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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: ARV-471
* Drug: ARV-471 in combination with palbociclib (IBRANCE®)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARV-471<br>Parts A and B: ARV-471 administered QD or BID for 28 day cycles. | Drug: ARV-471<br>* Parts A and B: ARV-471 administered QD or BID for 28 day cycles.<br>|
| Experimental: ARV-471 and palbociclib (IBRANCE®)<br>Part C: Daily oral dosages of ARV-471 for 28 days in combination with palbociclib (IBRANCE®) for 21 days. | Drug: ARV-471 in combination with palbociclib (IBRANCE®)<br>* Part C: Daily oral dosages of ARV-471 for 28 days in combination with palbociclib (IBRANCE®) for 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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] | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Metastatic Breast Cancer, Malignant Neoplasm of the Breast, mBC, ER+/HER2-, Locally Advanced Breast Cancer, ARV-471, Vepdegestrant, Palbociclib, Ibrance