Ribociclib + Endocrine Therapy for Breast Cancer Recurrence

(RaPhLRR Trial)

Recruiting at 16 trial locations

Overseen By Oana Danciu

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Oana Danciu

Must be taking: Endocrine therapy

Must not be taking: CDK4/6 inhibitors, Corticosteroids

Disqualifiers: Distant metastases, Major surgery, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 36 months

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, multicenter, single arm phase II study to evaluate the efficacy and safety of ribociclib and ET in patients with locoregional recurrence of HR-positive, HER2-negative breast cancer.

Will I have to stop taking my current medications?

If you are taking tamoxifen or toremifene, you will need to stop and have a washout period (time without taking these medications) of 35 days before starting the trial. Additionally, you cannot take certain medications, herbal supplements, or fruits that affect liver enzymes (CYP3A4/5) starting 7 days before the trial. Other medications may need to be reviewed by the study team.

What data supports the effectiveness of the drug Ribociclib combined with endocrine therapy for breast cancer recurrence?

Research shows that combining Ribociclib with letrozole significantly improves progression-free survival (the time during and after treatment that a patient lives with the disease without it getting worse) in patients with hormone receptor-positive, HER2-negative advanced breast cancer compared to letrozole alone. ^{1 2 3 4 5}

Is Ribociclib plus Endocrine Therapy safe for humans?

Ribociclib, when combined with letrozole, has been shown to have a manageable safety profile in treating advanced breast cancer. Common side effects include low white blood cell counts, nausea, tiredness, diarrhea, hair loss, vomiting, constipation, headache, and back pain. ^{3 5 6 7 8}

What makes the drug Ribociclib combined with endocrine therapy unique for breast cancer treatment?

Ribociclib, when combined with endocrine therapy like letrozole or fulvestrant, is unique because it significantly improves progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer compared to endocrine therapy alone. This combination is particularly effective for both premenopausal and postmenopausal women, offering a novel approach by targeting specific proteins (CDK 4/6) that help cancer cells grow. ^{1 2 3 4 9}

Research Team

Oana Danciu

Principal Investigator

University of Illinois at Chicago

Eligibility Criteria

This trial is for adults with hormone receptor positive, HER2-negative breast cancer that has locally recurred. They must be able to take oral medication, have good organ function and performance status, and not be pregnant or breastfeeding. Exclusions include prior CDK4/6 inhibitor treatment for recurrence, severe medical conditions, certain heart diseases, other malignancies affecting safety assessments, major surgery within 14 days before the study drug starts or GI issues affecting drug absorption.

Inclusion Criteria

I am 18 years old or older.

I finished my last cancer treatment less than 6 months ago.

I can safely receive hormone therapy as part of my treatment plan.

Exclusion Criteria

I do not have any severe health issues that would make it unsafe for me to join the study.

Treatment with any investigational drug within 30 days prior to registration or participation in any other type of medical research judged not to be scientifically or medically compatible with this study

I have Long QT syndrome or a family history of sudden death.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ribociclib and endocrine therapy of physician's choice. Ribociclib is administered at 400 mg daily for 21 days out of a 28-day cycle, and ET is administered as per physician's choice.

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of recurrence-free survival and overall survival.

3 years

Extension

Participants may continue endocrine therapy for up to 60 months as per physician's choice.

24 months

Treatment Details

Interventions

• Anastrozole
• Exemestane
• Fulvestrant
• Letrozole
• Ribociclib

Trial Overview The trial tests the effectiveness and safety of ribociclib combined with a physician's choice of endocrine therapy (Letrozole, Exemestane, Fulvestrant or Anastrozole) in patients who've had local breast cancer recurrence. It's an open label phase II study where all participants receive the same treatment without a comparison group.

Participant Groups

Group I: Investigational Group Experimental Treatment 5 Interventions

The drug ribociclib will be taken orally at a dose of 400 mg daily for 21 days out of a 28-day cycle. Ribociclib will be used in combination with ET per physician choice. All new subjects enrolled under the 08JUL2024 protocol or after will receive ribociclib 400mg daily for 21 days out of a 28-day cycle. Subjects receiving 600mg ribociclib under a prior protocol version will be switched to 400mg. Physician's choice of endocrine therapy includes: * 500 mg of fulvestrant received intramuscularly. This will be taken on Day 1 and Day 15 of Cycle 1 and on Day 1 of Cycle 2 and beyond. * 1 mg of anastrozole taken orally daily of the 28 day cycle. * 2.5 mg of letrozole taken orally daily of the 28 day cycle. * 25 mg of exemestane taken orally daily of the 28 day cycle. * Concomitant use with tamoxifen is not allowed. Premenopausal subjects must also be treated with ovarian suppression according to institutional standards or have undergone bilateral oophorectomy.

