Ribociclib for Brain Cancer

Overseen By Phase 0 Navigator

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nader Sanai

Must not be taking: CYP3A4/5 inducers/inhibitors, Warfarin

Disqualifiers: Concurrent malignancy, Heart disease, HIV, 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

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

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ribociclib, a medication that could help treat brain cancer. Researchers aim to understand how ribociclib works when administered before surgery to remove brain tumors. Participants will receive ribociclib at different times before their tumor surgery to study its effects. Individuals with a history of aggressive brain tumors, such as gliomas or meningiomas, that have recurred and are confirmed through MRI scans might be suitable candidates. As an Early Phase 1 trial, this research focuses on understanding ribociclib's effects in people, offering participants a chance to be among the first to receive this potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped before starting the study drug. If you are taking tamoxifen or toremifene, a washout period (time without taking the medication) of 5 half-lives is needed. Additionally, medications that strongly affect liver enzymes (CYP3A4/5) or those with a risk of heart rhythm issues must be stopped 7 days before starting the study drug.

Is there any evidence suggesting that ribociclib is likely to be safe for humans?

Research has shown that ribociclib, a drug commonly used for breast cancer, might also help treat certain brain tumors. Studies have found that ribociclib can effectively reach the brain and slow tumor growth by targeting specific proteins in cancer cells.

Regarding safety, previous studies have shown that ribociclib is well-tolerated. For instance, in one study where ribociclib was combined with another drug, patients managed the treatment without serious side effects. Ribociclib is already approved for breast cancer treatment, indicating a known safety profile. However, individual experiences can differ, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Ribociclib is unique because it targets specific proteins in cancer cells known as CDK4/6, which are crucial for cell division. Unlike traditional treatments for brain cancer, such as chemotherapy and radiation that attack rapidly dividing cells in general, ribociclib is designed to specifically halt the growth of cancer cells by disrupting their cycle. This targeted approach could potentially lead to fewer side effects and improved effectiveness. Researchers are excited about ribociclib because it offers a novel mechanism of action that could pave the way for more personalized and less invasive treatment options for brain cancer patients.

What evidence suggests that ribociclib might be an effective treatment for brain cancer?

Research shows that ribociclib, a drug approved for breast cancer, may help treat brain conditions. It has effectively treated breast cancer that has spread to the brain. Researchers hope ribociclib might also slow the growth of certain childhood brain tumors. However, earlier studies with recurrent glioblastoma (a type of brain cancer) found ribociclib alone was not very effective. In this trial, participants will receive ribociclib before surgical resection of their tumor to study its effects on brain tumor cells, including potential changes in their growth or survival. ^{1 2 3 6 7}

Who Is on the Research Team?

Nader Sanai, MD

Principal Investigator

Deputy Director of the Ivy Brain Tumor Center

Are You a Good Fit for This Trial?

Adults with recurrent glioma or meningioma who've had one prior surgery, can sign consent, and meet specific lab criteria. They must not have used ribociclib before, have other recent cancers (except certain skin/cervical cancers), significant heart issues, uncontrolled medical conditions, known hypersensitivity to ribociclib's components or be pregnant/nursing.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable)

Patient has voluntarily agreed to participate by giving written informed consent (personally or via legally-authorized representative(s), and assent if applicable)

You must have recovered from any side effects of previous cancer treatments, except for hair loss.

Exclusion Criteria

You have a history of being infected with HIV.

You have been treated with ribociclib before.

You have had another type of cancer within the past 3 years, except for certain types of skin cancer or cervical cancer that has been successfully treated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-surgical Treatment

Participants receive 5 doses of ribociclib (900 mg/d) prior to surgical resection of their tumor

1 week

1 visit (in-person)

Surgical Resection

Surgical resection of the brain tumor is performed after the final dose of ribociclib

1 day

1 visit (in-person)

Post-surgical Treatment

Patients with positive PK and PD effects continue treatment with ribociclib (21 days on, 7 days off) until unacceptable toxicity or disease progression

Variable, based on patient response

Follow-up

Participants are monitored for safety and effectiveness after treatment using radiographic and clinical response metrics

Until disease progression or unacceptable toxicity

What Are the Treatments Tested in This Trial?

Interventions

• Ribociclib

Trial Overview The trial tests Ribociclib given orally in 5 doses before tumor removal surgery. Patients are enrolled sequentially based on time intervals rather than randomized. The last dose is timed at one of three set periods before the operation.

How Is the Trial Designed?

