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Study of Ribociclib and Everolimus in HGG and DIPG

PHASE2RECRUITING

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 with a high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (cell cycle, PI3K/mTOR) that these drugs target. The main question the study aims to answer is whether the combination of ribociclib and everolimus can prolong the life of patients diagnosed with HGG, including DIPG.

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Study details:

This is a multicenter, international, phase II study of post-radiotherapy (RT) combination of ribociclib and everolimus to treat pediatric, adolescent, and young adult patients newly diagnosed with HGG and DIPG that harbor alterations of the cell cycle and/or PI3K/mTOR pathways to assess treatment efficacy (Part 2). The study will include a feasibility cohort (Part 1) to identify the dose of ribociclib PfOS (Powder for Oral Suspension) that is safe and tolerable in combination with everolimus. Efficacy for Part 2 study will be defined by progression-free survival (PFS; HGG \[stratum A\]) and Overall Survival (OS; DIPG \[stratum B\]), with key longitudinal biomarker correlatives.

Outcomes among patients with primary thalamic, spinal cord, and/or secondary (radiation related) HGG (strata C) will be descriptively analyzed. Objective radiographic response rates and agent-specific toxicities will also be assessed, with a feasibility cohort to determine the recommended phase II dose (RP2D) of the combination of ribociclib and everolimus in patients with metastatic disease who received upfront craniospinal irradiation (stratum D). Protocol therapy with the maintenance combination of ribociclib and everolimus 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. 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).

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:

Exclusion criteria

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.

Concomitant Medications: 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 have an uncontrolled infection are not eligible.

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.

Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible.

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.

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Eligibility

Age eligible for study : 12 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-08-22

Primary completion: 2028-08-28

Study completion finish: 2034-08-28

Study type

TREATMENT

Phase

PHASE2

Trial ID

NCT05843253

Intervention or treatment

DRUG: Ribociclib

DRUG: Everolimus

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

Condition: High Grade Glioma, Diffuse Intrinsic Pontine Glioma and more
DRUG: Ribociclib and other drugs
Randwick, New South Wales, Australia and more
Sponsor: Nationwide Children's Hospital

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Find a site

Closest Location:

Sydney Children's Hospital

Research sites nearby

Select from list below to view details:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 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).	DRUG: Ribociclib Ribociclib PO qd on days 1-21
EXPERIMENTAL: 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).	DRUG: Ribociclib Ribociclib PO qd on days 1-21
EXPERIMENTAL: Stratum C (n=6-12) Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG.	DRUG: Ribociclib Ribociclib PO qd on days 1-21
EXPERIMENTAL: Stratum D (n=6-12) Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation.	DRUG: Ribociclib Ribociclib PO qd on days 1-21

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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)

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Overall Survival in HGG	Determine distribution of OS for pediatric and young adult patients newly-diagnosed with HGG which harbor cell cycle and/or PI3K/mTOR pathway alterations treated with post-RT ribociclib and everolimus.	From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
Objective Response Rate (ORR) in HGG	Evaluate the radiographic objective response rate (ORR) defined as complete response (CR) + partial response (PR) in pediatric and young adult patients newly diagnosed with HGG treated with the combination of ribociclib and everolimus.	From Day 1 of protocol treatment through 30 days following end of protocol treatment
Objective Response Rate (ORR) in DIPG	Evaluate the radiographic objective response rate (ORR) defined as complete response (CR) + partial response (PR) in pediatric and young adult patients newly diagnosed with DIPG treated with the combination of ribociclib and everolimus.	From Day 1 of protocol treatment through 30 days following end of protocol treatment
Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0	Assess and further characterize the safety and toxicity of post-RT combination of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG, including DIPG. 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.	From Day 1 of protocol treatment through 30 days following end of protocol treatment
Evaluate Health-Related Quality of Life Outcomes	Evaluate health-related quality of life outcomes of pediatric and young adult patients newly-diagnosed with HGG, including DIPG, treated with combination of ribociclib and everolimus, by patient and/or parent reporting at key timepoints in therapy using the patient reported outcomes measurement information system (PROMIS) survey.	At the end of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 (each cycle is 28 days)

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References

Clinical Trials Gov: Study of Ribociclib and Everolimus in HGG and DIPG