What side effects are associated with this type of intervention?

Common treatments for breast cancer, particularly endocrine therapy and targeted therapies like PI3K and mTOR inhibitors, have various side effects. Endocrine therapies, such as tamoxifen and aromatase inhibitors, can cause hot flashes, bone density loss, cardiovascular risks, and an increased risk of endometrial cancer. Targeted therapies, including PI3K inhibitors and mTOR inhibitors, may lead to hyperglycemia, rash, diarrhea, and stomatitis. It is important for patients to discuss these potential side effects with their healthcare provider to manage and mitigate them effectively.

What prior FDA approvals exist?

The FDA has approved several treatments for breast cancer that combine endocrine therapy with targeted therapies. Notably, the combination of endocrine therapy with PI3K inhibitors like alpelisib and mTOR inhibitors such as everolimus has shown efficacy in treating hormone receptor-positive, HER2-negative breast cancer. These combinations aim to overcome resistance to endocrine therapy and improve patient outcomes. Additionally, targeted therapies like trastuzumab have been approved for HER2-positive breast cancer, often in combination with other agents to enhance treatment efficacy.

What other types of research exist?

Promising novel alternatives for breast cancer treatment in 2024 include: 1) Antibody-drug conjugates like Sacituzumab Govitecan (SG), which targets TROP-2 and has shown efficacy in hormone receptor-positive, HER2-negative breast cancer. 2) Selective RET inhibitors such as Selpercatinib and Pralsetinib, particularly for RET-mutated cancers. 3) Immunotherapies like Pembrolizumab combined with Lenvatinib, which have shown significant improvements in progression-free survival. These therapies offer new avenues for patients who have progressed on traditional endocrine and targeted therapies.

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CDK4/6 Inhibitor

Genetically-informed Therapy for Advanced Breast Cancer (GERTRUDE Trial)

Phase 2

Recruiting

Led By Mary Chamberlin, MD

Research Sponsored by Dartmouth-Hitchcock Medical Center

Eligibility Criteria Checklist

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

Must have

Post-menopausal women ≥18 years of age with metastatic ER+ breast cancer, or with locally recurrent ER+ disease not amenable to therapy for curative intent

Patient must have been treated with a CDK4/6i (either palbociclib, ribociclib, or abemaciclib) alone or in combination with an endocrine agent in the advanced disease setting

Must not have

Treatment with abemaciclib in the most recent or current line of therapy

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 6 - 12 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing combinations of medicines to treat advanced ER+/HER2- breast cancer. It focuses on patients who have previously received certain treatments. The goal is to find out if using multiple drugs together can work better than previous treatments. The medicines being tested are approved for treating HR-positive, HER2-negative metastatic breast cancer.

Who is the study for?

This trial is for post-menopausal women aged 18 or older with advanced ER+/HER2- breast cancer, who have been treated with CDK4/6 inhibitors like palbociclib. They can have up to three prior therapies after the inhibitor and one line of chemotherapy. Participants must not be currently on abemaciclib or any investigational cancer therapy within the last three weeks.

What is being tested?

The study tests combinations of drugs (Abemaciclib, Fulvestrant, Neratinib, Alpelisib, Everolimus) in patients previously treated with CDK4/6 inhibitors. It aims to find effective treatments based on genetic profiles that include specific alterations relevant to the study.

What are the potential side effects?

Potential side effects may include gastrointestinal issues such as diarrhea and nausea; skin reactions; blood clots; fatigue; decreased appetite; changes in liver function tests; and potential risk of infections due to lowered white blood cell counts.

Eligibility Criteria

Inclusion Criteria

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

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I am a post-menopausal woman over 18 with advanced ER+ breast cancer not treatable for a cure.

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I have been treated with a CDK4/6 inhibitor for advanced cancer.

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My tumor or blood sample was tested for specific genes in a certified lab after my cancer progressed.

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My cancer is estrogen receptor positive.

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My breast cancer is estrogen receptor positive, confirmed by a biopsy.

