Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors

Completed · Phase 1

Conditions studied: CNS Embryonal Tumor, Not Otherwise Specified, Malignant Glioma, Recurrent Atypical Teratoid/Rhabdoid Tumor, Recurrent Childhood Ependymoma, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Medulloblastoma, Refractory Diffuse Intrinsic Pontine Glioma

In brief

This phase I trial studies the side effects and best dose of ribociclib and everolimus and to see how well they work in treating patients with malignant brain tumors that have come back or do not respond to treatment. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib and everolimus may work better at treating malignant brain tumors.

Key facts

Study ID

NCT03387020

Run by

Pediatric Brain Tumor Consortium

People needed

22

Starts

2018-01-13

Expected to finish

2020-04-01

Last updated by the study team

2021-08-27

Who can join

Age: 1 and older, up to 21. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• ELIGIBILITY FOR SCREENING
• Patients with a histologically confirmed diagnosis of high-grade glioma (HGG), medulloblastoma, CNS embryonal tumor (not otherwise specified [NOS]), ependymoma, or atypical teratoid rhabdoid tumor (ATRT) that is recurrent, progressive or refractory
• Patients with recurrent diffuse intrinsic pontine glioma (DIPG) with typical radiographic appearance who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma World Health Organization (WHO) II-IV; Rb1 screening for these patients is required only if adequate tissue is available
• Patients with recurrent brainstem tumors with an atypical presentation who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma WHO II-IV; these patients must undergo Rb1 screening; these patients must have radiographic evidence of progression
• Patients with secondary malignant gliomas will be eligible for this study but should conform to all other eligibility requirements; patients with low-grade gliomas are excluded
• Formalin fixed paraffin embedded tumor tissue (preferably from the most recent recurrence) must be available to assess Rb1 protein status prior to enrollment on phase I or surgical study; if the subject has results from prior Rb1 IHC testing in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory the requirement for screening to assess Rb1 protein status is waived
• Patients with recurrent diffuse intrinsic brain stem glioma (DIPG) that has an atypical presentation must also submit the tumor tissue for Rb1 protein status confirmation or provide previous testing results from a CLIA certified laboratory; patients who have been biopsied for atypical DIPG but do not have sufficient tissue for Rb1 screening are not eligible
• Body surface area (BSA)
• Patients enrolled on dose level -1 must have BSA >= 0.55m\^2
• Patients enrolled on dose level -0.5 must have BSA >= 0.75m\^2
• Patients enrolled on dose level 0 must have BSA >= 0.55m\^2
• Patients enrolled on dose level 1 must have BSA >= 0.75m\^2
• Patients enrolled on dose level 2 and 3 must have BSA >= 0.45m\^2
• Patients who are candidates for enrollment for the phase I or surgical studies must sign a screening consent and provide pre-trial tumor material for Rb1 testing unless testing is not needed due to diagnosis or the availability of prior Rb1 IHC results; the screening consent is to be obtained according to institutional guidelines
• Patients screened for this trial should be expected to meet the criteria for treatment
• PRIOR TO STUDY ENROLLMENT
• PHASE I (STRATUM 1): Patient has intact Rb1 protein confirmed either from previous results or screened tissue; all testing must be performed in a CLIA certified laboratory; DIPG patients with radiographically typical appearance will be waived from this requirement
• PHASE I (STRATUM 1): Patients with a histologically confirmed diagnosis of a primary CNS tumor that is recurrent, progressive, or refractory; all tumors must have histologic verification of HGG, medulloblastoma, CNS embryonal tumor (NOS), ependymoma, or ATRT; patients with low-grade gliomas are excluded
• PHASE I (STRATUM 1): Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since last treatment, OR the appearance of a new tumor lesion since diagnosis
• Please note:
• Patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation
• Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma WHO II-IV. These patients must have radiographic evidence of progression
• SURGICAL STUDY (STRATUM 2): Patients must have recurrent or refractory disease with a histological diagnosis at either the time of diagnosis or at the time of recurrence of one of the following:
• HGG
• Medulloblastoma,

You may not qualify if…

• Patients who are otherwise deemed clinically unsuitable for surgical resection (applicable for surgical study only)
• Patients who are breast feeding
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient?s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients who are receiving any other anticancer or investigational or/and anti-neoplastic therapies, including chemotherapy, immunotherapy, target therapy, biological response modifiers
• Previous treatment with CDK4/6 inhibitors (such as PD-0332991, abemaciclib) and/or mTOR inhibitors (such as sirolimus, temsirolimus or everolimus)
• Patients who are currently receiving treatment with agents that are known to cause corrected QT (QTc) prolongation or induce Torsades de Pointes
• Known need for major surgery within 14 days of the first dose of ribociclib and everolimus; please note: gastrostomy, insertion of a gastrostomy (G) tube, ventriculo-peritoneal shunt, endoscopic ventriculostomy and central venous access are NOT considered major surgery
• Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment:
• Known strong and moderate inducers or inhibitors of CYP3A4/5, including enzyme inducing anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
• Substrates of CYP3A4/5 with a narrow therapeutic index
• Herbal preparations/medications (except for vitamins) including, but not limited to: St. John?s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng; patients should stop using all herbal medications and dietary supplements at least 7 days prior to enrollment
• Clinically significant active cardiac disease, uncontrolled heart disease and/or a history of cardiac dysfunction including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Documented cardiomyopathy
• Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by echocardiogram (ECHO)
• History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality within 12 months of screening
• Long QT syndrome or known family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
• Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
• Concomitant use of medication(s) with a known risk to prolong the QT interval and/or days prior to starting study drug) or replaced by safe alternative medication
• 12-lead electrocardiogram (ECG), any of the following cardiac parameters:
• QTc > 480 msec
• Hypertension defined as:
• Patients 1-17 years of age with blood pressure that is greater than or equal to the 95th percentile for age, height and gender at the time of enrollment; Patients who are ≥ 18 years of age with blood pressure > 140/90 mm of Hg at the time of enrollment.
• Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise.

Where it is running

• Children's Hospital Los Angeles — Los Angeles, California, United States
• Lucile Packard Children Hospital Stanford University — Palo Alto, California, United States
• Children's Hospital Colorado — Aurora, Colorado, United States
• Children's National Medical Center — Washington D.C., District of Columbia, United States
• Children's Healthcare of Atlanta — Atlanta, Georgia, United States
• National Cancer Institute Pediatric Oncology Branch — Bethesda, Maryland, United States
• Memorial Sloan Kettering Cancer Center — New York, New York, United States
• Cincinnati Children Hospital Medical Center — Cincinnati, Ohio, United States
• Children Hospital of Pittsburgh of UPMC — Pittsburgh, Pennsylvania, United States
• Pediatric Brain Tumor Consortium — Memphis, Tennessee, United States
• St. Jude Children Research Hospital — Memphis, Tennessee, United States
• Texas Children's Cancer Center — Houston, Texas, United States

Full record on ClinicalTrials.gov

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