Trial Title:
Study of Ribociclib and Everolimus in HGG and DIPG
NCT ID:
NCT05843253
Condition:
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
Conditions: Official terms:
Glioblastoma
Glioma
Astrocytoma
Diffuse Intrinsic Pontine Glioma
Everolimus
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Ribociclib and Everolimus
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Ribociclib
Description:
Ribociclib PO qd on days 1-21
Arm group label:
Stratum A (n=40)
Arm group label:
Stratum B (n=40)
Arm group label:
Stratum C (n=6-12)
Arm group label:
Stratum D (n=6-12)
Other name:
Kisqali
Intervention type:
Drug
Intervention name:
Everolimus
Description:
Everolimus PO qd on days 1-28
Arm group label:
Stratum A (n=40)
Arm group label:
Stratum B (n=40)
Arm group label:
Stratum C (n=6-12)
Arm group label:
Stratum D (n=6-12)
Other name:
Afinitor
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.
Detailed description:
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).
Criteria for eligibility:
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.
Inclusion Criteria:
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.
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.
Gender:
All
Minimum age:
12 Months
Maximum age:
39 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Children's Hospital Colorado
Address:
City:
Aurora
Zip:
80045
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Kathleen Dorris, MD
Phone:
720-777-8314
Email:
kathleen.dorris@childrenscolorado.org
Facility:
Name:
Children's National Medical Center
Address:
City:
Washington
Zip:
20010
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Eugene Hwang, MD
Phone:
202-476-5046
Email:
ehwang@childrensnational.org
Facility:
Name:
Ann & Robert H. Lurie Children's Hospital of Chicago
Address:
City:
Chicago
Zip:
60611
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Ashley Plant, MD
Phone:
312-227-4090
Email:
Aplant@luriechildrens.org
Facility:
Name:
Dana-Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Susan Chi, MD
Phone:
617-632-4386
Email:
Susan_chi@dfci.harvard.edu
Facility:
Name:
Duke University Health System
Address:
City:
Durham
Zip:
27708
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
David Ashley, MD
Phone:
919-681-3824
Email:
david.ashley@duke.edu
Facility:
Name:
Cincinnati Children's Hospital Medical Center
Address:
City:
Cincinnati
Zip:
45229
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Peter de Blank, MD
Phone:
513-517-2068
Email:
Peter.deBlank@cchmc.org
Facility:
Name:
Nationwide Children's Hospital
Address:
City:
Columbus
Zip:
43235
Country:
United States
Status:
Recruiting
Contact:
Last name:
Maryam Fouladi, MD
Phone:
614-722-5758
Email:
Maryam.fouladi@nationwidechildrens.org
Facility:
Name:
Children's Hospital of Philadelphia
Address:
City:
Philadelphia
Zip:
19104
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Michael J Fisher, MD
Phone:
215-590-5188
Email:
fisherm@email.chop.edu
Facility:
Name:
Texas Children's Hospital
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Patricia Baxter, MD
Phone:
832-824-4681
Email:
pabaxter@txch.org
Facility:
Name:
Seattle Children's Hospital
Address:
City:
Seattle
Zip:
98105
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Sarah Leary, MD
Phone:
206-987-2106
Email:
sarah.leary@seattlechildrens.org
Facility:
Name:
Sydney Children's Hospital
Address:
City:
Randwick
Zip:
2031
Country:
Australia
Status:
Not yet recruiting
Contact:
Last name:
David Ziegler, MBBS
Phone:
+61293821730
Email:
d.ziegler@unsw.edu.au
Facility:
Name:
Queensland Children's Hospital
Address:
City:
South Brisbane
Zip:
4101
Country:
Australia
Status:
Not yet recruiting
Contact:
Last name:
Tim Hassall, MBBS
Phone:
+61730683593
Email:
tim.hassall@health.qld.gov.au
Facility:
Name:
Perth Children's Hospital
Address:
City:
Perth
Zip:
6000
Country:
Australia
Status:
Not yet recruiting
Contact:
Last name:
Nick Gottardo, MBChB
Phone:
+61864560241
Email:
nick.gottardo@health.wa.gov.au
Facility:
Name:
The Hospital for Sick Children (SickKids)
Address:
City:
Toronto
Zip:
M5G1X8
Country:
Canada
Status:
Not yet recruiting
Contact:
Last name:
Eric Bouffet, MD
Phone:
4168137457
Email:
eric.bouffet@sickkids.ca
Facility:
Name:
Montreal Children's Hospital
Address:
City:
Montréal
Zip:
H4A3J1
Country:
Canada
Status:
Not yet recruiting
Contact:
Last name:
Genevieve Legault, MD
Phone:
5144124400
Phone ext:
60497
Email:
Genevieve.legault4@mcgill.ca
Facility:
Name:
Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
Address:
City:
Heidelberg
Zip:
69120
Country:
Germany
Status:
Not yet recruiting
Contact:
Last name:
Olaf Witt, MD
Phone:
0496221423570
Email:
o.witt@kitz-heidelberg.de
Facility:
Name:
Princess Máxima Center
Address:
City:
Utrecht
Zip:
3720
Country:
Netherlands
Status:
Not yet recruiting
Contact:
Last name:
Jasper van der Lugt, MD, PhD
Phone:
31 6 18559694
Email:
D.G.vanVuurden@prinsesmaximacentrum.nl
Facility:
Name:
Great Ormond Street Hospital
Address:
City:
London
Zip:
WC1N 3JH
Country:
United Kingdom
Status:
Not yet recruiting
Contact:
Last name:
Darren Hargrave, MD
Phone:
02078138525
Email:
darren.hargrave@nhs.net
Start date:
August 22, 2024
Completion date:
August 28, 2034
Lead sponsor:
Agency:
Nationwide Children's Hospital
Agency class:
Other
Collaborator:
Agency:
Novartis
Agency class:
Industry
Source:
Nationwide Children's Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05843253
