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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if certain drug combinations can effectively treat advanced ER+/HER2- breast cancer in patients who have previously tried treatments such as palbociclib, ribociclib, or abemaciclib (a type of targeted therapy). Participants will receive different drug combinations, such as fulvestrant paired with either alpelisib, neratinib, everolimus, or abemaciclib, based on specific genetic changes in their cancer. Post-menopausal women with metastatic breast cancer, especially those whose cancer has progressed after previous treatments, might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have shown promising results regarding the safety of the drug combinations in this trial.

For those considering the combination of alpelisib and fulvestrant, research indicates that this mix is generally well-tolerated. A large study with 571 patients found that while the treatment can cause side effects like high blood sugar, these were manageable.

The combination of neratinib and fulvestrant has also been studied. Findings suggest it is safe and tolerable, with diarrhea being a common side effect for some patients. However, medication mostly controlled this.

The everolimus and fulvestrant combination is another option. Past research shows it is typically safe, especially in older patients. Some reported side effects include mouth sores and fatigue, but these are usually mild.

Finally, the abemaciclib and fulvestrant duo has a safety profile consistent with what is already known about abemaciclib. Common side effects include diarrhea and fatigue, but they are often manageable.

These drug combinations are part of a Phase 2 trial, indicating they have already demonstrated a certain level of safety in earlier research. They are now being tested for effectiveness in this specific condition. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced breast cancer because they uniquely target specific genetic mutations, offering a more personalized approach. Unlike standard therapies that might not consider genetic variations, these treatments use a combination of drugs to target mutations in genes like ERBB2, PIK3CA, AKT1, MTOR, and PTEN. For instance, alpelisib targets PIK3CA mutations, while neratinib targets ERBB2 mutations, and everolimus addresses alterations in AKT1, MTOR, or PTEN. This tailored approach not only promises better effectiveness but also potentially reduces unnecessary side effects by focusing on the cancer's specific genetic drivers.

What evidence suggests that this trial's treatments could be effective for advanced breast cancer?

Research shows that the drug combinations tested in this trial could be promising for treating advanced breast cancer. Participants with a PIK3CA mutation will receive alpelisib and fulvestrant, which nearly doubled the time the cancer did not worsen compared to other treatments in previous studies. Those with an ERBB2 (HER2) mutation will receive neratinib and fulvestrant; early studies showed about 30% of patients experienced tumor shrinkage or stability. Participants with mutations in AKT1, MTOR, or PTEN will receive everolimus and fulvestrant, which extended the time without cancer progression to about 10.4 months in past research, longer than using fulvestrant alone. Lastly, participants without qualifying mutations for the other arms and without RB1 mutation or loss will receive abemaciclib with fulvestrant. Studies have shown this combination improves the time without cancer progression and overall survival, with an average of 16.9 months for patients with hormone receptor-positive, HER2-negative breast cancer. These combinations offer new hope for those who have already tried other treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Mary D. Chamberlin

Principal Investigator

Dartmouth-Hitchcock Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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]

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]

Citations

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Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After ... Abemaciclib plus ET reduces the risk of recurrence for patients with high-risk early breast cancer and improves progression-free survival (PFS) and overall ...

2. onclive.com onclive.com/view/abemaciclib-fulvestrant-improves-pfs-across-hr-her2-advanced-breast-cancer-subgroups

Abemaciclib/Fulvestrant Improves PFS Across HR+/HER2 In patients who had received CDK4/6 inhibition for less than 18 months, the median PFS with abemaciclib plus fulvestrant (n = 89) was 5.6 months ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0960977625006149

Metastatic Breast Cancer: A Propensity-Matched ... The RMST analysis confirmed a significant survival benefit of 5.96 months over the follow-up period (p<0.001). Abemaciclib was associated with ...

4. ascopubs.org ascopubs.org/doi/10.1200/OA-25-00052

Final Overall Survival Results From MONARCH 2 Consistent with the primary analysis, abemaciclib plus fulvestrant showed persistent PFS benefit at the final analysis. The median PFS was 16.9 ...

5. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2752266

The Effect of Abemaciclib Plus Fulvestrant on Overall ... Patients in the abemaciclib arm received a clinically meaningful median OS improvement of 9.4 months in this ET-resistant setting. To our ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/208716s019lbl.pdf

VERZENIO® (abemaciclib) tablets, for oral use The data described below reflect exposure to VERZENIO in 441 patients with. HR-positive, HER2-negative advanced breast cancer who received at least one dose of ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7794176/

Management of Abemaciclib‐Associated Adverse Events in ... This article presents the results of a comprehensive safety analysis of abemaciclib‐associated adverse events, focusing on management of serious adverse events ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02086

Abemaciclib Plus Fulvestrant in Advanced Breast Cancer ... No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib. Conclusion. Abemaciclib + ...

9. mayoclinic.org mayoclinic.org/drugs-supplements/abemaciclib-oral-route/description/drg-20406567

Abemaciclib (oral route) - Side effects & dosage Safety and efficacy have not been established. ... For advanced or metastatic breast cancer with anastrozole, exemestane, fulvestrant, or ...

10. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2017/faslodex-fulvestrant-receives-us-fda-approval-for-the-treatment-of-advanced-breast-cancer-in-combination-with-abemaciclib-11152017.html

FASLODEX® (fulvestrant) receives US FDA approval for ...