Triple Drug Combo for Breast Cancer

Recruiting at 1 trial location

Overseen By Adrienne G Waks, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Adrienne G. Waks

Must be taking: GNRH agonists

Must not be taking: MEK inhibitors, Strong CYP3A4 drugs

Disqualifiers: Active brain metastases, Uncontrolled hypertension, others

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

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

Compensation: Varies

Number of Visits: Unknown

63 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three drugs—VS-6766 (Avutometinib), abemaciclib (Verzenio), and fulvestrant (Faslodex)—to evaluate their safety and effectiveness in treating a specific type of breast cancer that is hormone receptor positive (HR+) and HER2-negative. The trial targets patients whose breast cancer has spread or recurred after unsuccessful previous treatments. Those who may benefit most are individuals with HR+/HER2-negative breast cancer that has progressed after certain other treatments. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have taken certain medications like chemotherapy, immunotherapy, or specific endocrine or biologic agents within a certain period before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that the combination of VS-6766, abemaciclib, and fulvestrant has been tested before. The results indicated that patients with breast cancer unresponsive to certain treatments experienced manageable side effects. In other words, patients generally tolerated the treatment well. However, the researchers are still collecting safety information. Since this trial is in its early stages, its progression is encouraging. This suggests that the initial safety results are promising enough to continue the research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for breast cancer, which typically focus on hormone therapy or chemotherapy, this triple drug combination of Abemaciclib, Fulvestrant, and VS-6766 brings a unique approach by targeting multiple pathways involved in cancer cell growth and survival. Abemaciclib is a CDK4/6 inhibitor that disrupts cell division, while Fulvestrant is an estrogen receptor antagonist that blocks hormone-driven cancer growth. The new addition, VS-6766, is a dual RAF/MEK inhibitor, which targets a different part of the cancer cell's signaling pathway, potentially stopping cancer cells from multiplying. Researchers are excited about this combination because it offers a multi-pronged attack on cancer cells, which might lead to more comprehensive and effective treatment outcomes compared to single-agent therapies.

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

This trial will evaluate the combination of VS-6766, abemaciclib, and fulvestrant for treating HR+/HER2-negative breast cancer. Research has shown that this combination may be beneficial, with early results indicating that 13.3% of patients experienced tumor shrinkage. Additionally, 46.7% of patients maintained stable disease, meaning their cancer did not progress. The duration patients lived without cancer worsening was significant. This combination has shown promise, particularly for patients whose cancer did not respond to previous treatments. Most side effects were manageable and not severe. ^{1 2 3 4 6}

Who Is on the Research Team?

Adrienne Waks, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults over 18 with HR+/HER2- metastatic or locally advanced breast cancer that worsened on CDK4/6 inhibitors. They must have had no more than two chemo treatments in the metastatic setting, be able to take oral meds, and agree to use contraception. Excluded are those who stopped abemaciclib due to toxicity, used MEK inhibitors before, or have certain infections or severe health conditions.

Inclusion Criteria

My organ and bone marrow functions are normal.

I agree to use birth control during the study.

I am a man or woman on GNRH agonist treatment for at least 4 weeks.

Exclusion Criteria

Any other serious and/or uncontrolled preexisting medical condition(s) that in the opinion of the Investigator would place the patient at unacceptably high risk for toxicity and therefore preclude participation in this study.

I have brain metastases, but they are stable and treated.

I have not had another type of cancer, or if I did, it meets certain conditions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Participants receive VS-6766, abemaciclib, and fulvestrant to determine the maximum tolerated dose and recommended phase II dose

4 weeks up to 2 years

Weekly visits for drug administration and monitoring

Phase 2 Dose Expansion

Participants receive VS-6766, abemaciclib, and fulvestrant at the recommended phase II doses to assess clinical benefit rate

6 months up to 3 years

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months up to 10 years

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• Fulvestrant
• VS-6766

Trial Overview The study tests VS-6766 combined with abemaciclib and fulvestrant's safety and effectiveness against HR+/HER2-negative breast cancer. Participants will receive these drugs to see how well they work together after other treatments failed.

How Is the Trial Designed?

Group I: Phase 2 Dose Expansion Experimental Treatment 3 Interventions

Participants will receive VS-6766 with abemaciclib and fulvestrant at the recommended phase II doses determined in the phase I portion of the study.

Group II: Phase 1 Dose Escalation Experimental Treatment 3 Interventions

During 28 day/4 week study cycle, participants will receive: * VS-6766 2x weekly for 3 out of the 4 week cycle * Abemaciclib 2x daily * Fulvestrant on day 1 of each study cycle (and day 15 of cycle 1 only)

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?

