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

48 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Ribociclib for brain cancer?

Ribociclib has shown promise in treating a type of brain cancer called medulloblastoma in mice, where it slowed tumor growth and increased survival when used with another drug, gemcitabine. This suggests it might be effective for brain cancer, although more research is needed. ^{1 2 3 4 5}

Is ribociclib safe for use in humans?

Ribociclib, also known as Kisqali, has been studied for safety in patients with advanced breast cancer. Common side effects include low white blood cell counts, nausea, tiredness, diarrhea, hair loss, vomiting, constipation, headache, and back pain. These side effects are generally manageable with careful monitoring and dose adjustments. ^{1 2 6 7 8}

What makes the drug Ribociclib unique for treating brain cancer?

Ribociclib is unique because it is an oral drug that can penetrate the brain, which is crucial for treating brain tumors. It works by inhibiting specific proteins (CDK4/6) that are important for cancer cell growth, potentially stopping the cancer cells from multiplying. ^{1 2 4 6 9}

What is the purpose of this trial?

In the proposed trial, patients will be administered ribociclib prior to surgical resection of their tumor. Patients will be enrolled in time-intervals sequentially (non-randomized). All patients will be orally-administered 5 doses of LEE011 (900 mg/d) with the final dose occurring at one of 3 intervals before brain tumor resection.

Research Team

Nader Sanai, MD

Principal Investigator

Deputy Director of the Ivy Brain Tumor Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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]

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]

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 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]

References

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

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]

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

Pharmaceutical Approval Update. [2020]

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

Combination of Ribociclib and Gemcitabine for the Treatment of Medulloblastoma. [2023]

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

Ribociclib: First Global Approval. [2018]

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. Germany pubmed.ncbi.nlm.nih.gov

CNS penetration of the CDK4/6 inhibitor ribociclib in non-tumor bearing mice and mice bearing pediatric brain tumors. [2020]

7. 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]

8. England pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of ribociclib in metastatic breast cancer patients: Does dose affect survival? [2023]

9. England pubmed.ncbi.nlm.nih.gov

Determination of total and unbound ribociclib in human plasma and brain tumor tissues using liquid chromatography coupled with tandem mass spectrometry. [2020]