A Phase 1/2 Trial of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Patients With ER+/HER2- Locally Advanced or Metastatic Breast Cancer (mBC)

• ClinicalTrials.gov Identifier: NCT04072952
• Recruitment Status: Recruiting
• First Posted: August 28, 2019
• Last Update Posted: June 5, 2023
• Sponsor: Arvinas Estrogen Receptor, Inc.
• Collaborator: Pfizer
• Information provided by (Responsible Party): Arvinas Inc. ( Arvinas Estrogen Receptor, Inc. )

Tracking Information

• First Submitted Date: August 27, 2019
• First Posted Date: August 28, 2019
• Last Update Posted Date: June 5, 2023
• Actual Study Start Date: August 5, 2019
• Estimated Primary Completion Date: March 25, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 13, 2022)

• Part A: Incidence of Dose Limiting Toxicities of ARV-471 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

Original Primary Outcome Measures (submitted: August 27, 2019)

• Incidence of Dose Limiting Toxicities of ARV-471 [ Time Frame: 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
• Number of Patients with Adverse Events as a measure of safety and tolerability of ARV-471 [ Time Frame: 28 Days ]
  Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug.
• Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-471 [ Time Frame: 28 Days ]
  Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.

Current Secondary Outcome Measures (submitted: June 2, 2023)

• Part A: Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC). [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471 ]
  Concentration-time curve (AUC) for single and multiple dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.
• Part A: Assessment of pharmacokinetic parameter maximum concentration (Cmax). [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471 ]
  Maximum concentration (Cmax) for single and multiple dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.
• Part A: Assessment of pharmacokinetic parameter minimum concentration (Cmin). [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471 ]
  Minimum concentration (Cmin) for single and multiple dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.
• Part A: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax). [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471 ]
  Time to maximum concentration (Tmax) for single and multiple dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.
• Part A: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating overall response rate per RECIST 1.1.
• Part A: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating clinical benefit response (CBR) rate based on the summation of complete responses (CRs), partial responses (PRs) and stable disease of 24 weeks duration or longer.
• Part A: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating disease control rate (complete response, partial response, stable disease).
• Part A: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating progression free survival.
• Part A: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response.
• Part B: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating overall response rate per RECIST 1.1 in patients with measurable disease at baseline.
• Part B: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response.
• Part B: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating progression-free survival.
• Part B: Assessment of anti-tumor activity of ARV-471 [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 will be assessed by evaluating overall survival.
• Part B: Evaluation of Plasma Concentrations of ARV-471 [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products] ]
  To characterize the pre-dose concentrations of ARV-471.
• Part B: Evaluation of Safety and Tolerability [ Time Frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration ]
  Further evaluation of safety and tolerability of ARV-471 will be based on adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug.
• Part B: Evaluation of Safety and Tolerability [ Time Frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration ]
  Further evaluation of safety and tolerability of ARV-471 will be based on Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.
• Part C:Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC) [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products ]
  Concentration-time curve (AUC) for single and multiple doses of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses, and of palbociclib when given alone and in combination with ARV-471.
• Part C: Assessment of pharmacokinetic parameter maximum concentration (Cmax). [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products ]
  Maximum concentration (Cmax) for single and multiple doses of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses, and of palbociclib when given alone and in combination with ARV-471
• Part C: Assessment of pharmacokinetic parameter minimum concentration (Cmin). [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products ]
  Minimum concentration (Cmin) for single and multiple dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.
• Part C: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax) [ Time Frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products ]
  Time to maximum concentration (Tmax) for single and multiple dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.
• Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 in combination with palbociclib will be assessed by evaluating overall response rate per RECIST 1.1 in patients with measurable disease at baseline.
• Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 in combination with palbociclib will be assessed by evaluating clinical benefit response (CBR) rate based on the summation of complete responses (CRs), partial responses (PRs) and stable disease of 24 weeks duration or longer.
• Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [ Time Frame: through study completion, up to approximately 2 years ]
  Anti-tumor activity of ARV-471 in combination with palbociclib will be assessed by evaluating time to event endpoints: progression free survival, duration of response.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1/2 Trial of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Patients With ER+/HER2- Locally Advanced or Metastatic Breast Cancer
• Official Title: A Phase 1/2, Open Label, Dose Escalation, and Cohort Expansion Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Patients With Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Locally Advanced or Metastatic Breast Cancer, Who Have Received Prior Hormonal Therapy and Chemotherapy in the Locally Advanced/Metastatic Setting
• Brief Summary: This is a Phase 1/2 dose escalation and cohort expansion study and will assess the safety, tolerability and anti-tumor activity 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
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 RP2D including a combination cohort with palbociclib (IBRANCE®)

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Breast Cancer

Intervention

• Drug: ARV-471
  Parts A and B: ARV-471 administered QD or BID for 28 day cycles.
• Drug: ARV-471 in combination with palbociclib (IBRANCE®)
  Part C: Daily oral dosages of ARV-471 for 28 days in combination with palbociclib (IBRANCE®) for 21 days

Study Arms

• Experimental: ARV-471
  Parts A and B: ARV-471 administered QD or BID for 28 day cycles.
  Intervention: Drug: ARV-471
• Experimental: ARV-471 and palbociclib (IBRANCE®)
  Part C: Daily oral dosages of ARV-471 for 28 days in combination with palbociclib (IBRANCE®) for 21 days.
  Intervention: Drug: ARV-471 in combination with palbociclib (IBRANCE®)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 13, 2022): 215
• Original Estimated Enrollment (submitted: August 27, 2019): 36
• Estimated Study Completion Date: September 25, 2024
• Estimated Primary Completion Date: March 25, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Part A, Part B, and Part C:

• Patients at least 18 years of age at the time of signing the informed consent.
• Patients 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.
• Patients must have measurable or non-measurable disease by RECIST criteria (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
• Patients 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 IHC testing and PD 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:

- Patients 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:

• Patients 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
• Patients must have received a CDK4/6 inhibitor
• Patients must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
• Women must be postmenopausal due to surgical or natural menopause.

Part C:

• Patients must have received at least one prior endocrine regimen.
• Patients must have received no more than two prior chemotherapy regimens for advanced disease.
• Women must be postmenopausal due to surgical or natural menopause.

Exclusion Criteria:

Part A, Part B, and Part C:

• Patients 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Arvinas Estrogen Receptor, Inc.; 475-345-3366; clinicaltrialsARV-471@arvinas.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04072952
• Other Study ID Numbers: ARV-471-mBC-101; C4891019 ( Other Identifier: Pfizer )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Arvinas Inc. ( Arvinas Estrogen Receptor, Inc. )
• Original Responsible Party: Arvinas Inc.
• Current Study Sponsor: Arvinas Estrogen Receptor, Inc.
• Original Study Sponsor: Arvinas Inc.
• Collaborators: Pfizer
• Investigators: Not Provided
• PRS Account: Arvinas Inc.
• Verification Date: June 2023