death due to any cause (up to approximately 4 years and 6 months) | 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. |
| Part A: Disease Control Rate (DCR) | From start of study treatment up to progressive disease or death (up to approximately 4 years and 6 months) | 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. |
| Part A: Progression-Free Survival (PFS) Per RECIST v1.1 | From start of study treatment up to progressive disease or death (up to approximately 4 years and 6 months) | 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. |
| Part A: Duration of Response | 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) | 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. |
| Part B: Overall Response Rate (ORR) by Investigator Per RECIST v1.1 | From start of study treatment until disease progression or death due to any cause (up to approximately 2 years and 11 months) | 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. |
| Part B: Progression-Free Survival (PFS) Per RECIST v1.1 | From start of study treatment up to progressive disease or death (up to approximately 2 years and 11 months) | 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. |
| Part B: Duration of Response | 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) | 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. |
| Part B: Overall Survival | From start of study treatment up to death (up to approximately 2 years and 11 months) | 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. |
| Part B: Number of Participants With TEAEs, Serious TEAEs and Treatment-Related TEAEs | From start of study treatment up to 30 days after end of study treatment (up to approximately 2 years and 11 months) | 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. |
| Part B: Pre-dose Concentrations of Vepdegestrant and Its Epimer ARV-473 | Predose on C1D15 and C1D28 to C26D28 | 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. |
| Part C: Area Under the Concentration-Time Curve During a Dosing Interval (AUCtau) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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. | 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. |
| 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 | 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. | 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. |
| Part C: Maximum Observed Plasma Concentration (Cmax) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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. | 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. |
| Part C: Minimum Observed Plasma Concentration (Cmin) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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. | 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. |
| Part C: Apparent Oral Plasma Clearance (CL/F) of Vepdegestrant and Palbociclib | 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. | 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. |
| Part C: Time of Maximum Observed Plasma Concentration (Tmax) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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. | 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. |
| Part C: Accumulation Ratio for AUC0-tau (Rac [AUCtau]) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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. | 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. |
| Part C: Accumulation Ratio for Cmax (Rac [Cmax]) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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. | 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. |
| Part C: Effective Half-life Based on Accumulation Ratio of RAUC(0-tau) (Effective T1/2) of Vepdegestrant, Its Epimer ARV-473 and Palbociclib | 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) | 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. |
| Part C: Epimer (ARV-473) to Parent (Vepdegestrant) Compound Molar Ratio for Cmax (MRCmax) | 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. | 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. |
| Part C: Epimer (ARV-473) to Parent (Vepdegestrant) Compound Molar Ratio for AUCtau (MRAUCtau) | 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. | 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. |
| Part C: Overall Response Rate (ORR) by Investigator Per RECIST v1.1 | From start of study treatment until disease progression or death due to any cause (up to approximately 3 years and 9 months) | 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. |
| Part C: Clinical Benefit Rate (CBR) | From start of study treatment until disease progression or death due to any cause (up to approximately 3 years and 9 months) | 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. |
| Part C: Progression-Free Survival (PFS) Per RECIST v1.1 | From start of study treatment up to progressive disease or death (up to approximately 3 years and 9 months) | 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. |
| Part C: Overall Survival | From start of study treatment up to death (up to approximately 3 years and 9 months) | 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. |
| Part C: Duration of Response | 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) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+, HER2-) locally Advanced or Metastatic Breast Cancer (mBC) who had received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting were enrolled at sites in the United States (US).
Pre-assignment details
Results have been reported until data cutoff 08-Feb-2024 for Parts A and B; 22-Nov-2024 for Part C. Full data sets will be reported by 05 March 2027.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.07 years STANDARD_DEVIATION 10.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 191 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 0 / 3 | 4 / 15 | 5 / 7 | 5 / 7 | 4 / 8 | 7 / 15 | 15 / 22 | 2 / 4 | 12 / 35 | 14 / 36 | 0 / 2 | 6 / 21 | 1 / 3 | 13 / 21 | 4 / 17 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 14 / 14 | 7 / 7 | 7 / 7 | 8 / 8 | 15 / 15 | 21 / 22 | 3 / 4 | 32 / 35 | 34 / 36 | 2 / 2 | 21 / 21 | 3 / 3 | 20 / 20 | 17 / 17 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 3 / 14 | 0 / 7 | 0 / 7 | 1 / 8 | 2 / 15 | 2 / 22 | 1 / 4 | 6 / 35 | 5 / 36 | 1 / 2 | 8 / 21 | 1 / 3 | 4 / 20 | 6 / 17 |
Outcome results
None listed