Ribociclib + Everolimus for Brain Tumors

Recruiting at 17 trial locations

Overseen By Kelsey H Troyer, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Nationwide Children's Hospital

Must not be taking: Investigational drugs, Anticancer agents, others

Disqualifiers: Pregnancy, Uncontrolled infection, 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: 28

Duration: 24 months

100 Participants Needed

Trial Summary

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

The trial protocol does not specify if you must stop taking your current medications, but you cannot take certain drugs. You cannot be on other investigational drugs, certain anti-cancer agents, strong enzyme inducers or inhibitors of CYP3A4/5, medications that prolong the QTc interval, or certain anticoagulants like warfarin. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination Ribociclib and Everolimus for brain tumors?

Research shows that Everolimus, when combined with other drugs, can effectively inhibit tumor growth by blocking important pathways that cancer cells use to survive. In a study with a similar drug combination, two out of five patients with specific brain tumors showed a positive response, suggesting potential effectiveness. ^{1 2 3 4 5}

Is the combination of Ribociclib and Everolimus safe for treating brain tumors?

In a study with children having brain tumors, Ribociclib and Everolimus were tested to find the safest dose, and no major safety issues were reported. Everolimus, used alone in other conditions, has shown some risks like low blood cell counts, but serious side effects were rare. ^{1 3 6 7 8}

How is the drug combination of Ribociclib and Everolimus unique for treating brain tumors?

The combination of Ribociclib and Everolimus is unique because it targets both the cell cycle and PI3K pathways, which are commonly altered in brain tumors, potentially offering a more effective treatment by addressing multiple pathways involved in tumor growth. ^{1 3 4 7 9}

What is the purpose of this trial?

This trial is testing whether the combination of ribociclib and everolimus can help children and young adults with aggressive brain tumors live longer. Everolimus is a medication that has been approved for treating various cancers. These drugs are taken by mouth and work by stopping cancer cells from growing. The study focuses on patients whose tumors have specific genetic changes that make them hard to treat with standard therapies.

Research Team

Maryam Fouladi, MD

Principal Investigator

Nationwide Children's Hospital

Margot Lazow, MD

Principal Investigator

Nationwide Children's Hospital

Eligibility Criteria

This trial is for young patients aged between 1 and 30 with high-grade gliomas, including DIPG. They must have a specific body surface area, certain genetic tumor changes, and be able to perform daily activities at least half the time. Pregnant individuals or those on certain drugs that affect liver enzymes or prolong QTc interval are excluded.

Inclusion Criteria

My vital organs, including my heart, lungs, and liver, are working well.

I've had surgery, radiation, and dexamethasone for my brain cancer.

My cancer has a specific genetic change that can be targeted by treatment.

Exclusion Criteria

My cancer does not have a specific genetic change known as biallelic RB1 loss.

I am not on any other cancer drugs or investigational drugs that could affect absorption.

Pregnant or breast-feeding women are not eligible for the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiotherapy

Participants undergo radiotherapy as part of the initial treatment phase

4-6 weeks

Treatment

Participants receive ribociclib and everolimus post-radiotherapy for up to 26 cycles

24 months

Monthly visits for each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

Treatment Details

Interventions

• Everolimus
• Ribociclib

Trial Overview The study tests Ribociclib and Everolimus in children and young adults with brain tumors like HGG/DIPG. It aims to see if these drugs can extend patients' lives by targeting specific genetic pathways involved in their cancer.

Participant Groups

Group I: Stratum D (n=6-12) Experimental Treatment 2 Interventions

Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation.

Group II: Stratum C (n=6-12) Experimental Treatment 2 Interventions

Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG.

Group III: Stratum B (n=40) Experimental Treatment 2 Interventions

Patients with DIPG, defined as a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4 glioma (e.g., diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma).

Group IV: Stratum A (n=40) Experimental Treatment 2 Interventions

Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata B, C, or D).

Everolimus is already approved in United States, European Union for the following indications:

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Nationwide Children's Hospital

Lead Sponsor

Trials

354

Recruited

5,228,000+

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

Findings from Research

In a phase 1 trial involving five pediatric and young adult patients with BRAFV600-mutated brain tumors, the combination of vemurafenib (a BRAF inhibitor) and everolimus (an mTOR inhibitor) showed promising results, with 40% of patients achieving a partial response and 20% maintaining stable disease for 12 months.

No patients experienced treatment discontinuation due to adverse events, suggesting that this combination therapy is safe and warrants further investigation for treating BRAF-mutant brain cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. Sen, S., Tanaka, R., Khatua, S., et al.[2021]

In a phase Ib trial with 19 patients, the combination of BEZ235 and everolimus showed limited efficacy in treating advanced tumors, with no confirmed tumor responses observed.

The study revealed that while BEZ235's systemic exposure increased with higher doses, its low oral bioavailability and gastrointestinal toxicity may hinder its effectiveness, and the combination altered the pharmacokinetics of everolimus, indicating potential drug-drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. Wise-Draper, TM., Moorthy, G., Salkeni, MA., et al.[2022]

Ribociclib and everolimus were found to be well-tolerated in a study involving 22 pediatric patients, with a recommended phase II dose established at 120 mg/m2 for ribociclib and 1.2 mg/m2 for everolimus, indicating their potential safety for use in children with brain tumors.

The study demonstrated that ribociclib achieved significantly higher concentrations in tumor tissue compared to plasma, with a mean tumor-to-plasma ratio of 19.8, suggesting effective delivery of the drug to the site of the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study. DeWire, MD., Fuller, C., Campagne, O., et al.[2023]

In a phase I study involving 94 patients with advanced non-small-cell lung cancer (NSCLC), the combination of the mTOR inhibitor everolimus and the EGFR inhibitor erlotinib showed acceptable tolerability, with maximum tolerated doses established at 5 mg of everolimus daily or 50 mg weekly alongside 150 mg of erlotinib daily.

The combination therapy resulted in disease control for a median duration of 9.3 months in patients receiving daily everolimus, with some achieving complete or partial responses, indicating potential efficacy in treating chemotherapy-refractory NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. Papadimitrakopoulou, VA., Soria, JC., Jappe, A., et al.[2015]

The combination of everolimus (RAD001) and the ATP-competitive mTOR inhibitor NVP-BEZ235 shows strong synergy in inhibiting mTOR pathway activation and tumor growth across various cancer types, including neuronal, renal, breast, lung, and hematopoietic cancers.

Using RAD001 allows for lower doses of BEZ235 to effectively inhibit tumor growth, which is important because RAD001 has a favorable safety profile, while the toxicity of BEZ235 is still being evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth. Nyfeler, B., Chen, Y., Li, X., et al.[2021]

The combination of everolimus and vatalanib (PTK/ZK) showed at least additive and potentially synergistic anti-tumor effects in a mouse model of melanoma, enhancing efficacy without increasing toxicity compared to either drug alone.

Pharmacokinetic studies revealed that vatalanib increased the plasma concentration of everolimus, but this interaction did not fully explain the enhanced anti-tumor activity, suggesting that the two drugs may work together through distinct mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. O'Reilly, T., Lane, HA., Wood, JM., et al.[2021]

In a study of 78 patients with metastatic renal cell carcinoma (mRCC) treated with everolimus, the median progression-free survival was 7 months, indicating a significant clinical benefit for patients who had previously failed VEGF-targeted therapies.

The treatment was generally well-tolerated, with serious adverse events occurring in only 6% of patients, primarily respiratory toxicity, suggesting that everolimus has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Metastatic renal cell carcinoma treated with everolimus--data from the RENIS Clinical Registry]. Büchler, T., Dusek, L., Fínek, J., et al.[2021]

A systematic review of phase II and III trials involving patients with solid tumors taking 10mg of everolimus daily revealed significant hematologic toxicities, with anemia occurring in 61.2% of patients and thrombocytopenia in 36.0%.

Everolimus significantly increases the risk of various hematologic toxicities, including high-grade thrombocytopenia (RR=7.46) and high-grade anemia (RR=3.92), indicating a need for careful monitoring of blood cell counts in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of hematologic toxicities in patients with solid tumors treated with everolimus: a systematic review and meta-analysis. Funakoshi, T., Latif, A., Galsky, MD.[2018]

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]

References

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

Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. [2021]

2. France pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. [2022]

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

A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study. [2023]

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

Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer. [2015]

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

RAD001 enhances the potency of BEZ235 to inhibit mTOR signaling and tumor growth. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. [2021]

7. Czech Republic pubmed.ncbi.nlm.nih.gov

[Metastatic renal cell carcinoma treated with everolimus--data from the RENIS Clinical Registry]. [2021]

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

Risk of hematologic toxicities in patients with solid tumors treated with everolimus: a systematic review and meta-analysis. [2018]

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

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