PBTC-050: A Phase I and Surgical Study of Ribociclib and Everolimus (RAD001) in Children With Recurrent or Refractory Malignant Brain Tumors

Why are we doing this research?

PURPOSE:

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.

DETAILED DESCRIPTION:

PRIMARY OBJECTIVES:

  • To estimate the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of ribociclib and everolimus in children with refractory or recurrent central nervous system (CNS) tumors. (Phase I) II. To describe the toxicity profile and define the dose-limiting toxicities (DLTs) of ribociclib and everolimus in children with refractory or recurrent CNS tumors. (Phase I) III. To characterize the pharmacokinetics of ribociclib and everolimus in children with refractory or recurrent CNS tumors, and the potential for drug-drug interactions between the two compounds in this population. (Phase I) IV. To characterize ribociclib concentrations in tumor, and plasma in children with refractory or recurrent CNS malignancies undergoing neurosurgical procedures. (Surgical Study).

Study Type: Interventional
Intervention Model: Single Group Assignment
Masking: None

Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 1 Year to 21 Years

ELIGIBILITY CRITERIA

Inclusion Criteria:

  • 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; in these cases, patients will not be required to sign a screening consent
  • 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
  • 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
  • Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to enrollment
  • Patients must be off all colony- forming growth factor(s) for at least 1 week prior to enrollment (i.e. filgrastim, sargramostim or erythropoietin); 2 weeks must have elapsed if patients received long-acting formulations
  • Female patients of childbearing potential must have a negative serum or urine pregnancy test
  • Patients of childbearing or child fathering potential must be willing to use a medically acceptable form of birth control while being treated on this study; ?Women of child-bearing potential? is defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation. Highly effective contraception methods include:
    • Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
    • Combination of any of the two following
      • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception
      • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
      • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
    • Note: oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction; in case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment
  • Female patients must agree not to breastfeed their infants while on study; patients of child fathering potential (defined as > Tanner stage 2) must use a condom during intercourse while taking the drug during treatment, for 8 weeks after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men during intercourse with a male or female partner in order to prevent delivery of the study drug via semen
  • The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines; assent, when appropriate, will be obtained according to institutional guidelines.

Exclusion Criteria:

  • 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

Conditions

  • Brain Spinal Tumors Medulloblastoma Relapse
  • Adult - Brain Spinal Tumors Medulloblastoma Relapse
  • Brain Spinal Tumor Low Grade Glioma Relapse
  • Adult - Brain Spinal Tumor Low Grade Glioma Relapse
  • Brain Spinal Tumor DIPG Relapse
  • Adult - Brain Spinal Tumor DIPG Relapse
  • Brain and Spinal Tumor Ependymoma Relapse
  • Adult - Brain and Spinal Tumor Ependymoma Relapse
  • Adult - Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Brain Spinal Neurofibromatosis OPG
  • Adult - Brain Spinal Neurofibromatosis OPG
  • Brain Spinal Neurofibromatosis Other
  • Adult - Brain Spinal Neurofibromatosis Other
  • Brain Spinal Other All Other
  • Adult - Brain Spinal Other All Other
  • Brain Spinal Other ATRT
  • Adult - Brain Spinal Other ATRT
  • Brain Spinal Other Craniopharyngioma
  • Adult - Brain Spinal Other Craniopharyngioma
  • Adult - Brain Spinal Other Germ Cell Tumor
  • Brain Spinal Other Germ Cell Tumor
  • Brain Spinal Other Choroid Plexus Tumor
  • Adult - Brain Spinal Other Choroid Plexus Tumor

Contact

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org