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

Breast Cancer Clinical Trial

— mBC  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04072952
• Other study ID #: ARV-471-mBC-101
• Secondary ID: C4891019
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: August 5, 2019
• Est. completion date: March 13, 2025

Study information

• Verified date: May 2024
• Source: Arvinas Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 217
• Est. completion date: March 13, 2025
• Est. primary completion date: September 13, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• ARV-471
Parts A and B: ARV-471 administered QD or BID for 28 day cycles.
• 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

Locations

Country	Name	City	State
United States	Clinical Trial Site	Ann Arbor	Michigan
United States	Clinical Trial Site	Boston	Massachusetts
United States	Clinical Trial Site	Boston	Massachusetts
United States	Clinical Trial Site	Bronx	New York
United States	Clinical Trial Site	Charlotte	North Carolina
United States	Clinical Trial Site	Chicago	Illinois
United States	Clinical Trial Site	East Brunswick	New Jersey
United States	Clinical Trial Site	Fort Myers	Florida
United States	Clinical Trial Site	Nashville	Tennessee
United States	Clinical Trial Site	Norwalk	Connecticut
United States	Clinical Trial Site	Palo Alto	California
United States	Clinical Trial Site	Saint Louis	Missouri
United States	Clinical Trial Site	San Francisco	California
United States	Clinical Trial Site	Santa Monica	California
United States	Clinical Trial Site	Seattle	Washington
United States	Clinical Trial Site	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Arvinas Estrogen Receptor, Inc.	Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Incidence of Dose Limiting Toxicities of ARV-471	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	28 Days
Primary	Part A: Number of Patients with Adverse Events as a measure of safety and tolerability of ARV-471	Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug.	First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Primary	Part A: Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-471	Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.	First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Primary	Part B: Assessment of anti-tumor activity of ARV-471	Clinical benefit response rate based on the summation of CRs, PRs and stable disease of 24 weeks duration or longer	through study completion, up to approximately 2 years
Primary	Part C: Incidence of Dose Limiting Toxicities of combination ARV-471 + palbociclib	First cycle dose-limiting toxicities and determination of a maximum tolerated dose (MTD) if applicable among the doses evaluated	28 Days
Primary	Part C: Number of Patients with Adverse Events as a measure of safety and tolerability of combination ARV-471 + palbociclib	Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug combination	First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Primary	Part C: Incidence of laboratory abnormalities as a measure of safety and tolerability of combination ARV-471 + palbociclib	Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing	First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Secondary	Part A: Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC).	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471
Secondary	Part A: Assessment of pharmacokinetic parameter maximum concentration (Cmax).	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471
Secondary	Part A: Assessment of pharmacokinetic parameter minimum concentration (Cmin).	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471
Secondary	Part A: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax).	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471
Secondary	Part A: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating overall response rate per RECIST 1.1.	through study completion, up to approximately 2 years
Secondary	Part A: Assessment of anti-tumor activity of ARV-471	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.	through study completion, up to approximately 2 years
Secondary	Part A: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating disease control rate (complete response, partial response, stable disease).	through study completion, up to approximately 2 years
Secondary	Part A: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating progression free survival.	through study completion, up to approximately 2 years
Secondary	Part A: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response.	through study completion, up to approximately 2 years
Secondary	Part B: Assessment of anti-tumor activity of ARV-471	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.	through study completion, up to approximately 2 years
Secondary	Part B: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response.	through study completion, up to approximately 2 years
Secondary	Part B: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating progression-free survival.	through study completion, up to approximately 2 years
Secondary	Part B: Assessment of anti-tumor activity of ARV-471	Anti-tumor activity of ARV-471 will be assessed by evaluating overall survival.	through study completion, up to approximately 2 years
Secondary	Part B: Evaluation of Plasma Concentrations of ARV-471	To characterize the pre-dose concentrations of ARV-471.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products]
Secondary	Part B: Evaluation of Safety and Tolerability	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.	First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Secondary	Part B: Evaluation of Safety and Tolerability	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.	First study drug dose through a minimum of 30 calendar Days After Last study drug administration
Secondary	Part C:Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC)	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products
Secondary	Part C: Assessment of pharmacokinetic parameter maximum concentration (Cmax).	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	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products
Secondary	Part C: Assessment of pharmacokinetic parameter minimum concentration (Cmin).	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products
Secondary	Part C: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax)	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.	At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products
Secondary	Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib	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.	through study completion, up to approximately 2 years
Secondary	Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib	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.	through study completion, up to approximately 2 years
Secondary	Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib	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.	through study completion, up to approximately 2 years