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

NCT04072952 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: ARV-471-mBC-101C4891019
• Study Type: interventional
• Target: 219
• Locations: 1 country
• Sites: 16

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.

Conditions

Breast Cancer

Keywords

Breast Cancer; Metastatic Breast Cancer; Malignant Neoplasm of the Breast; mBC; ER+/HER2-; Locally Advanced Breast Cancer; ARV-471; Vepdegestrant; Palbociclib; Ibrance

Outcome Measures

Primary Outcomes (6)

• Part A: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment

  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.

  Baseline (Day 1) up to C1D28

• Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-Related TEAEs

  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.

  From start of study treatment up to 30 days after end of study treatment (up to approximately 4 years and 6 months)

• Part B: Clinical Benefit Rate (CBR)

  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.

  From start of study treatment until disease progression or death due to any cause (up to approximately 2 years and 11 months)

• Part C: Number of Participants With Dose Limiting Toxicities (DLTs) During First Cycle of Treatment

  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.

  Baseline (Day 1) up to C1D28

• Part C: Number of Participants With TEAEs, Serious TEAEs and Treatment-Related TEAEs

  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.

  From start of study treatment up to 30 days after end of study treatment (up to approximately 3 years and 9 months)

• Part C: Maximum Tolerated Dose (MTD)

  MTD is the highest dose of a drug that can be given to participants without causing unacceptable DLTs, as determined during a clinical study.

  Baseline (Day 1) up to C1D28

Secondary Outcomes (38)

• 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: 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

Study Arms (16)

Part A - Phase 1: Vepdegestrant 30 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 60 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 100 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 120 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 180 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 200 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 360 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 500 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part A - Phase 1: Vepdegestrant 700 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part B - Phase 2: Vepdegestrant 200 mg (Dose Expansion)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part B - Phase 2: Vepdegestrant 500 mg (Dose Expansion)

EXPERIMENTAL

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.

Drug: Vepdegestrant

Part C - Phase 1b: Vepdegestrant 180 mg+ Palbociclib 125 mg (Dose Escalation)

EXPERIMENTAL

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).

Drug: Vepdegestrant; Drug: Palbociclib

Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 125 mg (Dose Expansion)

EXPERIMENTAL

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.

Drug: Vepdegestrant; Drug: Palbociclib

Part C - Phase 1b: Vepdegestrant 400 mg + Palbociclib 125 mg (Dose Escalation)

EXPERIMENTAL

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.

Drug: Vepdegestrant; Drug: Palbociclib

Part C - Phase 1b: Vepdegestrant 500 mg + Palbociclib 125 mg (Dose Expansion)

EXPERIMENTAL

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.

Drug: Vepdegestrant; Drug: Palbociclib

Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg (Dose Expansion)

EXPERIMENTAL

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.

Drug: Vepdegestrant; Drug: Palbociclib

Interventions

Vepdegestrant DRUG

Vepdegestrant administered QD for 28-day cycles

Also known as: ARV-471

Part A - Phase 1: Vepdegestrant 100 mg (Dose Escalation); Part A - Phase 1: Vepdegestrant 120 mg (Dose Escalation); Part A - Phase 1: Vepdegestrant 180 mg (Dose Escalation); Part A - Phase 1: Vepdegestrant 200 mg (Dose Escalation); Part A - Phase 1: Vepdegestrant 30 mg (Dose Escalation); Part A - Phase 1: Vepdegestrant 360 mg (Dose Escalation); Part A - Phase 1: Vepdegestrant 60 mg (Dose Escalation); Part B - Phase 2: Vepdegestrant 200 mg (Dose Expansion); Part B - Phase 2: Vepdegestrant 500 mg (Dose Expansion); Part C - Phase 1b: Vepdegestrant 180 mg+ Palbociclib 125 mg (Dose Escalation); Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg (Dose Expansion); Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 125 mg (Dose Expansion); Part C - Phase 1b: Vepdegestrant 400 mg + Palbociclib 125 mg (Dose Escalation); Part C - Phase 1b: Vepdegestrant 500 mg + Palbociclib 125 mg (Dose Expansion)

Palbociclib DRUG

Daily oral dosages of vepdegestrant for 28 days in combination with palbociclib for 21 days

Also known as: IBRANCE®

Part C - Phase 1b: Vepdegestrant 180 mg+ Palbociclib 125 mg (Dose Escalation); Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg (Dose Expansion); Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 125 mg (Dose Expansion); Part C - Phase 1b: Vepdegestrant 400 mg + Palbociclib 125 mg (Dose Escalation); Part C - Phase 1b: Vepdegestrant 500 mg + Palbociclib 125 mg (Dose Expansion)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Arvinas Estrogen Receptor, Inc.: lead
• Pfizer: collaborator

Study Sites (16)

Clinical Trial Site

Palo Alto, California, 94304, United States

Location

Clinical Trial Site

San Francisco, California, 94158, United States

Location

Clinical Trial Site

Santa Monica, California, 90404, United States

Location

Clinical Trial Site

Norwalk, Connecticut, 06856, United States

Location

Clinical Trial Site

Fort Myers, Florida, 33901, United States

Location

Clinical Trial Site

Tampa, Florida, 33612, United States

Location

Clinical Trial Site

Chicago, Illinois, 60637, United States

Location

Clinical Trial Site

Boston, Massachusetts, 02114, United States

Location

Clinical Trial Site

Boston, Massachusetts, 02215, United States

Location

Clinical Trial Site

Ann Arbor, Michigan, 48109, United States

Location

Clinical Trial Site

St Louis, Missouri, 63110, United States

Location

Clinical Trial Site

East Brunswick, New Jersey, 08816, United States

Location

Clinical Trial Site

The Bronx, New York, 10461, United States

Location

Clinical Trial Site

Charlotte, North Carolina, 28204, United States

Location

Clinical Trial Site

Nashville, Tennessee, 37203, United States

Location

Clinical Trial Site

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Arvinas Operations, Inc
• Organization: Arvinas Operations, Inc

clinicaltrialsARV-471@arvinas.com

+1 475-234-5733

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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®)

Study Record Dates

• First Submitted: August 27, 2019
• First Posted: August 28, 2019
• Study Start: September 22, 2019
• Primary Completion: September 13, 2024
• Study Completion: March 5, 2026
• Last Updated: September 29, 2026
• Results First Posted: September 29, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (16)