What side effects are associated with this type of intervention?

Common treatments for breast cancer, including endocrine therapies like tamoxifen and aromatase inhibitors, often cause side effects such as alopecia, bone density loss, and cardiovascular risks. Targeted therapies, such as EGFR inhibitors, can lead to skin issues like acneiform rash, hirsutism, and pruritus. CDK4/6 inhibitors, when combined with endocrine therapies, may increase the incidence of alopecia. HER2-targeted therapies like trastuzumab can cause fatigue, nausea, and potential cardiac issues. These side effects are generally manageable and reversible upon cessation of therapy.

What prior FDA approvals exist?

The FDA has approved several targeted therapies for breast cancer that inhibit pathways activated by specific genetic changes. For HER2-positive breast cancer, trastuzumab (Herceptin) and its combinations, such as trastuzumab with pertuzumab (Perjeta) and chemotherapy, have been approved. Additionally, trastuzumab emtansine (T-DM1, Kadcyla) and fam-trastuzumab deruxtecan (Enhertu) are approved for patients with HER2-positive metastatic breast cancer. For hormone receptor-positive, HER2-negative breast cancer, CDK4/6 inhibitors like palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) are approved in combination with endocrine therapy. These treatments target specific genetic pathways to inhibit cancer growth and progression.

What other types of research exist?

Promising novel alternatives to targeted therapy for breast cancer patients in 2024 include immunotherapy, antibody-drug conjugates (ADCs), and personalized cancer vaccines. Immunotherapy, such as immune checkpoint inhibitors, has shown potential in enhancing the body's immune response against cancer cells. ADCs, which combine monoclonal antibodies with cytotoxic drugs, offer targeted delivery of chemotherapy to cancer cells, minimizing damage to healthy tissue. Personalized cancer vaccines, designed to elicit a strong immune response against specific tumor antigens, are also being explored in clinical trials and may provide a tailored approach to treatment.

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Protein Kinase Inhibitor

Subtype-Targeted Therapeutics for Breast Cancer

Q: What is the mechanism of action of this treatment?

Common treatments for breast cancer, particularly targeted therapies, work by interfering with specific molecular pathways activated by genetic changes in cancer cells. For example, hormone receptor-positive therapies block estrogen or progesterone receptors, HER2-targeted therapies inhibit the HER2 protein, and PI3K/AKT/mTOR inhibitors disrupt signaling pathways crucial for cancer cell growth. These targeted approaches are important for breast cancer patients as they enable personalized treatment plans, potentially increasing efficacy and reducing side effects compared to traditional chemotherapy.

Phase 2

Waitlist Available

Led By George Sledge

Research Sponsored by Stanford University

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Pre-Screening Phase: Biopsy-proven ER-positive, HER2-negative breast cancer with ER-positivity and PR-positivity defined as ≥1% cells staining positive by immunohistochemistry. HER2-negativity 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

Must not have

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

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 15 or 19 days, based on the duration specified for the assigned therapy

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug that targets specific genetic changes found in some breast cancers. It aims to slow down tumor growth more effectively than standard treatments. The study focuses on patients with certain types of breast cancer that have these genetic features.

Who is the study for?

This trial is for adults with ER-positive, HER2-negative breast cancer that hasn't been treated yet. The tumor must be at least 1 cm and could be a new case or a local recurrence in the breast. Participants need to have certain gene changes in their tumors and meet specific health criteria.

What is being tested?

The study tests if adding targeted drugs like Alpelisib, Tamoxifen, Zotatifin, or Fulvestrant before surgery can slow tumor growth better than standard hormone therapy alone. Each drug targets different genetic changes in the tumors.

What are the potential side effects?

Potential side effects may include nausea, fatigue, skin rash, high blood sugar levels (especially with Alpelisib), hot flashes (common with Tamoxifen), liver enzyme changes (with Fulvestrant), and other reactions depending on individual health conditions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

Select...

You have breast cancer that is estrogen receptor-positive and HER2-negative, confirmed by a biopsy. The tumor must be at least 1 centimeter in size and located in the breast. You must be at least 18 years old and able to understand and sign a consent form.

Select...

My breast tumor is a specific type based on lab tests and has a growth rate of at least 10%.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I am allergic to the medication or its ingredients used in this study.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 15 or 19 days, based on the duration specified for the assigned therapy

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~15 or 19 days, based on the duration specified for the assigned therapy

This trial's timeline: 3 weeks for screening, Varies for treatment, and 15 or 19 days, based on the duration specified for the assigned therapy for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Percentage change in Ki67

Secondary study objectives

Ki67 <10% on-treatment measurement

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

14Treatment groups

Experimental Treatment

Active Control

Group I: IC8:Zotatifin in combination with FulvestrantExperimental Treatment2 Interventions

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.

Group II: IC7:Zotatifin in combination with FulvestrantExperimental Treatment2 Interventions

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.

Group III: IC6:Zotatifin in combination with FulvestrantExperimental Treatment2 Interventions

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.

Group IV: IC4:Zotatifin in combination with FulvestrantExperimental Treatment2 Interventions

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.

Group V: IC3:Zotatifin in combination with FulvestrantExperimental Treatment2 Interventions

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.

Group VI: IC2:Zotatifin in combination with FulvestrantExperimental Treatment2 Interventions

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.

Group VII: IC1:Alpelisib in combination with Tamoxifen (closed to enrollment)Experimental Treatment2 Interventions

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

Group VIII: IC1:Tamoxifen (closed to enrollment)Active Control1 Intervention

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

Group IX: IC2:FulvestrantActive Control1 Intervention

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.

Group X: IC3:FulvestrantActive Control1 Intervention

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.

Group XI: IC4:FulvestrantActive Control1 Intervention

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..

Group XII: IC6:FulvestrantActive Control1 Intervention

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.

Group XIII: IC7:FulvestrantActive Control1 Intervention

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.

Group XIV: IC8:FulvestrantActive Control1 Intervention

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

First Studied

Drug Approval Stage

How many patients have taken this drug

Alpelisib

2018

Completed Phase 3

~960

Tamoxifen

2005

Completed Phase 4

~30110

Zotatifin

2021

Completed Phase 1

~40

Fulvestrant

2011

Completed Phase 3

~3520

0 / 3Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for breast cancer, particularly targeted therapies, work by interfering with specific molecular pathways activated by genetic changes in cancer cells. For example, hormone receptor-positive therapies block estrogen or progesterone receptors, HER2-targeted therapies inhibit the HER2 protein, and PI3K/AKT/mTOR inhibitors disrupt signaling pathways crucial for cancer cell growth. These targeted approaches are important for breast cancer patients as they enable personalized treatment plans, potentially increasing efficacy and reducing side effects compared to traditional chemotherapy.

Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies.Intervention in the context of development: pathways toward new treatments.Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer.