CDK 4/6 Inhibitor + Endocrine Therapy for Breast Cancer

(LEADER Trial)

Not currently recruiting at 2 trial locations

Overseen By Arielle Medford, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must be taking: Adjuvant endocrine therapy

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Brain metastases, Uncontrolled heart disease, HIV, 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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of Ribociclib (a CDK 4/6 inhibitor) and hormone therapy to determine its effectiveness in treating ER-positive breast cancer, which grows in response to estrogen. The study includes two groups: one receiving Ribociclib with hormone therapy, and the other receiving only hormone therapy. It seeks women diagnosed with this specific type of breast cancer who have completed surgery and are currently on hormone therapy. The goal is to determine if adding Ribociclib can improve treatment outcomes. Participants should not have any other major health conditions or cancers from the past five years. 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 all current medications, but you cannot take tamoxifen during the study with ribociclib. If you're on tamoxifen, you may need to switch to an aromatase inhibitor before or during screening. Also, you cannot take medications that affect CYP3A4, so check with your doctor about any other drugs you are taking.

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

Research has shown that treatment using Ribociclib with hormone therapy for ER-positive breast cancer is generally manageable for patients. Studies have tested Ribociclib with hormone therapy in many patients with similar conditions. Common side effects include tiredness, nausea, and low blood cell counts, but these can often be managed.

The FDA has already approved the treatment for some types of breast cancer, indicating it has passed safety checks for those uses. While this trial explores a new combination of Ribociclib and hormone therapy, earlier research supports its safety. Participants should discuss any concerns with their doctor and report any side effects during the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for breast cancer?

Ribociclib is unique because it targets a specific protein called CDK 4/6, which plays a crucial role in cancer cell growth. Unlike standard endocrine therapies that primarily focus on blocking hormones like estrogen, ribociclib works by inhibiting these proteins, potentially stopping cancer cells from multiplying. Researchers are excited about ribociclib because combining it with endocrine therapy could enhance treatment effectiveness, offering a new avenue for managing breast cancer more effectively than current options alone.

What evidence suggests that this trial's treatments could be effective for ER-positive Breast Cancer?

Research has shown that combining ribociclib with hormone therapy, which participants in this trial may receive, effectively treats ER-positive breast cancer. Studies have found that this combination helps patients live longer without cancer recurrence. Specifically, one study found that after three years, 90.8% of patients using ribociclib with hormone therapy remained free of invasive cancer, compared to lower rates for those using hormone therapy alone. This suggests that ribociclib can improve outcomes for breast cancer patients. ^{1 2 6 7 8}

Who Is on the Research Team?

Arielle Medford, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for women at least 18 years old with ER-positive, HER2-negative breast cancer who've had surgery and been on endocrine therapy for 6+ months without major issues. They should be within 10 years of diagnosis and plan to continue therapy for another year. No prior CDK 4/6 inhibitors, recent chemo or radiotherapy, other cancers in the last 5 years, or severe health conditions.

Inclusion Criteria

I have never used CDK 4/6 inhibitors.

I haven't had any cancer other than breast cancer in the last 5 years.

I am fully active or can carry out light work.

Exclusion Criteria

I am using effective birth control and will continue for 8 weeks after the study ends.

My cancer has spread to my brain or other parts of my body.

I am not taking drugs that affect CYP3A4 enzyme activity.

Timeline for a Trial Participant

Pre-screening

Pre-screening with ctDNA to detect minimal residual disease

2-4 weeks

Treatment

Participants receive ribociclib in combination with endocrine therapy

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Endocrine therapy
• Ribociclib

Trial Overview The study tests Ribociclib combined with adjuvant endocrine therapy as a treatment option for ER-positive breast cancer. Participants will have taken endocrine therapy previously and are now adding Ribociclib to see if it improves outcomes.

How Is the Trial Designed?

Group I: Ribociclib + Endocrine Rx Experimental Treatment 2 Interventions

Ribociclib will be administered. Endocrine therapy will be administered.

Group II: Endocrine Rx Active Control 1 Intervention

Endocrine therapy will be administered.

