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

NCT05843253 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: CONNECT TarGeT-AR01FD008167
• Study Type: interventional
• Target: 120
• Locations: 7 countries
• Sites: 21

Brief Summary

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 high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (cell cycle, PI3K/mTOR) that these drugs target or 2) ribociclib and temozolomide to treat pediatric and young adult patients newly diagnosed with diffuse hemispheric glioma (DHG), H3G34-mutant. 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.

Conditions

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; High Grade Glioma

Outcome Measures

Primary Outcomes (5)

• Progression-Free Survival (PFS) in HGG (Part 2, Stratum A)

  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.

  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

• Overall Survival (OS) in DIPG (Part 2, Stratum B)

  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.

  From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months

• Establish MTD and RP2D of ribociclib and everolimus (Part 2, Stratum D)

  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.

  Completion of Cycle 1 (28 days)

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

  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

  Completion of Cycle 1 (28 days)

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

  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.

  Completion of Cycle 1 (28 days)

Secondary Outcomes (5)

• Overall Survival in HGG

  From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months

• Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0

  From Day 1 of protocol treatment through 30 days following end of protocol treatment

• Evaluate Health-Related Quality of Life Outcomes

  At the end of every other Cycle (each cycle is 28 days)

• Overall Survival in DHG, H3G34-mutant

  From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months

• Number of participants with ribociclib and temozolomide-related adverse events as assessed by CTCAE v5.0

  From Day 1 of protocol treatment through 30 days following end of protocol treatment

Study Arms (5)

Stratum A (n=40)

EXPERIMENTAL

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

Drug: Ribociclib; Drug: Everolimus

Stratum B (n=40)

EXPERIMENTAL

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).

Drug: Ribociclib; Drug: Everolimus

Stratum C (n=6-12)

EXPERIMENTAL

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

Drug: Ribociclib; Drug: Everolimus

Stratum D (n=6-12)

EXPERIMENTAL

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

Drug: Ribociclib; Drug: Everolimus

Stratum E (n=20)

EXPERIMENTAL

Patients with localized H3G34-mutant DHG

Drug: Ribociclib; Drug: Temozolomide (TMZ)

Interventions

Ribociclib DRUG

Ribociclib PO qd on days 1-21

Also known as: Kisqali

Stratum A (n=40); Stratum B (n=40); Stratum C (n=6-12); Stratum D (n=6-12); Stratum E (n=20)

Everolimus DRUG

Everolimus PO qd on days 1-28

Also known as: Afinitor

Stratum A (n=40); Stratum B (n=40); Stratum C (n=6-12); Stratum D (n=6-12)

Temozolomide (TMZ) DRUG

Temozolomide PO qd on days 1-5 for the first 13 cycles

Stratum E (n=20)

Eligibility Criteria

• Age: 12 Months - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• ) Age: patients must be ≥12 months and ≤39 years of age at the time of enrollment on TarGeT-SCR. For the Part 1 Initial Feasibility Cohort (receiving ribociclib and everolimus) only: patients must be \<21 years of age at the time of enrollment on this protocol.
• ) 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.
• ) 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.
• ) 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:

You may not qualify if:

• Pregnant or Breast-Feeding Pregnant or breast-feeding women will not be entered on this study due to known potential risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use at least one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy
• 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
• 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.

Sponsors & Collaborators

• Novartis: collaborator
• Nationwide Children's Hospital: lead

Study Sites (21)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

NOT YET RECRUITING

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

RECRUITING

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

NOT YET RECRUITING

C.S. Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

RECRUITING

Duke University Health System

Durham, North Carolina, 27708, United States

RECRUITING

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, 43235, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

NOT YET RECRUITING

Texas Children's Hospital

Houston, Texas, 77030, United States

RECRUITING

Seattle Children's Hospital

Seattle, Washington, 98105, United States

RECRUITING

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

RECRUITING

Queensland Children's Hospital

South Brisbane, Queensland, 4101, Australia

RECRUITING

Royal Children's Hospital

Melbourne, Victoria, 3052, Australia

RECRUITING

Perth Children's Hospital

Perth, Western Australia, 6000, Australia

RECRUITING

The Hospital for Sick Children (SickKids)

Toronto, Ontario, M5G1X8, Canada

NOT YET RECRUITING

Montreal Children's Hospital

Montreal, Quebec, H4A3J1, Canada

NOT YET RECRUITING

Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)

Heidelberg, Baden-Wurttemberg, 69120, Germany

NOT YET RECRUITING

Princess Máxima Center

Utrecht, 3720, Netherlands

NOT YET RECRUITING

Starship Children's Hospital

Auckland, Grafton, 1023, New Zealand

NOT YET RECRUITING

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma; Astrocytoma; Glioblastoma; Brain Neoplasms

Interventions

ribociclib; Everolimus; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Margot Lazow, MD

  Nationwide Children's Hospital

  STUDY CHAIR

• Maryam Fouladi, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kelsey H Troyer, PhD

CONTACT

16147223284; kelsey.troyer@nationwidechildrens.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Ribociclib and Everolimus OR Ribociclib and Temozolomide

Study Record Dates

• First Submitted: April 20, 2023
• First Posted: May 6, 2023
• Study Start: August 22, 2024
• Primary Completion (Estimated): August 31, 2029
• Study Completion (Estimated): August 28, 2034
• Last Updated: April 22, 2026

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); AU (4); GB (1); NL (1); DE (1); US (11); NZ (1)