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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 219
- 试验地点
- 16
- 主要终点
- Part A: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •- 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.
- •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
- •Participants must have received at least one prior endocrine regimen.
- •Participants must have received no more than two prior chemotherapy regimens for advanced disease.
排除标准
- •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.
研究组 & 干预措施
Part A - Phase 1: Vepdegestrant 360 mg (Dose Escalation)
Participants received vepdegestrant 360 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg (Dose Expansion)
Participants initially received palbociclib 100 mg orally QD starting on C1D1, for 21 days followed by 7 days off and then received vepdegestrant 200 mg QD with food on C1D9, given continuously (28-day cycle). Palbociclib was administered alone from C1D1 to C1D8 prior to starting vepdegestrant on C1D9. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Palbociclib (Drug)
Part A - Phase 1: Vepdegestrant 100 mg (Dose Escalation)
Participants received vepdegestrant 100 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part B - Phase 2: Vepdegestrant 200 mg (Dose Expansion)
Participants received vepdegestrant 200 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 30 mg (Dose Escalation)
Participants received vepdegestrant 30 milligrams (mg) orally once daily (QD) with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after the end of treatment (EOT) or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 500 mg (Dose Escalation)
Participants received vepdegestrant 500 mg QD or 250 mg twice daily (BID), orally with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part C - Phase 1b: Vepdegestrant 400 mg + Palbociclib 125 mg (Dose Escalation)
Participants received vepdegestrant 400 mg orally QD with food, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 60 mg (Dose Escalation)
Participants received vepdegestrant 60 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 700 mg (Dose Escalation)
Participants received vepdegestrant 700 mg QD or as BID dose (400 mg in the morning and 300 mg in the evening), orally with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 200 mg (Dose Escalation)
Participants received vepdegestrant 200 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 120 mg (Dose Escalation)
Participants received vepdegestrant 120 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part A - Phase 1: Vepdegestrant 180 mg (Dose Escalation)
Participants received vepdegestrant 180 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part B - Phase 2: Vepdegestrant 500 mg (Dose Expansion)
Participants received vepdegestrant 500 mg orally QD with food in continuous daily dosing (on 28-day cycles). Vepdegestrant was administered in tablet form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 125 mg (Dose Expansion)
Participants received vepdegestrant 200 mg orally QD with food, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Palbociclib (Drug)
Part C - Phase 1b: Vepdegestrant 500 mg + Palbociclib 125 mg (Dose Expansion)
Participants received vepdegestrant 500 mg orally QD with food, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Palbociclib (Drug)
Part C - Phase 1b: Vepdegestrant 180 mg+ Palbociclib 125 mg (Dose Escalation)
Participants initially received vepdegestrant 180 mg tablets orally QD with food then upon availability of the 100-mg tablets was rounded up to 200 mg QD, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed up for survival after at least 3 months after the EOT or Follow-up visit (whichever occurred later).
干预措施: Palbociclib (Drug)
Part C - Phase 1b: Vepdegestrant 180 mg+ Palbociclib 125 mg (Dose Escalation)
Participants initially received vepdegestrant 180 mg tablets orally QD with food then upon availability of the 100-mg tablets was rounded up to 200 mg QD, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed up for survival after at least 3 months after the EOT or Follow-up visit (whichever occurred later).
干预措施: Vepdegestrant (Drug)
Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 125 mg (Dose Expansion)
Participants received vepdegestrant 200 mg orally QD with food, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg (Dose Expansion)
Participants initially received palbociclib 100 mg orally QD starting on C1D1, for 21 days followed by 7 days off and then received vepdegestrant 200 mg QD with food on C1D9, given continuously (28-day cycle). Palbociclib was administered alone from C1D1 to C1D8 prior to starting vepdegestrant on C1D9. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
Part C - Phase 1b: Vepdegestrant 400 mg + Palbociclib 125 mg (Dose Escalation)
Participants received vepdegestrant 400 mg orally QD with food, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Palbociclib (Drug)
Part C - Phase 1b: Vepdegestrant 500 mg + Palbociclib 125 mg (Dose Expansion)
Participants received vepdegestrant 500 mg orally QD with food, given continuously (28-day cycle) in combination with palbociclib 125 mg orally QD for 21 days followed by 7 days off treatment to complete a 28-day cycle. Vepdegestrant was administered in tablet form and palbociclib in capsule form. Treatment was continued at the investigator's discretion until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Participants were followed for survival every 3 months after EOT or Follow-up visit (whichever occurred later) until death, lost to follow-up, or withdrawal of consent.
干预措施: Vepdegestrant (Drug)
结局指标
主要结局
Part A: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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.
Part A: Incidence of Dose Limiting Toxicities of ARV-471
时间窗: 28 Days
First Cycle Dose limiting toxicities characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug
Part A: Number of Patients with Adverse Events as a measure of safety and tolerability of ARV-471
时间窗: First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug.
Part A: Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-471
时间窗: First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.
Part B: Assessment of anti-tumor activity of ARV-471
时间窗: through study completion, up to approximately 2 years
Clinical benefit response rate based on the summation of CRs, PRs and stable disease of 24 weeks duration or longer
Part C: Incidence of Dose Limiting Toxicities of combination ARV-471 + palbociclib
时间窗: 28 Days
First cycle dose-limiting toxicities and determination of a maximum tolerated dose (MTD) if applicable among the doses evaluated
Part C: Number of Patients with Adverse Events as a measure of safety and tolerability of combination ARV-471 + palbociclib
时间窗: First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug combination
Part C: Incidence of laboratory abnormalities as a measure of safety and tolerability of combination ARV-471 + palbociclib
时间窗: First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing
次要结局
- 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.)
- 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))
- 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)
- 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)
- 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)
- Part A: Apparent Oral Plasma Clearance (CL/F) of Vepdegestrant(Pre-dose, 1, 2, 4, 6, 8, 12 (optional) hours post dose on C1D15)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- Part B: Overall Survival(From start of study treatment up to death (up to approximately 2 years and 11 months))
- 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))
- Part B: Pre-dose Concentrations of Vepdegestrant and Its Epimer ARV-473(Predose on C1D15 and C1D28 to C26D28)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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))
- 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.)
- 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.)
- 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))
- 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))
- 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))
- Part C: Overall Survival(From start of study treatment up to death (up to approximately 3 years and 9 months))
- 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))
- Part A: Assessment of pharmacokinetic parameter maximum concentration (Cmax).(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471)
- Part A: Assessment of pharmacokinetic parameter minimum concentration (Cmin).(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471)
- Part A: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax).(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471)
- Part B: Evaluation of Plasma Concentrations of ARV-471(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products])
- Part C:Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC)(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products)
- Part C: Assessment of pharmacokinetic parameter maximum concentration (Cmax).(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products)
- Part C: Assessment of pharmacokinetic parameter minimum concentration (Cmin).(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products)
- Part C: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax)(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products)
- Part A: Assessment of anti-tumor activity of ARV-471(through study completion, up to approximately 2 years)
- Part B: Assessment of anti-tumor activity of ARV-471(through study completion, up to approximately 2 years)
- Part B: Evaluation of Safety and Tolerability(First study drug dose through a minimum of 30 calendar Days After Last study drug administration)
- Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib(through study completion, up to approximately 2 years)
- Part A: Assessment of pharmacokinetic (PK) parameter area under the concentration-time curve (AUC).(At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471)