Ribociclib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Kisqali for:

• Breast cancer

Approved in United States as Kisqali for:

• Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer

Approved in Canada as Kisqali for:

• Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer

Approved in Japan as Kisqali for:

• Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer

Approved in Switzerland as Kisqali for:

• Hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

Ribociclib, a CDK4/6 inhibitor used in treating hormone receptor-positive metastatic breast cancer, was associated with a rare case of grade 3 acute kidney injury (AKI) in an elderly woman, leading to treatment discontinuation after recurrence upon re-initiation.

While previous studies (MONALEESA 2-3-7) reported no severe AKI cases causing treatment discontinuation, this case highlights the potential for serious kidney-related side effects, suggesting that close monitoring of kidney function is necessary during ribociclib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib induced acute kidney injury: A case report. Gulturk, I., Yilmaz, M., Ozmen, A., et al.[2022]

The addition of CDK4 and 6 inhibitors (like abemaciclib, palbociclib, or ribociclib) to endocrine therapy significantly improves progression-free survival and response rates in patients with HR+ and HER2- metastatic breast cancer, establishing these inhibitors as a new standard of care.

Exploratory analyses suggest that abemaciclib may be particularly beneficial for women with poor prognosis indicators, although further confirmation is needed for these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib, a CDK4 and CDK6 inhibitor for the treatment of metastatic breast cancer. Martin, M., Garcia-Saenz, JA., Manso, L., et al.[2021]

In Brazil, the lack of access to the CDK4/6 inhibitor ribociclib for premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer could lead to 538 premature deaths over six years, highlighting the drug's potential impact on survival rates.

The study estimated that using ribociclib in combination with endocrine therapy could significantly improve survival outcomes, with 1,805 patients surviving at 72 months compared to 1,267 patients receiving endocrine therapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of access to CDK4/6 inhibitors for premenopausal patients with metastatic breast cancer in Brazil: estimation of the number of premature deaths. Reinert, T., Pellegrini, R., Barrios, CH.[2022]

In the phase III MONALEESA trials, ribociclib, a CDK4/6 inhibitor, showed improved progression-free survival (PFS) in patients with hormone receptor-positive advanced breast cancer, particularly in those with specific gene alterations like ERBB2 and MDM2.

Patients with high tumor mutational burden and certain gene alterations (ANO1, CDKN2A/2B/2C, RB1) were found to be less sensitive to ribociclib, suggesting that these biomarkers could help tailor treatment strategies for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials. André, F., Su, F., Solovieff, N., et al.[2023]

Ribociclib, a CDK4/6 inhibitor used for treating HR-positive, HER-2 negative metastatic breast cancer, can lead to severe complications such as lactic acidosis when combined with metformin, especially in patients with preexisting renal issues.

A case study of a 62-year-old patient highlighted the risk of elevated serum creatinine and acute respiratory failure after starting ribociclib and fulvestrant, emphasizing the need for caution with drug interactions in long-term treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lactic acidosis, a potential toxicity from drug-drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: A case report. Lagampan, C., Poovorawan, N., Parinyanitikul, N.[2022]

The MONALEESA-7 trial demonstrated that adding the CDK4/6 inhibitor ribociclib to standard endocrine therapy significantly improved survival rates in premenopausal and perimenopausal women with advanced HR-positive, HER2-negative breast cancer.

This study provides the first definitive evidence supporting the effectiveness of CDK4/6 inhibitors as a first-line treatment option for this specific group of breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib Extends Survival in HR+ Breast Cancer. [2019]

Oral CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib significantly improve progression-free survival by 40-45% when combined with endocrine therapy in hormone-responsive HER2-negative advanced breast cancer, particularly in post-menopausal women.

These inhibitors have varying toxicity profiles and monitoring requirements, and ongoing clinical trials are exploring their use in other breast cancer subtypes and in combination with other therapies to overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of CDK4/6 Inhibitors in Breast Cancer. Murphy, CG.[2020]

In the phase 3b CompLEEment-1 trial involving 339 patients, ribociclib combined with letrozole showed a safety profile consistent with earlier pivotal trials, indicating it is a well-tolerated treatment for HR+/HER2- advanced breast cancer.

While 63.1% of patients experienced treatment-related adverse events, only 10.6% discontinued treatment, suggesting that ribociclib has manageable side effects, with no fatal events reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib plus letrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer with no prior endocrine therapy: subgroup safety analysis from the phase 3b CompLEEment-1 trial. Borstnar, S., Palacova, M., Łacko, A., et al.[2023]

In the MONALEESA-2 study involving 213 US patients with hormone receptor-positive, HER2-negative advanced breast cancer, ribociclib combined with letrozole significantly improved progression-free survival (PFS) to 27.6 months compared to 15.0 months with letrozole alone, indicating its efficacy as a first-line treatment.

