Ribociclib + Bicalutamide for Breast Cancer

Recruiting at 2 trial locations

Overseen By Amber Ryba

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ruth O'Regan, M.D.

Must not be taking: AR antagonists, CDK 4/6 inhibitors

Disqualifiers: Active infection, Pregnancy, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, ribociclib and bicalutamide, to determine their effectiveness in treating advanced androgen receptor-positive triple-negative breast cancer. The focus is on the safety and effectiveness of these drugs in patients whose cancer has spread or cannot be surgically removed. The trial is open to individuals with advanced triple-negative breast cancer who meet specific medical criteria, such as having undergone certain prior treatments. Participants must not have active brain involvement from their cancer and must be able to swallow the study medications. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the chance to contribute to groundbreaking research.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications. However, you must stop taking any strong inducers or inhibitors of CYP3A4/5, systemic corticosteroids, and herbal supplements like St. John's Wort at least 7-14 days before starting the study drugs. Also, you cannot take medications that prolong the QT interval or warfarin. Please consult with the trial team for specific guidance on your medications.

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

Research shows that the combination of ribociclib and bicalutamide is under investigation as a treatment for advanced AR+ triple-negative breast cancer. Studies have found that this combination can help nearly half of the patients by either shrinking their tumors or keeping their disease stable.

Regarding safety, ribociclib is already approved for use with other drugs for certain breast cancers, indicating its safety profile is well-known. Bicalutamide is used for prostate cancer, providing some information about its safety. However, since the combination of these two drugs is still under study, specific safety details are still being collected.

The trials are testing different doses to determine the safest and most effective amount. This careful testing helps identify any possible side effects and ensures the treatment is manageable. While specific side effects aren't listed here, the ongoing studies aim to understand the balance between benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining ribociclib and bicalutamide for breast cancer treatment because of their unique approach to targeting cancer cells. Unlike standard treatments, which often include chemotherapy and hormone therapy like tamoxifen or aromatase inhibitors, ribociclib is a CDK4/6 inhibitor that specifically blocks proteins involved in cell division, potentially slowing the growth of cancer cells. Bicalutamide, commonly used in prostate cancer, acts as an androgen receptor antagonist, which may enhance the effect of ribociclib by further interrupting cancer cell growth. This combination holds promise for offering a more targeted attack on breast cancer cells, possibly leading to improved outcomes for patients.

What evidence suggests that ribociclib and bicalutamide might be an effective treatment for advanced AR+ triple-negative breast cancer?

Research has shown that combining ribociclib with bicalutamide may help treat advanced AR+ (androgen receptor-positive) triple-negative breast cancer. In earlier studies, about 42% of patients experienced some benefit, and 25% had a complete response, meaning their cancer became undetectable. Another study found that 49% of patients saw benefits, including cancer shrinking or remaining stable. This trial will explore the effectiveness of this combination, as these results suggest it might help control the disease for some patients. ^{1 3 4 5 6}

Who Is on the Research Team?

Kari B. Wisinski

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for adults with advanced AR+ triple-negative breast cancer who haven't had certain treatments, have no active brain metastases, and whose major organs function well. They must not be pregnant or breastfeeding, agree to use contraception, and can swallow pills. Excluded are those with recent heart issues, strokes, uncontrolled conditions that could affect safety or compliance, known HIV infection or other active cancers needing treatment.

Inclusion Criteria

I am a woman who can have children and I have a recent negative pregnancy test.

I've been mostly active and able to care for myself in the last 28 days.

I can swallow pills.

Exclusion Criteria

I have not used CDK 4/6 inhibitors, except in a study for early-stage breast cancer.

You have eaten certain fruits within a week before joining the study.

I am taking medication that affects my heart's rhythm and cannot stop.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose escalation of ribociclib with bicalutamide to determine maximum tolerated dose

28 days per cycle

Multiple visits for dose escalation and monitoring

Phase II Treatment

Ribociclib at RP2D combined with bicalutamide for up to 4 cycles

16 weeks

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Bicalutamide
• Ribociclib

Trial Overview The study tests ribociclib in combination with bicalutamide on patients with a specific type of breast cancer (AR+ TNBC). It's an open-label phase II trial without randomization or blinding. Participants will receive both drugs to see how effective this combo is against their cancer.

How Is the Trial Designed?

Group I: Arm A - Phase I Experimental Treatment 2 Interventions

Dose Escalation Cohort 1 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-21 of a 28 day cycle. Cohort 2 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-28 of a 28 day cycle. Cohort 3 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 600mg PO daily on days 1-21 of a 28 day cycle. Experimental: Arm B - Phase II Investigational Treatment The maximum safe dose of ribociclib in combination with bicalutamide will be given to up to 25 patients.

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

Approved in European Union as Casodex for:

• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in United States as Casodex for:

• Metastatic prostate cancer

Approved in Japan as Casodex for:

• Metastatic prostate cancer
• Locally advanced prostate cancer

Approved in Canada as Casodex for:

• Metastatic prostate cancer
• Locally advanced prostate cancer

Who Is Running the Clinical Trial?

Ruth O'Regan, M.D.

Lead Sponsor

Trials

1

Recruited

40+

Kari Wisinski

Lead Sponsor

Trials

3

Recruited

120+

University of Wisconsin, Madison

Collaborator

Trials

1,249

Recruited

3,255,000+

Big Ten Cancer Research Consortium

Collaborator

Trials

11

Recruited

450+

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 is a selective oral inhibitor of CDK 4 and 6, specifically approved for treating hormone receptor-positive breast cancer.

When combined with an aromatase inhibitor, ribociclib significantly improves progression-free survival in patients with metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cycling Toward Progress: Ribociclib, a CDK 4/6 Inhibitor for Breast Cancer. Spring, L., Bardia, A.[2019]

Ribociclib, when combined with letrozole, significantly improves progression-free survival in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer, as shown in the MONALEESA-2 trial.

Ongoing trials (MONALEESA-3 and MONALEESA-7) further support ribociclib's efficacy, demonstrating significant progression-free survival benefits in both treatment-naive and previously treated postmenopausal patients, as well as in pre/perimenopausal women with ovarian function suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONALEESA clinical program: a review of ribociclib use in different clinical settings. Yardley, DA.[2020]

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 study of 51 patients undergoing treatment for prostate cancer with bicalutamide, localized radiotherapy improved gynaecomastia in about 26% and breast pain in about 32% of those treated, indicating some efficacy in managing these side effects.

The treatment was generally well-tolerated, with mild and short-lived adverse events reported in 44% of patients, suggesting that radiotherapy is a safe option for alleviating symptoms associated with bicalutamide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer. Van Poppel, H., Tyrrell, CJ., Haustermans, K., et al.[2014]

Bicalutamide, an androgen receptor antagonist approved for treating locally advanced prostate cancer, is associated with significant breast-related side effects, affecting nearly 90% of patients, leading to withdrawal in about 16% of cases.

Tamoxifen has shown promise as the most effective treatment for managing these breast events, but further research is needed to optimize its use and understand its impact on prostate cancer control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of bicalutamide-induced breast events. Sieber, PR.[2014]

In the phase III MONALEESA-7 trial, ribociclib combined with endocrine therapy significantly improved overall survival (OS) in pre-/perimenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer, with a median OS of 58.7 months compared to 48.0 months for the placebo group.

The study included 672 patients and showed that ribociclib not only delayed the time to first chemotherapy but also had consistent OS benefits across various subgroups, including those under 40 years old, indicating its efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Lu, YS., Im, SA., Colleoni, M., et al.[2023]

The phase IIIb CompLEEment-1 study demonstrated that ribociclib combined with letrozole is safe and effective for patients with hormone receptor-positive, HER2-negative advanced breast cancer, including high-risk subgroups such as those with CNS metastases and poor performance status.

No new safety concerns were identified, and the treatment showed manageable adverse effects, with all patient subgroups experiencing meaningful clinical benefits, confirming the efficacy of this combination therapy in populations often underrepresented in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib plus letrozole in subgroups of special clinical interest with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Subgroup analysis of the phase IIIb CompLEEment-1 trial. Cottu, P., Ring, A., Abdel-Razeq, H., et al.[2022]

Ribociclib, used for treating metastatic hormone-positive breast cancer, can cause severe liver toxicity, as demonstrated in a case where a 54-year-old woman developed acute fulminant toxic hepatitis after treatment.

Despite discontinuing ribociclib, the patient's liver toxicity persisted, highlighting the need for careful monitoring and alternative treatment options, such as exemestane, in cases of severe adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case report of fulminant hepatitis due to ribociclib with confirmed by liver biopsy in breast cancer. Topcu, A., Yasin, AI., Shbair, AT., et al.[2021]

Ribociclib, a CDK 4/6 inhibitor, has been shown to significantly improve progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer when used in combination with letrozole, based on the results of the MONALEESA-2 phase 3 trial involving a randomized, double-blind design.

The study highlights ribociclib's effectiveness across various patient subgroups, including those with different ages and disease histories, establishing it as a valuable treatment option for managing advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. Hortobagyi, GN.[2019]

LNCaP-Bic cells, which are resistant to the anti-androgen bicalutamide, show a significantly lower rate of apoptosis when treated with TRAIL compared to the non-resistant LNCaP cells, indicating a novel mechanism of resistance in prostate cancer.

The study found that TRAIL treatment unexpectedly increased Bcl-2 levels in LNCaP-Bic cells, suggesting alterations in the TRAIL-signaling pathway that contribute to their reduced sensitivity to apoptosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased resistance to trail-induced apoptosis in prostate cancer cells selected in the presence of bicalutamide. Mitterberger, M., Neuwirt, H., Cavarretta, IT., et al.[2014]

Bicalutamide, particularly at a 150-mg daily dose, is effective as a monotherapy for locally advanced prostate cancer, providing similar survival outcomes to castration, while also improving quality of life.

When combined with a luteinizing hormone-releasing hormone agonist (LHRH-A), a lower 50-mg daily dose of bicalutamide shows equivalent efficacy to flutamide, with the added benefit of better tolerability and longer median survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development. Kolvenbag, GJ., Blackledge, GR., Gotting-Smith, K.[2022]

In a study involving 1,218 patients with early prostate cancer, bicalutamide 150 mg significantly reduced the risk of disease progression by 57% compared to standard care alone, demonstrating its efficacy as an immediate therapy.

The study, with a median follow-up of 3 years, showed no difference in overall survival between bicalutamide and placebo, indicating that while it effectively delays disease progression, its impact on long-term survival is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer. First report from the Scandinavian Prostatic Cancer Group Study No. 6. Iversen, P., Tammela, TL., Vaage, S., et al.[2019]

The combination of antiestrogen therapy and ribociclib, a CDK4/6 inhibitor, significantly improved progression-free survival in women with metastatic HR-positive, HER2-negative breast cancer compared to letrozole alone.

These findings come from a large phase III trial, which may support FDA approval for this combination treatment, highlighting its potential efficacy in managing this type of breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib Lengthens Breast Cancer Survival. [2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12405098/

Advances of androgen receptor in triple-negative breast ... Preliminary findings demonstrated that 42% of patients showed a clinical benefit, with a pathological complete response (pCR) rate of 25% [78].

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03090165?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AMBER%20AND%20ten)))&rank=6

NCT03090165 | Ribociclib and Bicalutamide in AR+ TNBC This is a non-randomized, single arm, open label study of the combination of bicalutamide with ribociclib in subjects with advanced AR+ TNBC.

3. 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.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10705204/

Breast Cancer Treatment: To tARget or Not? That Is the Question This drug treatment was shown to achieve a CBR of 49%. This was measured by summing complete and partial responses as well as stable disease at or after 24 ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-04098

Ribociclib and Bicalutamide for the Treatment of Advanced ... Giving ribociclib and bicalutamide may help control the disease in patients with AR positive triple negative breast cancer. Eligibility Criteria ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03090165

NCT03090165 | Ribociclib and Bicalutamide in AR+ TNBC This is a non-randomized, single arm, open label study of the combination of bicalutamide with ribociclib in subjects with advanced AR+ TNBC.