Genetically-informed Therapy for Advanced Breast Cancer

(GERTRUDE Trial)

Overseen By Research Nurse

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Dartmouth-Hitchcock Medical Center

Must be taking: CDK4/6 inhibitors

Must not be taking: Investigational cancer therapies

Disqualifiers: Untreated CNS disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 months

135 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you cannot be on abemaciclib in your most recent treatment. You also cannot take other anti-cancer therapies during the study, except for certain bone therapies.

What data supports the effectiveness of the drug combination used in the Genetically-informed Therapy for Advanced Breast Cancer trial?

Research shows that abemaciclib, when used as a first-line therapy, significantly improves progression-free survival in advanced ER-positive, HER2-negative breast cancer. Additionally, alpelisib combined with fulvestrant has shown clinical benefits in patients with PIK3CA-mutant, hormone receptor-positive, HER2-negative advanced breast cancer, even after multiple prior treatments. ^{1 2 3 4 5}

What safety data exists for targeted therapies like Abemaciclib and Everolimus in breast cancer treatment?

Targeted therapies like Abemaciclib and Everolimus have shown improved outcomes in breast cancer treatment, but they can have complex and potentially severe side effects. Recognizing and managing these side effects requires a team approach and understanding of drug interactions. ^{3 4 6 7 8}

How is the drug combination of Abemaciclib, Alpelisib, Everolimus, Fulvestrant, and Neratinib unique for advanced breast cancer?

This drug combination is unique because it targets specific genetic mutations in advanced breast cancer, such as ESR1 and PIK3CA mutations, using a mix of inhibitors that work on different pathways, potentially offering a personalized treatment approach after progression on other therapies. ^{2 3 4 5 9}

What is the purpose of this trial?

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.

Research Team

Mary D. Chamberlin

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

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.

Inclusion Criteria

I am willing and able to sign the consent form for this study.

My cancer will be genetically profiled for the study, using a tumor or blood sample.

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

Exclusion Criteria

My brain condition has been stable for at least 3 months without treatment.

You have taken any new cancer treatments in the past 3 weeks.

I am not on any cancer treatments except for bone-strengthening drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of targeted therapies based on genetic mutations until the end of the primary treatment phase

6-12 months

Regular visits as per cycle schedule

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Abemaciclib
• Alpelisib
• Everolimus
• Fulvestrant
• Neratinib

Trial Overview 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.

Participant Groups

Group I: Arm D- abemaciclib and fulvestrant Experimental Treatment 2 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 fulvestrant Experimental Treatment 2 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 fulvestrant Experimental Treatment 2 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 fulvestrant Experimental Treatment 2 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.

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Findings from Research

In a study of 348 postmenopausal women with hormone receptor-positive metastatic breast cancer, everolimus-based therapy (EVE) showed significantly longer progression-free survival (PFS) compared to fulvestrant monotherapy (FUL), with a hazard ratio of 0.71.

EVE was particularly effective for patients who had previously progressed on nonsteroidal aromatase inhibitors, indicating its potential as a preferred treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer. Hao, Y., Lin, PL., Xie, J., et al.[2018]

In a study of 13 women with advanced breast cancer who had previously undergone multiple treatments, alpelisib combined with endocrine treatment resulted in a median progression-free survival of 5.5 months, indicating its efficacy even after prior therapies like everolimus.

The clinical benefit rate at 6 months was 46.1%, which is comparable to previous studies, suggesting that alpelisib remains a relevant treatment option for patients with advanced breast cancer, including those with specific mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib Efficacy in Hormone Receptor-Positive HER2-Negative PIK3CA-Mutant Advanced Breast Cancer Post-Everolimus Treatment. Raphael, A., Salmon-Divon, M., Epstein, J., et al.[2022]

Interim results from the MONARCH3 study show that abemaciclib, a CDK4/6 inhibitor, is an effective first-line treatment for advanced ER-positive, HER2-negative breast cancer.