The most common side effects of ribociclib included neutropenia (72%), nausea (69%), and fatigue (60%), highlighting the importance of monitoring for these adverse events during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. Yardley, DA., Hart, L., Favret, A., et al.[2020]

Ribociclib, approved by the FDA for treating advanced breast cancer, significantly improves progression-free survival when combined with letrozole compared to a placebo, as shown in a study of 668 patients.

The overall response rate for patients receiving ribociclib plus letrozole was 52.7%, compared to 37.1% for those on placebo, indicating its efficacy, although common side effects included neutropenia and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. Shah, A., Bloomquist, E., Tang, S., et al.[2019]

Ribociclib, a CDK 4/6 inhibitor, significantly improves median progression-free survival (PFS) in women with HR+/HER2- metastatic breast cancer when used in combination with endocrine therapy, with PFS ranging from 8 to 13 months across three phase III trials.

The treatment is well tolerated, particularly in elderly patients, and while it has some dose-limiting toxicities like neutropenia and QTc prolongation, it maintains health-related quality of life and reduces pain scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. Rascon, K., Flajc, G., De Angelis, C., et al.[2020]

In a phase 2 trial involving 106 postmenopausal women with early stage hormone receptor-positive, HER2-negative breast cancer, the combination of ribociclib and letrozole resulted in 46.9% of patients achieving low-risk-of-relapse (ROR) disease at surgery, similar to the 46.1% in the chemotherapy group.

The safety profile showed that while both treatments had significant adverse events, ribociclib plus letrozole had a lower incidence of severe neutropenia compared to chemotherapy, suggesting it may be a safer alternative for some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Prat, A., Saura, C., Pascual, T., et al.[2021]

Ribociclib is an effective CDK4/6 inhibitor approved for first-line treatment of hormone-receptor-positive/HER2-negative metastatic breast cancer, showing promise in overcoming hormone resistance.

The review highlights the importance of managing toxicity associated with ribociclib and discusses ongoing clinical trials exploring new combinations and settings for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer. López-Tarruella, S., Jerez, Y., Márquez-Rodas, I., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40996773/

Ribociclib Plus Endocrine Therapy in Hormone Receptor- ... Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs ...

2. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2839158

Ribociclib Plus Endocrine Therapy in Hormone Receptor ... Adjuvant endocrine therapy (ET) improves outcomes for patients with HR-positive/ERBB2-negative early breast cancer (EBC) and is standard of care ...

3. kisqali-hcp.com kisqali-hcp.com/metastatic-breast-cancer/efficacy/efficacy-across-trials

Efficacy Across Trials | mBC KISQALI + AI or fulvestrant is proven to help a broad range of patients with HR+/HER2- mBC live longer—and that means more time doing what they love.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05816655

Study Details | NCT05816655 | Comparison of ... The results of this study suggested that delaying the occurrence of ESR1 mutations and early response to them are necessary to increase the effectiveness of ...

5. esmoopen.com esmoopen.com/article/S2059-7029(25)01727-2/fulltext

Adjuvant ribociclib plus nonsteroidal aromatase inhibitor ... Ribociclib plus endocrine therapy in early breast cancer. N Engl J ... breast cancer: 4-year outcomes from the NATALEE randomized clinical trial.

6. novartis.com novartis.com/us-en/news/media-releases/novartis-kisqali-5-year-natalee-data-demonstrate-28-reduction-risk-recurrence-broadest-early-breast-cancer-patient-population

Novartis Kisqali® 5-year NATALEE data demonstrate 28% ... Results showed a 28.4% reduction in risk of recurrence (HR=0.716; 95% CI 0.618-0.829; nominal p-value <0.0001) in the broadest population of ...

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1911149

Overall Survival with Ribociclib plus Fulvestrant in ... Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor–positive, HER2- ...

8. us.kisqali.com us.kisqali.com/metastatic-breast-cancer/proven-results/results-with-kisqali

Clinical Trial Results | mBC Review clinical trial results in women living with HR+, HER2- metastatic breast cancer who were treated with KISQALI. See full Prescribing and Safety Info.