Umbrella Trial Testing Integrative Subtype-Targeted Therapeutics in HR+ /HER2-Negative Breast Cancer

An Umbrella, Randomized, Controlled, Pre-Operative Trial Testing Integrative Subtype-Targeted Therapeutics in Hormone Receptor-Positive, HER2-Negative Breast Cancer

The purpose of this study is to learn if adding a new drug that is targeted at a specific genetic change found in some breast tumors pre-operatively will slow the growth of the tumor more than standard anti-hormone therapy used to treat this type of breast cancer. Different therapies are being tested based on the specific gene changes in the tumor. Not every tumor will have a gene change that is being studied.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; HER2-negative Breast Cancer; ER Positive Breast Cancer
• Intervention / Treatment: Drug: Alpelisib; Drug: Tamoxifen; Drug: Fulvestrant; Drug: Zotatifin

Detailed Description

Primary Objective: To evaluate the efficacy of investigational agent compared with standard endocrine therapy in in reducing Ki67 values based on digital pathology (QuPath) from baseline to on-treatment biopsy after an specific treatment duration (i.e. 14 days) in ER-positive, HER2-negative tumors (tumor size ≥1 cm) with Ki67 ≥ 10%, for different integrative subtype categories identified at integrative subtype screening.

Secondary Objective: To evaluate the efficacy of investigational agent compared with standard endocrine therapy on the proportion of subjects with Ki67 < 10% after a specific treatment duration (i.e. 14 days)

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Allison Zhang; Phone Number: 650-736-5790; Email: axkong@stanford.edu

Study Locations

• United States
  • California
    • Stanford, California, United States, 94304
      • Recruiting
      • Stanford University
      • Principal Investigator: Jennifer Caswell-Jin, MD
      • Contact: Allison Zhang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pre-Screening Phase
• Biopsy-proven ER-positive, HER2-negative breast cancer. ER-positivity and PR-positivity are defined as ≥1% cells staining positive by immunohistochemistry. HER2-negativity is defined by IHC or FISH, per ASCO-CAP 2018 guidelines. Breast tumor must be intact and tumor size must be ≥ 1 cm as measured by ultrasound, mammogram, MRI, or clinical exam. If tumor is locally recurrent, it must be in the breast (not skin, node, or chest wall recurrence). Ki67 may or may not have been done locally but if done locally, must be ≥ 5%. Any nodal status is allowed, as M0 or M1 disease.
• Women or men, age ≥ 18 years old.
• Performance status 0 to 1 (by Eastern Cooperative Oncology Group [ECOG] scale).
• Ability to understand and the willingness to sign a written informed consent document.

Treatment Phase

• Breast tumor classifies as relevant integrative subtype per tumor sequencing performed and analyzed by central laboratory.
• Breast tumor Ki67 score ≥ 10% as assessed by central laboratory.
• Each investigational agent specific inclusion criteria can be found in the agent-specific appendix

Exclusion Criteria:

• Pregnant woman, as confirmed by positive serum hCG test prior to initiating study treatment. Nursing (lactating) woman also not allowed.
• Prior breast cancer-directed therapy (surgery, radiation, chemotherapy, or endocrine therapy) is not allowed, with the exception of people with in-breast recurrences. People with in-breast recurrences cannot have had breast cancer-directed therapy (radiation, chemotherapy, or endocrine therapy; surgery is acceptable) within the 6 months prior to signing the pre-screening consent. Pre-endocrine therapy for breast cancer risk reduction is allowed.
• Known hypersensitivity to study agent (IP) or standard endocrine therapy drug, or to any of the excipients of study agent (IP) or standard endocrine therapy drug.
• Each study agent specific exclusion criteria can be found in the agent-specific appendix

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IC1:Alpelisib in combination with Tamoxifen; Integrative subtype IC1, Treatment (14 days, - 2 or + 7 days): Take assigned alpelisib pills, 300 mg (two 150 mg tablets) with food, once daily by mouth. Tamoxifen pills, 20 mg once daily by mouth	Drug: Alpelisib; Alpelisib 300 mg; Other Names: Piqray; BYL719; Drug: Tamoxifen; Tamoxifen 20 mg; Other Names: TAM; Soltamox
Active Comparator: IC1:Tamoxifen; Integrative subtype 1, Treatment (14 days, -2 to +7 days): Take assigned tamoxifen pills, 20 mg once daily by mouth	Drug: Tamoxifen; Tamoxifen 20 mg; Other Names: TAM; Soltamox
Active Comparator: IC2:Fulvestrant; Integrative subtype 2, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex
Active Comparator: IC6:Fulvestrant; Integrative subtype 6, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex
Experimental: IC2:Zotatifin in combination with Fulvestrant; Integrative subtype 2, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex; Drug: Zotatifin; Zotatifin 0.10mg/kg (by weight); Other Names: eFT226
Experimental: IC3:Zotatifin in combination with Fulvestrant; Integrative subtype 3, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex; Drug: Zotatifin; Zotatifin 0.10mg/kg (by weight); Other Names: eFT226
Active Comparator: IC3:Fulvestrant; Integrative subtype 3, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1. on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex
Experimental: IC4:Zotatifin in combination with Fulvestrant; Integrative subtype 4, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex; Drug: Zotatifin; Zotatifin 0.10mg/kg (by weight); Other Names: eFT226
Active Comparator: IC4:Fulvestrant; Integrative subtype 4, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1..	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex
Experimental: IC6:Zotatifin in combination with Fulvestrant; Integrative subtype 6, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex; Drug: Zotatifin; Zotatifin 0.10mg/kg (by weight); Other Names: eFT226
Experimental: IC7:Zotatifin in combination with Fulvestrant; Integrative subtype 7, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex; Drug: Zotatifin; Zotatifin 0.10mg/kg (by weight); Other Names: eFT226
Active Comparator: IC7:Fulvestrant; Integrative subtype 7, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex
Experimental: IC8:Zotatifin in combination with Fulvestrant; Integrative subtype 8, Treatment (14 days, - 2 to +7 days). Zotatifin (calculated by weight, 0.10 mg/kg) should be administered as a 60-minute IV infusion on Days 1. A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex; Drug: Zotatifin; Zotatifin 0.10mg/kg (by weight); Other Names: eFT226
Active Comparator: IC8:Fulvestrant; Integrative subtype 8, Treatment (14 days, - 2 to +7 days) A total of 500 mg Fulvestrant should be administered intramuscularly as two 5mL injection on Day 1.	Drug: Fulvestrant; Fulvestrant 500 mg; Other Names: Faslodex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage change in Ki67	The primary outcome for this study is the change in digital pathology software-assessed quantitative Ki67 IHC from pre-treatment specimen to the on-treatment specimen. For analysis purposes, the change in Ki67 will be assessed on log-transformed values. The outcome will be expressed as mean and standard deviation.	Measured pre-treatment and after treatment 15 or 19 days, based on the duration specified for the assigned therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ki67 <10% on-treatment measurement	The proportions of subjects with Ki67 less than 10% after treatment. The outcome will be reported as a number without dispersion.	15 or 19 days, based on the duration specified for the assigned therapy

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Jennifer Caswell-Jin, Stanford Universiy

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2023
• Primary Completion (Anticipated): September 1, 2025
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: October 28, 2021
• First Submitted That Met QC Criteria: October 28, 2021
• First Posted (Actual): November 1, 2021

Study Record Updates

• Last Update Posted (Actual): March 23, 2023
• Last Update Submitted That Met QC Criteria: March 21, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Estrogen Receptor Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Fulvestrant; Tamoxifen
• Other Study ID Numbers: IRB-52869; BRS0124 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No