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Ribociclib and Everolimus or Temozolomide for High-Grade Glioma and DIPG

This study is testing two drug combinations for children and young adults (ages 12 months to 39 years) with certain types of brain tumors: high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), or diffuse hemispheric glioma (DHG) with a specific genetic change (H3G34-mutant). One combination uses ribociclib and everolimus, which target specific pathways (cell cycle, PI3K/mTOR) in cancer cells. The other combination uses ribociclib and temozolomide. The main goal is to see if these treatments can help patients live longer without their disease getting worse. For some patients, the study will also determine the safest and most effective dose of ribociclib and everolimus. The study is looking for about 120 participants.

Study design
This is an interventional study, meaning participants will receive specific treatments. It is a multicenter, international Phase 2 study.
What's involved
Ribociclib is taken by mouth daily for 21 days. Everolimus is taken by mouth daily for 28 days. Temozolomide is taken by mouth daily for 5 days for the first 13 cycles.
Compensation
Not stated in the trial record.
Follow-up
Progression-Free Survival will be assessed for up to 60 months. Overall Survival will be assessed for up to 60 months.

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NCT05843253

Study of Ribociclib and Everolimus in HGG and DIPG or Ribociclib and Temozolomide in DHG, H3G34-mutant

Recruiting
PHASE2Ages 12–39InterventionalTreatment
Nationwide Children's Hospital
~120 participants
Updated 2026-05-29 on ClinicalTrials.gov
What's tested:RibociclibEverolimusTemozolomide (TMZ)

At a glance

Recruiting sites
12 of 20 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Progression-Free Survival (PFS) in HGG (Part 2, Stratum A)
Measured over From date on treatment until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up to 60 months
+4 more outcomes measured

Conditions

High Grade Glioma
Diffuse Intrinsic Pontine Glioma
Anaplastic Astrocytoma
Glioblastoma
Glioblastoma Multiforme
Diffuse Midline Glioma, H3 K27M-Mutant
Metastatic Brain Tumor
WHO Grade III Glioma
WHO Grade IV Glioma
Diffuse Hemispheric Glioma, H3 G34-Mutant

Explore related trials

Diffuse Hemispheric GliomaDiffuse Intrinsic Pontine GliomaMalignant GliomaCCND1 GeneCDK4 GeneCDK6 GeneCDKN2A GeneCDKN2C GeneCyclin-Dependent Kinase 4 Inhibitor BG1/S-Specific Cyclin-D2H3G34HamartinPIK3CA GenePIK3R1 GenePTEN GeneTSC2 Gene

Where it's being run

20 sites across 19 states
Ohio2
Colorado1
District of Columbia1
Illinois1
Massachusetts1
Michigan1
North Carolina1
Pennsylvania1

Study leadership

  • Margot Lazow, MD · STUDY_CHAIR · Nationwide Children's Hospital
  • Maryam Fouladi, MD · PRINCIPAL_INVESTIGATOR · Nationwide Children's Hospital

Who to contact

Kelsey H Troyer, PhD
[email protected]
16147223284
Email the study team

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Eligibility criteria

Inclusion

For the diagnosis of DIPG, patients must have 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
All other HGGs must be WHO grade 3 or 4.
Patients without measurable disease are eligible.
Patients with metastatic or multifocal disease or gliomatosis cerebri who received upfront CSI are eligible
Patients with a primary spinal HGG are eligible
Patients with secondary, radiation-related HGG are eligible.
Pathogenic alterations presumed to cause activation of cell cycle:
Amplification of CDK4 or CDK6
Deletion of CDKN2A, CDKN2B, or CDKN2C
Amplification of CCND1 or CCND2
Pathogenic alterations presumed to cause activation of the PI3K/mTOR pathway:
Deletion or mutation of PTEN
Mutation or amplification of PIK3CA
Mutation of PIK3R1
Deletion or mutation of TSC1 or TSC2
Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded from TarGeT-A
Patients whose tumors harbor other alterations suspected to activate the cell cycle and/or PI3K/mTOR pathway could potentially also be eligible, but only following consensus recommendation by the international multidisciplinary molecular screening committee.
For Stratum E: H3G34 (R/V) mutation
Surgery, RT, dexamethasone are permissible. Temozolomide administered concurrently with RT is permissible. Avastin/bevacizumab use is permitted given the last dose was administered \> 21 days prior to enrollment. No other prior anticancer therapy for HGG will be allowed.
Patients must have received photon or proton RT.
Patients must have started RT \< 42 calendar days from initial diagnosis defined as the date of diagnostic biopsy or resection. If a patient underwent 2 upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery.
RT delivered via photon or proton beam, must have been administered at a standard dose including (54 Gy in 30 fractions for DIPG, 54-59.4 Gy in 30-33 fractions), 45 Gy-54 Gy for primary spinal disease, and/or 36 Gy-39.6 Gy craniospinal for patients with spinal or leptomeningeal metastatic disease with supplemental boost to 45-54 Gy for metastasis within the thecal sac and 54 Gy-60 Gy for intracranial metastasis. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Sponsor-Investigator to confirm eligibility prior to study enrollment.
Patients must enroll and start treatment No later than 35 calendar days post-completion of RT. The earliest patients can begin protocol treatment is 28 calendar days post-completion of RT.
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3
Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
Hemoglobin \>8 g/dL (may be transfused)
Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR
Maximum serum creatinine based on (Schwartz et al. J. Peds, 106:522, 1985) age/gender as follows: 1 to \< 2 years=0.6 mg/dL for males and females; 2 to \< 6 years=0.8 mg/dL for males and females; 6 to \< 10 years= 1.0 mg/dL for males and females; 10 to \< 13 years=1.2 mg/dL for males and females. 13 to \< 16 years=1.5 mg/dL for males and 1.4 mg/dL for females.
Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age
AST(SGOT)/ALT(SGPT) ≤ 3 times institutional upper limit of normal
Serum albumin ≥ 2g/dL
Ejection fraction of ≥ 50% by echocardiogram
QTc ≤ 450 msec (by Bazett formula)

Exclusion

Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation.
Progesterone-only hormonal contraception associated with inhibition of ovulation.
Intra Uterine Device (IUD)
Intra Uterine hormone releasing system
Bilateral tubal occlusion
Vasectomized partner
Sexual abstinence (avoiding having heterosexual intercourse) The following contraceptive measures are NOT considered effective
Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation
Male or female condom with or without spermicide
Cap, diaphragm or sponge with spermicide 2. Concomitant Medications
Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported.
Patients who are currently receiving another investigational drug are not eligible.
Patients who are currently receiving other anti-cancer agents are not eligible, with the exception of temozolomide given concurrently with RT only.
Patients who are receiving enzyme inducing anticonvulsants that are strong inducers or inhibitors of CYP3A4/5 are not eligible.
Patients who are receiving strong inducers or inhibitors of CYP3A4/5 are not eligible and should be avoided from 14 days prior to enrollment to the end of the study.
Patients who are receiving medications known to prolong QTc interval are not eligible.
Patients who are receiving therapeutic anticoagulation with warfarin or other coumadin-derived anticoagulants are not eligible. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed as long as the patient has adequate coagulation defined as aPTT \< 1.5Xs ULN and INR \< 1.5. 3. Patients who have an uncontrolled infection are not eligible. 4. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible. 5. Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible. 6. Patients with prior or ongoing clinically significant medical or psychiatric condition that, in the investigator's opinion, could affect the safety of the subject, or could impair the assessment of study results are not eligible.

What this trial measures

  • Progression-Free Survival (PFS) in HGG (Part 2, Stratum A)From date on treatment until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up to 60 months

    To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG by estimating the distribution of PFS compared to molecularly-stratified and matched historical controls.

  • Overall Survival (OS) in DIPG (Part 2, Stratum B)From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months

    To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with DIPG by estimating the distribution of OS compared to molecularly-stratified and matched historical controls.

  • Establish MTD and RP2D of ribociclib and everolimus (Part 2, Stratum D)Completion of Cycle 1 (28 days)

    To identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and everolimus given to patients with metastatic HGG who have received craniospinal irradiation CSI.

  • Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0 (Part 1- initial feasibility study)Completion of Cycle 1 (28 days)

    Identify the safe dose of ribociclib powder for oral solution (PfOS) formulation in combination with everolimus that is feasible in pediatric patients with newly-diagnosed HGG, including DIPG, with cell cycle and/or PI3K/mTOR pathway alterations. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0 in the first 6-12 patients enrolled

  • Establish RP2D of ribociclib and temozolomide (Phase 1 Run-In Stratum E)Completion of Cycle 1 (28 days)

    Establish RP2D of ribociclib and temozolomide (Phase 1 Run-In Stratum E) Description: To identify the Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and temozolomide given to patients with newly diagnosed localized DHG, H3G34-mutant who have received RT.