Umbrella Trial of Subtype-Targeted Therapies in ER+/HER2- Breast Cancer

Jennifer Lee Caswell-Jin

Status and phase: Completed; Phase 2

Conditions: Breast Cancer; ER Positive Breast Cancer; HER2-negative Breast Cancer

Treatments: Drug: Zotatifin; Drug: Tamoxifen; Drug: Fulvestrant; Drug: Alpelisib

Study type: Interventional

Funder types: Other; Other U.S. Federal agency; Industry

Identifiers

NCT05101564

NCI-2023-02578 (Other Identifier)

IRB-52869

Details and patient eligibility

About

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.

Full 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)

Enrollment: 19 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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19 participants in 14 patient groups

IC1:Alpelisib in combination with Tamoxifen (closed to enrollment)

Experimental group

Description:

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

Treatment:

Drug: Alpelisib

Drug: Tamoxifen

IC1:Tamoxifen (closed to enrollment)

Active Comparator group

Description:

Integrative subtype 1, Treatment (14 days, -2 to +7 days): Take assigned tamoxifen pills, 20 mg once daily by mouth

Treatment:

Drug: Tamoxifen

IC2:Zotatifin in combination with Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Zotatifin

IC2:Fulvestrant

Active Comparator group

Description:

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.

Treatment:

Drug: Fulvestrant

IC3:Zotatifin in combination with Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Zotatifin

IC3:Fulvestrant

Active Comparator group

Description:

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.

Treatment:

Drug: Fulvestrant

IC4:Zotatifin in combination with Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Zotatifin

IC4:Fulvestrant

Active Comparator group

Description:

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..

Treatment:

Drug: Fulvestrant

IC6:Zotatifin in combination with Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Zotatifin

IC6:Fulvestrant

Active Comparator group

Description:

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.

Treatment:

Drug: Fulvestrant

IC7:Zotatifin in combination with Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Zotatifin

IC7:Fulvestrant

Active Comparator group

Description:

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.

Treatment:

Drug: Fulvestrant

IC8:Zotatifin in combination with Fulvestrant

Experimental group

Description:

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.

Treatment:

Drug: Fulvestrant

Drug: Zotatifin

IC8:Fulvestrant

Active Comparator group

Description:

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.

Treatment:

Drug: Fulvestrant