mBC: 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

• Sponsor: Arvinas Estrogen Receptor, Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04072952
• Collaborator: Pfizer (Industry)
• Enrollment: 215
• Locations: 17
• Arms: 2
• Anticipated Duration (Months): 45.9
• Patients Per Site: 12.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: ARV-471; Drug: ARV-471 in combination with palbociclib (IBRANCE®)	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 215 participants
• 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®)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
• 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
• Actual Study Start Date: Aug 5, 2019
• Anticipated Primary Completion Date: Sep 1, 2022
• Anticipated Study Completion Date: Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ARV-471 Parts A and B: ARV-471 administered QD or BID for 28 day cycles.	Drug: ARV-471; Parts A and B: ARV-471 administered QD or BID for 28 day cycles.
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.	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

Outcome Measures

Primary Outcome Measures

1. Part A: Incidence of Dose Limiting Toxicities of ARV-471 [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

2. Part A: Number of Patients with Adverse Events as a measure of safety and tolerability of ARV-471 [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.

3. Part A: Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-471 [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.

4. Part B: Assessment of anti-tumor activity of ARV-471 [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

5. Part C: Incidence of Dose Limiting Toxicities of combination ARV-471 + palbociclib [28 Days]

   First cycle dose-limiting toxicities and determination of a maximum tolerated dose (MTD) if applicable among the doses evaluated

6. Part C: Number of Patients with Adverse Events as a measure of safety and tolerability of combination ARV-471 + palbociclib [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

7. Part C: Incidence of laboratory abnormalities as a measure of safety and tolerability of combination ARV-471 + palbociclib [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

Secondary Outcome Measures

1. Part A: Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC). [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.

2. Part A: Assessment of pharmacokinetic parameter maximum concentration (Cmax). [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.

3. Part A: Assessment of pharmacokinetic parameter minimum concentration (Cmin). [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.

4. Part A: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax). [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.

5. Part A: Assessment of anti-tumor activity of ARV-471 [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.

6. Part A: Assessment of anti-tumor activity of ARV-471 [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.

7. Part A: Assessment of anti-tumor activity of ARV-471 [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).

8. Part A: Assessment of anti-tumor activity of ARV-471 [through study completion, up to approximately 2 years]

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

9. Part A: Assessment of anti-tumor activity of ARV-471 [through study completion, up to approximately 2 years]

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

10. Part B: Assessment of anti-tumor activity of ARV-471 [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.

11. Part B: Assessment of anti-tumor activity of ARV-471 [through study completion, up to approximately 2 years]

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

12. Part B: Assessment of anti-tumor activity of ARV-471 [through study completion, up to approximately 2 years]

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

13. Part B: Assessment of anti-tumor activity of ARV-471 [through study completion, up to approximately 2 years]

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

14. Part B: Evaluation of Plasma Concentrations of ARV-471 [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.

15. Part B: Evaluation of Safety and Tolerability [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.

16. Part B: Evaluation of Safety and Tolerability [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.

17. Part C:Assessment of pharmacokinetic parameter area under the concentration-time curve (AUC) [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 dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.

18. Part C: Assessment of pharmacokinetic parameter maximum concentration (Cmax). [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 dose of ARV-471 PK parameters will be assessed when applicable after a single dose and after multiple doses.

19. Part C: Assessment of pharmacokinetic parameter minimum concentration (Cmin). [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.

20. Part C: Assessment of pharmacokinetic parameter time to maximum concentration (Tmax) [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.

21. Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [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.

22. Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [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.

23. Part C: Assessment of anti-tumor activity of ARV-471 in combination with palbociclib [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Palo Alto	California	United States	94304
2	Clinical Trial Site	San Francisco	California	United States	94158
3	Clinical Trial Site	Santa Monica	California	United States	90404
4	Clinical Trial Site	Norwalk	Connecticut	United States	06856
5	Clinical Trial Site	Fort Myers	Florida	United States	33901
6	Clinical Trial Site	Tampa	Florida	United States	33612
7	Clinical Trial Site	Chicago	Illinois	United States	60637
8	Clinical Trial Site	Boston	Massachusetts	United States	02114
9	Clinical Trial Site	Boston	Massachusetts	United States	02215
10	Clinical Trial Site	Ann Arbor	Michigan	United States	48109
11	Clinical Trial Site	Saint Louis	Missouri	United States	63110
12	Clinical Trial Site	East Brunswick	New Jersey	United States	08816
13	Clinical Trial Site	Bronx	New York	United States	10461
14	Clinical Trial Site	Charlotte	North Carolina	United States	28204
15	Clinical Trial Site	Knoxville	Tennessee	United States	37909
16	Clinical Trial Site	Nashville	Tennessee	United States	37203
17	Clinical Trial Site	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Arvinas Estrogen Receptor, Inc.
• Pfizer

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Arvinas Estrogen Receptor, Inc.
• ClinicalTrials.gov Identifier: NCT04072952
• Other Study ID Numbers: ARV-471-mBC-101
• First Posted: Aug 28, 2019
• Last Update Posted: May 18, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Arvinas Estrogen Receptor, Inc.: Breast Cancer; Metastatic Breast Cancer; Malignant Neoplasm of the Breast; mBC; ER+/HER2-; Locally Advanced Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Palbociclib

Study Results

No Results Posted as of May 18, 2022