Group I: Administration of ribociclib Experimental Treatment 1 Intervention

Subjects will be administered ribociclib prior to surgical resection of their tumor. All patients will be orally-administered 5 doses of LEE011 (900 mg/d) with the final dose occurring at one of 3 following intervals before brain tumor resection: Cohort 1: last ribociclib dose 2-4 hours prior to craniotomy for tumor resection Cohort 2: last ribociclib dose 6-8 hours prior to craniotomy for tumor resection Cohort 3: last ribociclib dose 23-25 hours prior to craniotomy for tumor resection

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?

Nader Sanai

Lead Sponsor

Trials

11

Recruited

440+

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

Ivy Brain Tumor Center

Collaborator

Trials

12

Recruited

910+

Barrow Neurological Institute

Collaborator

Trials

27

Recruited

7,100+

Published Research Related to This Trial

In a real-world study of 53 women with HR+/HER2- metastatic breast cancer treated with ribociclib, the most common adverse event was neutropenia, affecting 69.8% of patients, but these side effects were manageable with monitoring and dose adjustments.

The median progression-free survival (PFS) for patients on ribociclib was 27.3 months, and importantly, dose reductions did not correlate with disease progression, suggesting that ribociclib remains effective even with adjusted dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of ribociclib in metastatic breast cancer patients: Does dose affect survival? Fernández-Cuerva, C., Chinchilla-Alarcón, T., Alcaraz-Sánchez, JJ.[2023]

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]

Ribociclib is an oral medication that inhibits CDK 4 and 6, leading to cell cycle arrest in cancer cells, and has been approved in the USA for treating advanced breast cancer in combination with an aromatase inhibitor.

The drug is currently undergoing further phase III trials for breast cancer and is being tested in early-phase trials for other types of solid tumors and blood cancers, highlighting its potential as a versatile cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib: First Global Approval. Syed, YY.[2018]

Ribociclib (Kisqali) is effective for treating HR+/HER2- advanced or metastatic breast cancer in postmenopausal women, providing a targeted therapy option for this patient group.

Safinamide (Xadago) serves as an adjunctive treatment for patients with Parkinson's disease, enhancing overall management of the condition, while avelumab (Bavencio) is approved for metastatic Merkel cell carcinoma, demonstrating its efficacy in a rare and aggressive skin cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmaceutical Approval Update. Choy, M.[2020]

Ribociclib, a CDK4/6 inhibitor, effectively penetrates the central nervous system and, when combined with gemcitabine, significantly slows tumor progression and increases survival in mouse models of Group 3 medulloblastoma (G3MB).

The combination therapy was well tolerated and led to a notable decrease in genes associated with cell-cycle progression and DNA damage response, while promoting genes linked to neuronal identity, suggesting a potential new treatment strategy for children with this aggressive form of brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Ribociclib and Gemcitabine for the Treatment of Medulloblastoma. Pribnow, A., Jonchere, B., Liu, J., et al.[2023]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6863147/

A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma ... Ribociclib monotherapy showed limited clinical efficacy in patients with recurrent glioblastoma. Combination therapy with CDK4/6 and PI3K/mTOR ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02345824

Early-Phase Study to Assess Inhibitor Ribociclib in Patients ... This will be completed to assess whether ribociclib treatment induces changes in brain tumor cell fate (proliferation, apoptosis, senescence) and E2F activation ...

3. thebraintumourcharity.org thebraintumourcharity.org/news/research-news/our-research-reveals-ribociclib-as-potential-new-drug-to-target-rare-childhood-brain-tumour/

Ribociclib - a potential new drug to for rare childhood ... Ribociclib is a drug used to treat breast cancer but our research suggests it may help slow the growth of a rare childhood brain tumour.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7650094/

Ribociclib in Breast Cancer Brain Metastases: A Case Report Our case shows clinical evidence that an endocrine combination therapy with ribociclib is effective in breast cancer brain metastases, which is also supported ...

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

Clinical Trial Results | mBC KISQALI + hormone therapy has been proven to help people like you live longer · With KISQALI + hormone therapy, half of all patients with HR+, HER2- mBC:.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8132306/

A Phase I and surgical study of ribociclib and everolimus in ... Ribociclib and everolimus were well tolerated and demonstrated similar pharmacokinetic properties as in adults. Potential therapeutic ribociclib concentrations ...

7. physicianresources.dana-farber.org physicianresources.dana-farber.org/news/adolescent-glioma-subtype-responds-to-cdk4/6-inhibitor

Adolescent Glioma Subtype Responds to CDK4/6 Inhibitor ... safety data needed to administer the medicine safely. When treated with ribociclib, the patient's cancer stopped progressing for 18 months.