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

Phase 2Active Not RecruitingNCT04072952

Arvinas Estrogen Receptor, Inc.217 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

217

Conditions

Breast Cancer

Interventions

ARV-471DRUG

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

ARV-471 in combination with palbociclib (IBRANCE®)DRUG

Part C: Daily oral dosages of ARV-471 for 28 days in combination with palbociclib (IBRANCE®) for 21 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 immunohistochemistry (IHC) testing and pharmacodynamics (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.

Locations (16)

Clinical Trial Site

Palo Alto, California, United States

Clinical Trial Site

San Francisco, California, United States

Clinical Trial Site

Santa Monica, California, United States

Clinical Trial Site

Norwalk, Connecticut, United States

Clinical Trial Site

Fort Myers, Florida, United States

Clinical Trial Site

Tampa, Florida, United States

Clinical Trial Site

Chicago, Illinois, United States

Clinical Trial Site

Boston, Massachusetts, United States

Clinical Trial Site

Boston, Massachusetts, United States

Clinical Trial Site

Ann Arbor, Michigan, United States

...and 6 more locations

Outcomes

Primary Outcomes

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

Time frame: 28 Days

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.

Time frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration

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.

Time frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration

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

Time frame: through study completion, up to approximately 2 years

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

Time frame: 28 Days

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

Time frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration

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

Time frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration

Secondary Outcomes

Part A: Assessment of pharmacokinetic (PK) 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.

Time frame: 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 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.

Time frame: 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).

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.

Time frame: 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).

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.

Time frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of ARV-471

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.

Time frame: through study completion, up to approximately 2 years

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.

Data from ClinicalTrials.gov

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Time frame: through study completion, up to approximately 2 years

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).

Time frame: through study completion, up to approximately 2 years

Part A: Assessment of anti-tumor activity of ARV-471

Anti-tumor activity of ARV-471 will be assessed by evaluating progression free survival.

Time frame: through study completion, up to approximately 2 years

Part A: Assessment of anti-tumor activity of ARV-471

Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response.

Time frame: through study completion, up to approximately 2 years

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.

Time frame: through study completion, up to approximately 2 years

Part B: Assessment of anti-tumor activity of ARV-471

Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response.

Time frame: through study completion, up to approximately 2 years

Part B: Assessment of anti-tumor activity of ARV-471

Anti-tumor activity of ARV-471 will be assessed by evaluating progression-free survival.

Time frame: through study completion, up to approximately 2 years

Part B: Assessment of anti-tumor activity of ARV-471

Anti-tumor activity of ARV-471 will be assessed by evaluating overall survival.

Time frame: through study completion, up to approximately 2 years

Part B: Evaluation of Plasma Concentrations of ARV-471

To characterize the pre-dose 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]

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.

Time frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration

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.

Time frame: First study drug dose through a minimum of 30 calendar Days After Last study drug administration

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.

Time frame: 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).

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

Time frame: 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).

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.

Time frame: 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)

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.

Time frame: At predefined intervals throughout the ARV-471 treatment period, up to approximately 4 weeks after last dose of investigational products

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.

Time frame: through study completion, up to approximately 2 years

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.

Time frame: through study completion, up to approximately 2 years

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.

Time frame: through study completion, up to approximately 2 years