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I've had a PET/CT scan or a CT scan with contrast and a bone scan.

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I am post-menopausal according to NCCN guidelines.

Exclusion Criteria

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

Select...

I am currently being treated with abemaciclib.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 6 - 12 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~6 - 12 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 6 - 12 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Rate of clinical benefit within each arm in patients previously treated with a CDK4/6 inhibitor.

Secondary study objectives

Incidence rate of adverse events within each treatment arm.

Progression-free survival within each treatment arm.

Rate of objective response within each treatment arm.

Awards & Highlights

No Placebo-Only Group

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

Trial Design

4Treatment groups

Experimental Treatment

Group I: Arm D- abemaciclib and fulvestrantExperimental Treatment2 Interventions

If a participant does not have a qualifying mutation/alteration for Arms A/B/C, and the participant does not have mutation or loss of RB1, the subject will be assigned to Treatment Arm D and given the combination of abemaciclib and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Abemaciclib will be administered orally in 1 tablet (150 mg) taken 2 times per day, in combination with fulvestrant as described above.

Group II: Arm C- everolimus and fulvestrantExperimental Treatment2 Interventions

If a subject does not have a qualifying ERBB2 or PIK3CA mutation, but they have a qualifying mutation/alteration in AKT1, MTOR, or PTEN, the subject will be assigned to Treatment Arm C and given the combination of everolimus and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Everolimus will be administered orally in 1 tablet (10 mg per tablet) taken 1 time per day, in combination with fulvestrant as described above.

Group III: Arm B- alpelisib and fulvestrantExperimental Treatment2 Interventions

If a participant does not have a qualifying ERBB2 (HER2) mutation, but they have a qualifying PIK3CA mutation, the subject will be assigned to Treatment Arm B and given the combination of alpelisib and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Alpelisib will be administered orally in 2 tablets (total dose of 300 mg) taken 1 time per day with food, in combination with fulvestrant as described above.

Group IV: Arm A- neratinib and fulvestrantExperimental Treatment2 Interventions

Participants with a qualifying ERBB2 (HER2) mutation will be assigned to Treatment Arm A and given the combination of neratinib and fulvestrant until the end of the primary treatment phase. Fulvestrant (500 mg) will be administered by intramuscular injection into the buttocks on Cycle 1 Day 1 and Day 15, and on Day 1 of subsequent Cycles. Neratinib will initially be administered orally in 3 tablets (total dose of 120 mg) taken 1 time per day with food on Cycle 1 Days 1-7, in combination with fulvestrant starting on Cycle 1 Day 1 as described above. The dose of neratinib will be increased to 4 tablets (total dose of 160 mg) taken 1 time per day with food on Cycle 1 Days 8-14, and then increased further to 6 tablets (240 mg) taken once daily with food thereafter.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Abemaciclib

2019

Completed Phase 2

~1890

Fulvestrant

2011

Completed Phase 3

~3510

Neratinib

2014

Completed Phase 2

~1970

Alpelisib

2018

Completed Phase 3

~960

Everolimus

2010

Completed Phase 4

~1510

0 / 8Eligibility 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 include endocrine therapy and targeted therapy. Endocrine therapy blocks hormones like estrogen that fuel hormone receptor-positive breast cancer, using agents such as tamoxifen, letrozole, and fulvestrant. Targeted therapies, including PI3K and mTOR inhibitors, disrupt specific molecular pathways crucial for cancer cell growth and survival. PI3K inhibitors target the PI3K/AKT/mTOR pathway, while mTOR inhibitors directly inhibit the mTOR protein. Combining these therapies can enhance treatment efficacy, overcome resistance, and improve progression-free survival in advanced breast cancer patients.

A new era of improving progression-free survival with dual blockade in postmenopausal HR(+), HER2(-) advanced breast cancer.A review of an unfavorable subset of breast cancer: estrogen receptor positive progesterone receptor negative.Endocrine and targeted manipulation of breast cancer: summary statement for the Sixth Cambridge Conference.