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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05843253




Registration number
NCT05843253
Ethics application status
Date submitted
20/04/2023
Date registered
6/05/2023
Date last updated
12/04/2024

Titles & IDs
Public title
Study of Ribociclib and Everolimus in HGG and DIPG
Scientific title
PhaseII Study of Ribociclib and Everolimus Following Radiotherapy in Pediatric and Young Adult Patients Newly Diagnosed With HGG Including DIPG, Which Harbor Alterations of the Cell Cycle and/or PI3K/mTOR Pathways
Secondary ID [1] 0 0
TarGeT-A
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High Grade Glioma 0 0
Diffuse Intrinsic Pontine Glioma 0 0
Anaplastic Astrocytoma 0 0
Glioblastoma 0 0
Glioblastoma Multiforme 0 0
Diffuse Midline Glioma, H3 K27M-Mutant 0 0
Metastatic Brain Tumor 0 0
WHO Grade III Glioma 0 0
WHO Grade IV Glioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ribociclib
Treatment: Drugs - Everolimus

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).

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).

Experimental: Stratum C (n=6-12) - Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG.

Experimental: Stratum D (n=6-12) - Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation.


Treatment: Drugs: Ribociclib
Ribociclib PO qd on days 1-21

Treatment: Drugs: Everolimus
Everolimus PO qd on days 1-28
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-Free Survival (PFS) in HGG (Part 2, Stratum A)
Timepoint [1] 0 0
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
Primary outcome [2] 0 0
Overall Survival (OS) in DIPG (Part 2, Stratum B)
Timepoint [2] 0 0
From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
Primary outcome [3] 0 0
Establish MTD and RP2D of ribociclib and everolimus (Part 2, Stratum D)
Timepoint [3] 0 0
Completion of Cycle 1 (28 days)
Primary outcome [4] 0 0
Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0 (Part 1- initial feasibility study)
Timepoint [4] 0 0
Completion of Cycle 1 (28 days)
Secondary outcome [1] 0 0
Overall Survival in HGG
Timepoint [1] 0 0
From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months
Secondary outcome [2] 0 0
Objective Response Rate (ORR) in HGG
Timepoint [2] 0 0
From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcome [3] 0 0
Objective Response Rate (ORR) in DIPG
Timepoint [3] 0 0
From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcome [4] 0 0
Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0
Timepoint [4] 0 0
From Day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcome [5] 0 0
Evaluate Health-Related Quality of Life Outcomes
Timepoint [5] 0 0
At the end of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 (each cycle is 28 days)

Eligibility
Key inclusion criteria
TarGeT-A study strata definitions Part1: Initial Feasibility Study for the combination of
ribociclib PfOS formulation with everolimus: Enrollment on this cohort will be limited to
patients aged <21 years with primary intracranial localized HGG and DIPG

Part 2

- Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic HGG
(who do not meet criteria for strata C-D)

- Stratum B: Patients with DIPG

- Stratum C: Patients with primary thalamic, spinal cord, and/or
secondary/radiation-related HGG.

- Stratum D: Patients with metastatic/disseminated HGG, multifocal HGG, and/or
gliomatosis cerebri who received CSI.



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

1.1) 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 only: patients must be <21
years of age at the time of enrollment on this protocol.

1.2) Diagnosis: patients with newly-diagnosed HGG, including DIPG are eligible. All
patients must have 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. Inclusion criteria for assignment to TarGeT-A, for all strata:

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

- Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded
from this treatment protocol (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.

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 but discouraged. No other prior anticancer therapy for HGG will
be allowed.

- Patients must have received photon or proton RT.

- Patients must have started RT within 31 calendar days of 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, 59.4 Gy in 33 fractions or 54-60 Gy in 30
fractions for other HGG), 45 Gy-50.4 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) 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

2.6) Contraception: Male and female patients of childbearing potential must be willing to
use a highly effective contraception method.
Minimum age
12 Months
Maximum age
39 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

1. 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

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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
30/05/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/05/2034
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Washington
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Canada
State/province [11] 0 0
Quebec
Country [12] 0 0
Germany
State/province [12] 0 0
Baden-Württemberg
Country [13] 0 0
Netherlands
State/province [13] 0 0
Utrecht
Country [14] 0 0
United Kingdom
State/province [14] 0 0
London

Funding & Sponsors
Primary sponsor type
Other
Name
Nationwide Children's Hospital
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Novartis
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05843253
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Margot Lazow, MD
Address 0 0
Nationwide Children's Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Leonie Mikael, PhD
Address 0 0
Country 0 0
Phone 0 0
16147223284
Fax 0 0
Email 0 0
leonie.mikael@nationwidechildrens.org
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05843253