Patients receiving abemaciclib in combination with letrozole experienced significantly improved progression-free survival compared to those receiving a placebo with endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

In patients with hormone receptor-positive, HER2-negative metastatic breast cancer who progressed on palbociclib, those without CDK4/6 inhibitor resistance mutations (CDKi-R[-]) had a median progression-free survival (PFS) of 7.0 months on abemaciclib, compared to just 3.5 months for those with mutations (CDKi-R[+]), indicating that the presence of these mutations significantly impacts treatment efficacy.

This study is the first to identify a genomic panel that may help predict sensitivity to abemaciclib in patients with ESR1 mutations after progression on palbociclib, suggesting that further research could refine this panel to better guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. Brett, JO., Dubash, TD., Johnson, GN., et al.[2023]

In a real-life study of 233 patients with advanced breast cancer who had PIK3CA mutations, treatment with alpelisib and fulvestrant resulted in a median progression-free survival (PFS) of 5.3 months, indicating its efficacy even after multiple prior treatments.

However, 39.1% of patients discontinued alpelisib due to adverse events, highlighting the importance of monitoring for side effects in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program. Bello Roufai, D., Gonçalves, A., De La Motte Rouge, T., et al.[2023]

Targeted agents like CDK4/6 inhibitors have improved outcomes for patients with HR-positive, HER2-negative metastatic breast cancer compared to traditional endocrine therapies, but they come with complex and potentially severe adverse events that require careful management.

Despite the increased risk of hematologic toxicities and the need for more frequent physician visits, these side effects are generally manageable without needing to consult specialists, highlighting the importance of a multidisciplinary approach in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of toxicities associated with targeted therapies for HR-positive metastatic breast cancer: a multidisciplinary approach is the key to success. Cazzaniga, ME., Danesi, R., Girmenia, C., et al.[2020]

In the BALLET trial involving 2131 postmenopausal patients with hormone-receptor positive HER2-negative breast cancer, the combination of everolimus and exemestane significantly improved progression-free survival while maintaining a manageable safety profile.

The most common adverse events, such as stomatitis and asthenia, typically occurred within the first three months of treatment, highlighting the importance of close monitoring and early intervention during this period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus plus exemestane in hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: incidence and time course of adverse events in the phase IIIb BALLET population. Ciruelos, E., Jerusalem, G., Martin, M., et al.[2021]

Everolimus, an mTOR inhibitor, shows promise in treating metastatic breast cancer by targeting the PI3K/AKT/mTOR pathway, which is often upregulated in resistant cases, indicating a potential mechanism to overcome therapy resistance.

Current clinical trials are investigating the efficacy and safety of everolimus in combination with hormone therapy or trastuzumab, suggesting it could enhance treatment outcomes for women with metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and its role in hormone-resistant and trastuzumab-resistant metastatic breast cancer. Keck, S., Glencer, AC., Rugo, HS.[2021]

New combinations of endocrine therapy (ET) for hormone receptor-positive (HR+) advanced breast cancer, such as fulvestrant plus anastrozole or palbociclib plus letrozole, have shown improved progression-free survival, especially in ET-naïve patients.

While these combinations are generally safe, they carry risks of serious toxicities, necessitating careful monitoring and patient education, and the use of circulating tumor DNA as a biomarker may help tailor treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer. Pritchard, KI., Chia, SK., Simmons, C., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer. [2018]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Alpelisib Efficacy in Hormone Receptor-Positive HER2-Negative PIK3CA-Mutant Advanced Breast Cancer Post-Everolimus Treatment. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Management of toxicities associated with targeted therapies for HR-positive metastatic breast cancer: a multidisciplinary approach is the key to success. [2020]

7. Italy pubmed.ncbi.nlm.nih.gov

Everolimus plus exemestane in hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: incidence and time course of adverse events in the phase IIIb BALLET population. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Everolimus and its role in hormone-resistant and trastuzumab-resistant metastatic breast cancer. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Enhancing Endocrine Therapy Combination Strategies for the Treatment of Postmenopausal HR+/HER2- Advanced Breast Cancer. [2018]