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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

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

Conditions
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Breast Cancer, HER2-negative Breast Cancer, ER Positive Breast Cancer

Intervention / Treatment
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* Drug: Alpelisib
* Drug: Tamoxifen
* Drug: Zotatifin
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IC1:Alpelisib in combination with Tamoxifen<br>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<br>* Alpelisib 300 mg<br>* Other names: BYL719;Drug: Tamoxifen<br>* Tamoxifen 20 mg<br>* Other names: TAM;|
| Active Comparator: IC1:Tamoxifen<br>Integrative subtype 1, Treatment (14 days, -2 to +7 days): Take assigned tamoxifen pills, 20 mg once daily by mouth | Drug: Tamoxifen<br>* Tamoxifen 20 mg<br>* Other names: TAM;|
| Experimental: IC2:Zotatifin in combination with Fulvestrant<br>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: Zotatifin<br>* Zotatifin 0.10mg/kg (by weight)<br>* Other names: eFT226;Drug: Fulvestrant<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Active Comparator: IC2:Fulvestrant<br>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<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Experimental: IC3:Zotatifin in combination with Fulvestrant<br>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: Zotatifin<br>* Zotatifin 0.10mg/kg (by weight)<br>* Other names: eFT226;Drug: Fulvestrant<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Active Comparator: IC3:Fulvestrant<br>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<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Experimental: IC4:Zotatifin in combination with Fulvestrant<br>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: Zotatifin<br>* Zotatifin 0.10mg/kg (by weight)<br>* Other names: eFT226;Drug: Fulvestrant<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Active Comparator: IC4:Fulvestrant<br>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<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Experimental: IC6:Zotatifin in combination with Fulvestrant<br>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: Zotatifin<br>* Zotatifin 0.10mg/kg (by weight)<br>* Other names: eFT226;Drug: Fulvestrant<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Active Comparator: IC6:Fulvestrant<br>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<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Experimental: IC7:Zotatifin in combination with Fulvestrant<br>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: Zotatifin<br>* Zotatifin 0.10mg/kg (by weight)<br>* Other names: eFT226;Drug: Fulvestrant<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Active Comparator: IC7:Fulvestrant<br>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<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Experimental: IC8:Zotatifin in combination with Fulvestrant<br>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: Zotatifin<br>* Zotatifin 0.10mg/kg (by weight)<br>* Other names: eFT226;Drug: Fulvestrant<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|
| Active Comparator: IC8:Fulvestrant<br>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<br>* Fulvestrant 500 mg<br>* Other names: Faslodex;|

What is the study measuring?
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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 |