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

Approved in European Union as Arimidex for:

• Breast cancer
• Early breast cancer in postmenopausal women

Approved in United States as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Approved in Japan as Arimidex for:

• Breast cancer

Who Is Running the Clinical Trial?

Oana Danciu

Lead Sponsor

Trials

1

Recruited

200+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

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]

In a study of 600 patients with hormone receptor-positive, HER2-negative metastatic breast cancer, both ribociclib and palbociclib combined with letrozole showed similar benefits in progression-free survival and overall survival.

The findings suggest that while both treatments are effective, the choice between ribociclib and palbociclib may depend on individual factors like endocrine sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment efficacy of ribociclib or palbociclib plus letrozole in hormone receptor-positive/HER2-negative metastatic breast cancer. Kahraman, S., Erul, E., Seyyar, M., et al.[2023]

In the MONALEESA-7 trial involving 672 premenopausal women with advanced HR-positive breast cancer, ribociclib combined with endocrine therapy significantly improved progression-free survival (23.8 months) compared to placebo (13.0 months), indicating its efficacy as a first-line treatment option.

The safety profile of ribociclib was manageable, with common grade 3 or 4 adverse events like neutropenia occurring in 61% of patients, but no treatment-related deaths were reported, suggesting that while there are risks, the benefits may outweigh them for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Tripathy, D., Im, SA., Colleoni, M., et al.[2022]

Ribociclib, when combined with letrozole or fulvestrant, has shown improved progression-free survival and overall survival in postmenopausal women with hormone receptor-positive breast cancer, based on a Phase III study involving 668 participants.

While ribociclib is effective, it has a higher risk of liver function abnormalities and can cause QTc prolongation, making it less suitable for patients with certain cardiac conditions; alternative CDK 4/6 inhibitors like palbociclib or abemaciclib may be safer options in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. Parati, MC., Pedersini, R., Perego, G., et al.[2022]

In a study of 554 Italian patients with hormone receptor-positive, HER2-negative advanced breast cancer, ribociclib combined with letrozole showed a clinical benefit rate of 71.7% and a median time to progression of 26.7 months, indicating effective treatment outcomes.

The treatment was associated with manageable safety profiles, with 98.9% of patients experiencing all-grade adverse events, primarily neutropenia, but health-related quality of life scores remained stable during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study. De Laurentiis, M., Caputo, R., Mazza, M., et al.[2022]

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]

In the MONALEESA-2 study involving 668 postmenopausal women with advanced breast cancer, ribociclib combined with letrozole significantly improved progression-free survival (PFS) to 25.3 months compared to 16.0 months for placebo plus letrozole, demonstrating a strong treatment benefit.

The safety profile of ribociclib plus letrozole remained manageable over an extended follow-up period, with no new toxicities reported, indicating that this combination therapy is both effective and safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Hortobagyi, GN., Stemmer, SM., Burris, HA., et al.[2022]

In the phase 3 MONALEESA-2 study involving 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, the combination of ribociclib (RIB) and letrozole (LET) significantly improved the duration of response (DoR) to 26.7 months compared to 18.6 months with placebo plus LET.

Patients receiving RIB also experienced greater tumor shrinkage and pain reduction, with 32% showing a significant tumor response at 8 weeks, reinforcing the efficacy of RIB plus LET as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial. Janni, W., Alba, E., Bachelot, T., et al.[2019]

Ribociclib, when combined with letrozole, has shown significant efficacy in treating hormone receptor positive (HR+) and HER2-negative advanced breast cancer, as evidenced by a complete clinical response in a postmenopausal patient with aggressive disease after just three months of treatment.

The treatment was well tolerated with minimal side effects, and the patient maintained a complete response for 15 months, highlighting the potential for long-lasting benefits in managing advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Clinical Response in Locally Advanced Metastatic de novo Breast Cancer after Front-Line Treatment with Ribociclib/Letrozole within the RIBANNA Study. Rudlowski, C., Beermann, N., Leitzen, L., et al.[2022]

References

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

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Treatment efficacy of ribociclib or palbociclib plus letrozole in hormone receptor-positive/HER2-negative metastatic breast cancer. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Ribociclib in the Treatment of Hormone-Receptor Positive/HER2-Negative Advanced and Early Breast Cancer: Overview of Clinical Data and Patients Selection. [2022]

5. France pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study. [2022]

6. United States 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. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Complete Clinical Response in Locally Advanced Metastatic de novo Breast Cancer after Front-Line Treatment with Ribociclib/Letrozole within the RIBANNA Study. [2022]