Ribociclib + Everolimus for Brain Tumors

Recruiting at 20 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

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining two drugs, ribociclib and everolimus (also known as Afinitor, Votubia, or Zortress), or ribociclib and temozolomide, can extend the lives of children and young adults with specific aggressive brain tumors. It targets high-grade gliomas (HGG) and diffuse hemispheric gliomas (DHG) with genetic changes affecting cell growth pathways. Those recently diagnosed with these conditions and possessing specific genetic markers in their tumors might be suitable candidates. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research shows that the combination of ribociclib and everolimus is generally well-tolerated by children with certain brain tumors. In earlier studies, children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG) received this combination after radiotherapy. The treatment was mostly well-received, and researchers determined a recommended dose for further study. No specific reports of severe side effects emerged in these trials, suggesting that the combination is relatively safe for this group.

For ribociclib and temozolomide, each drug has been studied separately and approved for certain conditions, providing some confidence in their safety. However, using them together in this trial remains under investigation, so more information may be needed to fully confirm their safety.

Overall, current safety data suggest that both treatment combinations in this trial are tolerable for most patients, though further study is always necessary to enhance understanding. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for high-grade gliomas (HGGs), which typically involve surgery, radiation, and chemotherapy, the combination of Ribociclib and Everolimus offers a unique approach by targeting specific pathways in cancer cells. Ribociclib is a CDK4/6 inhibitor that disrupts the cancer cell cycle, potentially halting tumor growth, while Everolimus, an mTOR inhibitor, interferes with cancer cell metabolism and proliferation. Researchers are excited about these treatments because they focus on molecular targets that could lead to more effective and personalized therapies for brain tumors, potentially improving outcomes for patients who have limited options with current treatments.

What evidence suggests that this trial's treatments could be effective for brain tumors?

Research has shown that combining ribociclib and everolimus may help treat brain tumors like high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG). In this trial, participants will be assigned to different strata based on their specific type of brain tumor, such as Stratum A for localized, intracranial, non-pontine, and non-thalamic HGG, or Stratum B for DIPG. An earlier study found that two out of five patients with certain brain tumors responded positively to this drug combination, indicating it might shrink tumors or slow their growth. These drugs target key pathways that promote tumor cell growth, potentially managing these aggressive cancers. While more research is needed, the initial results offer promise for those considering this treatment. ^{1 2 3 4 6}

Who Is on the Research Team?

Maryam Fouladi, MD

Principal Investigator

Nationwide Children's Hospital

Margot Lazow, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Stratum E (n=20) Experimental Treatment 2 Interventions

Patients with localized H3G34-mutant DHG

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

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

Group IV: 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 V: 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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05843253

Study of Ribociclib and Everolimus in HGG and DIPG or ... The goal of this study is to determine the efficacy of the 1) ribociclib and everolimus to treat pediatric and young adult patients newly diagnosed with a ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9122788/

Phase I study of ribociclib and everolimus in children with ... The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03355794

NCT03355794 | A Study of Ribociclib and Everolimus ... The combination of ribociclib and everolimus has not been tested in children or in people with brain tumors and is considered investigational. The goals of ...

4. cincinnatichildrens.org cincinnatichildrens.org/service/c/clinical-trials/studies/TarGeT-A-052925

Study of Ribociclib and Everolimus in HGG and DIPG The goal of this study is to determine the efficacy of the study drugs ribociclib and everolimus to treat pediatric and young adult patients newly diagnosed ...

5. withpower.com withpower.com/trial/phase-2-glioblastoma-7-2023-79346

Ribociclib + Everolimus for Brain Tumors In a study with a similar drug combination, two out of five patients with specific brain tumors showed a positive response, suggesting potential effectiveness.

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

A Phase I and surgical study of ribociclib and everolimus in ... Outcome for recurrent or refractory malignant brain tumors remains poor, despite aggressive multimodal therapy. Improved understanding of the genomic landscape ...