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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)

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ClinicalTrials.gov Identifier: NCT04072952
Recruitment Status : Recruiting
First Posted : August 28, 2019
Last Update Posted : December 14, 2020
Sponsor:
Information provided by (Responsible Party):
Arvinas Inc.

Tracking Information
First Submitted Date  ICMJE August 27, 2019
First Posted Date  ICMJE August 28, 2019
Last Update Posted Date December 14, 2020
Actual Study Start Date  ICMJE August 5, 2019
Estimated Primary Completion Date March 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2020)
  • 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: 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.
  • Part A: 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.
  • Part B: Assessment of anti-tumor activity of ARV-471 [ Time Frame: 28 Days ]
    Clinical benefit response rate based on the summation of CRs, PRs and stable disease of 6 months 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: 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 combination
  • Part C: Incidence of laboratory abnormalities as a measure of safety and tolerability of combination ARV-471 + palbociclib [ Time Frame: 28 Days ]
    Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing
Original Primary Outcome Measures  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2020)
  • Part A: Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC). [ Time Frame: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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 6 months duration or longer.
  • Part A: Assessment of anti-tumor activity of ARV-471 [ Time Frame: 28 Days ]
    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: 28 Days ]
    Anti-tumor activity of ARV-471 will be assessed by evaluating time to event endpoints: progression free survival, duration of response.
  • Part B: Assessment of anti-tumor activity of ARV-471 [ Time Frame: 28 Days ]
    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: 28 Days ]
    Anti-tumor activity of ARV-471 will be assessed by evaluating duration of response, progression-free survival and overall survival.
  • Part B: Evaluation of Safety and Tolerability [ Time Frame: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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 C: Assessment of pharmacokinetic parameter maximum concentration (Cmax). [ Time Frame: 28 Days ]
    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 C: Assessment of pharmacokinetic parameter minimum concentration (Cmin). [ Time Frame: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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: 28 Days ]
    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 6 months duration or longer.
  • Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [ Time Frame: 28 Days ]
    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  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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 and tolerability 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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  ICMJE Breast Cancer
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 10, 2020)
145
Original Estimated Enrollment  ICMJE
 (submitted: August 27, 2019)
36
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date March 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Part A:

  • 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 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.
  • Patients must be willing to undergo a 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 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 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 no more than one prior endocrine therapy in the advanced setting unless the patient recurred during adjuvant treatment or within the 12 months of completion of adjuvant endocrine therapy in which case no prior endocrine therapy is required in the advanced setting.
  • Patients must have received no more than one prior chemotherapy regimen for advanced disease.
  • Women must be postmenopausal due to surgical or natural menopause.

Exclusion Criteria:

Part A:

  • 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.
  • Patients who have received 4 or more regimens of chemotherapy for locally advanced or mBC.
  • 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.

Part B:

  • Patients who have received more than 1 regimen of chemotherapy for locally advanced or mBC.

Part C:

  • Patients have received more than one regimen of chemotherapy for advanced/metastatic disease (regardless of prior adjuvant chemotherapy use) in addition to endocrine therapy.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jennifer Ranciato 475-234-5700 jennifer.ranciato@arvinas.com
Contact: Elmer Berghorn 860-759-9881 elmer.berghorn@arvinas.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04072952
Other Study ID Numbers  ICMJE ARV-471-mBC-101
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  ICMJE
Plan to Share IPD: No
Responsible Party Arvinas Inc.
Study Sponsor  ICMJE Arvinas Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Arvinas Inc.
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP