Study of Ribociclib and Everolimus in HGG and DIPG or Ribociclib and Temozolomide in DHG, H3G34-mutant
NCT ID: NCT05843253
Last Updated: 2025-11-10
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE2
120 participants
INTERVENTIONAL
2024-08-22
2034-08-28
Brief Summary
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The main question the study aims to answer is whether the combinations of ribociclib and everolimus or ribociclib and temozolomide can prolong the life of patients diagnosed with HGG/DIPG or DHG H3G34-mutant.
Detailed Description
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The study was amended in October 2025 to also include an additional stratum, Stratum E, which will serve patients with localized DHG, H3G34-mutant with the combination of ribociclib and temozolomide. As most DHG, H3G34-mutant tumors are MGMT promoter methylated and receive temozolomide as part of standard of care, we are studying the adjuvant combination of ribociclib and temozolomide following upfront RT. Stratum E will open with a Phase 1 Run-In to determine the RP2D of ribociclib PfOS formulation in combination with temozolomide in patients newly-diagnosed with DHG, H3G34-mutant post-RT, with PK testing. Once the RP2D is determined, patients with localized DHG, H3G34-mutant will be enrolled on the Stratum E efficacy expansion cohort to descriptively assess survival outcomes, with similar longitudinal biomarker correlatives to the other strata.
Protocol therapy with the maintenance combination of either 1) ribociclib and everolimus or 2) ribociclib and temozolomide must begin 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. Each cycle will be 28 days in duration and treatment can continue up to a total of 26 cycles. For Strata A-D, Ribociclib will be given orally once daily for 3 weeks (days 1-21), with one week off. Everolimus will be given orally daily continuously (days 1-28). For Stratum E, Ribociclib will be given orally once daily for 3 weeks (days 1-21), and temozolomide will be given days 1-5 for the first 13 cycles (Year 1), and ribociclib alone will be given orally once daily for 3 weeks (days 1-21) for the subsequent 13 cycles (Year 2).
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Stratum A (n=40)
Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata B, C, or D).
Ribociclib
Ribociclib PO qd on days 1-21
Everolimus
Everolimus PO qd on days 1-28
Stratum B (n=40)
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).
Ribociclib
Ribociclib PO qd on days 1-21
Everolimus
Everolimus PO qd on days 1-28
Stratum C (n=6-12)
Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG.
Ribociclib
Ribociclib PO qd on days 1-21
Everolimus
Everolimus PO qd on days 1-28
Stratum D (n=6-12)
Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation.
Ribociclib
Ribociclib PO qd on days 1-21
Everolimus
Everolimus PO qd on days 1-28
Stratum E (n=20)
Patients with localized H3G34-mutant DHG
Ribociclib
Ribociclib PO qd on days 1-21
Temozolomide (TMZ)
Temozolomide PO qd on days 1-5 for the first 13 cycles
Interventions
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Ribociclib
Ribociclib PO qd on days 1-21
Everolimus
Everolimus PO qd on days 1-28
Temozolomide (TMZ)
Temozolomide PO qd on days 1-5 for the first 13 cycles
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
1.2) Diagnosis: patients with newly-diagnosed HGG, including DIPG are eligible. All patients must have histologic confirmation tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR:
* 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.
1.3) Disease status: There are no disease status requirements for enrollment
* 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.
2.1) Presence of at least one relevant actionable somatic alteration, detailed here:
* 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
2.2) Performance Level: Karnofsky ≥ 50% for patients \> 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of ag. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
2.3) Prior Therapy for HGG:
* 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.
2.4) Organ Function Requirements
2.4.1) Adequate Bone Marrow Function Defined as:
* 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)
2.4.2) Adequate Renal Function Defined as:
* 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.
2.4.3) Adequate Liver Function Defined as:
* 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
2.4.4) Adequate Cardiac Function Defined as:
* Ejection fraction of ≥ 50% by echocardiogram
* QTc ≤ 450 msec (by Bazett formula)
2.4.5) Adequate Neurologic Function Defined as: Patients with seizure disorder may be enrolled if well-controlled on anticonvulsants that are not strong inducers or inhibitors of CYP3A4/5.
2.4.6) Adequate Pulmonary Function Defined as: No evidence of dyspnea at rest, and a pulse oximetry \>94% on room air if there is clinical indication for determination.
2.5) Ability to take medications by mouth: For ribociclib and everolimus strata, patients must be able to take study medications by mouth as administration via NG/NJ/G tube is not allowed.
2.6) Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines
2.7) Contraception: Male and female patients of childbearing potential must be willing to use a highly effective contraception method.
Exclusion Criteria
A highly effective contraception method is defined as one that results in a low failure rate (\<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods:
* 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.
12 Months
39 Years
ALL
No
Sponsors
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Novartis
INDUSTRY
Nationwide Children's Hospital
OTHER
Responsible Party
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Principal Investigators
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Margot Lazow, MD
Role: STUDY_CHAIR
Nationwide Children's Hospital
Maryam Fouladi, MD
Role: PRINCIPAL_INVESTIGATOR
Nationwide Children's Hospital
Locations
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Children's Hospital Colorado
Aurora, Colorado, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
C.S. Mott Children's Hospital
Ann Arbor, Michigan, United States
Duke University Health System
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Nationwide Children's Hospital
Columbus, Ohio, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Texas Children's Hospital
Houston, Texas, United States
Seattle Children's Hospital
Seattle, Washington, United States
Sydney Children's Hospital
Randwick, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Perth Children's Hospital
Perth, Western Australia, Australia
The Hospital for Sick Children (SickKids)
Toronto, Ontario, Canada
Montreal Children's Hospital
Montreal, Quebec, Canada
Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
Heidelberg, Baden-Wurttemberg, Germany
Princess Máxima Center
Utrecht, , Netherlands
Great Ormond Street Hospital
London, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Holly Lindsay, MD
Role: primary
Eugene Hwang, MD
Role: primary
Ashley Plant, MD
Role: primary
Susan Chi, MD
Role: primary
Santhosh Upadhyaya, MD
Role: primary
David Ashley, MD
Role: primary
Peter de Blank, MD
Role: primary
Maryam Fouladi, MD
Role: primary
Michael J Fisher, MD
Role: primary
Patricia Baxter, MD
Role: primary
Sarah Leary, MD
Role: primary
David Ziegler, MBBS
Role: primary
Tim Hassall, MBBS
Role: primary
Nick Gottardo, MBChB
Role: primary
Eric Bouffet, MD
Role: primary
Genevieve Legault, MD
Role: primary
Olaf Witt, MD
Role: primary
Jasper van der Lugt, MD, PhD
Role: primary
Darren Hargrave, MD
Role: primary
Other Identifiers
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CONNECT TarGeT-A
Identifier Type: -
Identifier Source: org_study_id