Adrienne G. Waks

Lead Sponsor

Trials

4

Recruited

240+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Verastem Oncology

Collaborator

Trials

2

Recruited

90+

Published Research Related to This Trial

In a pooled analysis of 1152 patients from the MONARCH 2 and MONARCH 3 studies, abemaciclib combined with endocrine therapy showed a consistent improvement in progression-free survival (PFS) across all age groups, indicating its efficacy in treating HR+, HER2- advanced breast cancer regardless of age.

Older patients experienced higher rates of clinically relevant side effects, such as diarrhea and nausea, but these were manageable with dose adjustments, suggesting that while safety concerns exist, the treatment remains effective for older populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. Goetz, MP., Okera, M., Wildiers, H., et al.[2022]

In the MONARCH 2 study, abemaciclib combined with fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor positive, HER2-negative advanced breast cancer, showing consistent benefits across both first-line and second-line treatment groups.

The most substantial benefits were seen in patients with primary resistance to endocrine therapy and those with visceral disease, indicating that abemaciclib may be particularly effective for these subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONARCH 2: Subgroup Analysis of Patients Receiving Abemaciclib Plus Fulvestrant as First-Line and Second-Line Therapy for HR+, HER2--Advanced Breast Cancer. Neven, P., Johnston, SRD., Toi, M., et al.[2022]

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

Abemaciclib combined with endocrine therapy (ET) significantly improves quality-adjusted life years (QALYs) in patients with high-risk hormone receptor positive, HER2-negative early breast cancer, with an increase of 0.99 QALYs compared to ET alone.

The treatment is considered cost-effective in Italy, with an incremental cost-effectiveness ratio of €22,651 per QALY gained, and a 99% likelihood of being cost-effective at a threshold of €30,000 per QALY.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of abemaciclib with endocrine therapy (ET) versus ET alone for HR+, HER2-, node-positive, high-risk early breast cancer in Italy. Davie, A., Traoré, S., Giovannitti, M., et al.[2023]

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 phase III study involving 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer, abemaciclib significantly improved progression-free survival compared to placebo, with a hazard ratio of 0.54, indicating a strong efficacy as initial therapy.

The most common side effect of abemaciclib was diarrhea, occurring in 81.3% of patients, but most cases were mild (grade 1), suggesting that while there are some adverse effects, the treatment has a tolerable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. Goetz, MP., Toi, M., Campone, M., et al.[2022]

In the MONARCH 2 study involving 669 women with advanced breast cancer, the combination of abemaciclib and fulvestrant significantly improved progression-free survival (PFS) to a median of 16.4 months compared to 9.3 months with fulvestrant alone.

The combination therapy also achieved a higher objective response rate (ORR) of 48.1% versus 21.3% in the control group, while maintaining a tolerable safety profile, with common side effects including diarrhea and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Sledge, GW., Toi, M., Neven, P., et al.[2022]

Citations

1. dana-farber.org dana-farber.org/clinical-trials/22-490

A single arm phase 1/2 trial of abemaciclib + avutometinib ... This research is being done to evaluate the safety and effectiveness of a drug currently known as VS-6766 in combination with the drugs abemaciclib and ...

2. onclive.com onclive.com/view/avutometinib-abemaciclib-fulvestrant-combo-is-active-safe-in-cdk4-6-inhibitor-resistant-hr-her2-metastatic-breast-cancer

Avutometinib/Abemaciclib/Fulvestrant Combo Is Active ... Preliminary efficacy results included a 13.3% overall response rate and a 46.7% stable disease rate, with a median progression-free survival of ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05608252

NCT05608252 | VS-6766+Abema+Fulv in Met HR+/HER- BC This research is being done to evaluate the safety and effectiveness of a drug currently known as VS-6766 in combination with the drugs abemaciclib and ...

4. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_2/CT028/761490/Abstract-CT028-A-single-arm-phase-1-trial-of

Abstract CT028: A single-arm phase 1 trial of avutometinib ... There were no grade 4-5 TRAEs. ORR was 13% (1 CR, 1 PR; including a pt previously treated with fulvestrant and abema), 24-week CBR was 25%, ...

5. physicianresources.dana-farber.org physicianresources.dana-farber.org/news/head-and-neck-breast-lung-and-survivorship-studies-headline-dana-farber-research-at-aacr-annual-meeting-2025

Head and Neck, Breast, Lung and Survivorship Studies ... The combination showed a manageable safety profile and signs of anti-cancer effects in patients with cancer that was resistant to CDK4/6 ...

6. researchgate.net researchgate.net/publication/391180285_Abstract_CT028_A_single-arm_phase_1_trial_of_avutometinib_RAFMEK_inhibitor_abemaciclib_abema_and_fulvestrant_in_CDK46_inhibitor_CDK46i-pretreated_patients_pts_with_HR_metastatic_breast_cancer_MBC

Abstract CT028: A single-arm phase 1 trial of avutometinib ... PK data will be presented. Conclusions The combination of avutometinib, abema, and fulvestrant showed a manageable safety profile and ...