Clinical Trials /

A Study of Ribociclib and Everolimus Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)

NCT03355794

Description:

In this research study, we want to learn about the safety of the study drugs, ribociclib and everolimus, when given together at different doses after radiation therapy. We also want to learn about the effects, if any, these drugs have on children and young adults with brain tumors. We are asking people to be in this research study who have been diagnosed with a high grade glioma, their tumor has been screened for the Rb1 protein, and they have recently finished radiation therapy. If a patient has DIPG or a Bi-thalamic high grade glioma, they do not need to have the tumor tissue screened for the Rb1 protein, but do need to have finished radiation therapy. Tumor cells grow and divide quickly. In normal cells, there are proteins that control how fast cells grow but in cancer cells these proteins no longer work correctly making tumor cells grow quickly. Both study drugs work in different ways to slow down the growth of tumor cells. The researchers think that if the study drugs are given together soon after radiation therapy, it may help improve the effect of the radiation in stopping or slowing down tumor growth. The study drugs, ribociclib and everolimus, have been approved by the United States Food and Drug Administration (FDA). Ribociclib is approved to treat adults with breast cancer and everolimus is approved for use in adults and children who have other types of cancers. The combination of ribociclib and everolimus has not been tested in children or in people with brain tumors and is considered investigational. The goals of this study are: - Find the safest dose of ribociclib and everolimus that can be given together after radiation. - Learn the side effects (both good and bad) the study drugs have on the body and tumor. - Measure the levels of study drug in the blood over time. - Study the changes in the endocrine system that may be caused by the tumor, surgery or radiation.

Related Conditions:
  • Anaplastic Astrocytoma
  • Diffuse Astrocytoma
  • Diffuse Intrinsic Pontine Glioma
  • Glioblastoma
  • Glioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of Ribociclib and Everolimus Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)
  • Official Title: A Phase I Study of Ribociclib and Everolimus Following Radiation Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and RB+ Biopsied DIPG and High Grade Gliomas (HGG)

Clinical Trial IDs

  • ORG STUDY ID: CONNECT1701_LEE/RAD17T-MD-1604
  • NCT ID: NCT03355794

Conditions

  • Diffuse Intrinsic Pontine Glioma
  • Malignant Glioma of Brain
  • High Grade Glioma
  • Bithalamic High Grade Glioma
  • Brainstem Glioma
  • Glioblastoma
  • Anaplastic Astrocytoma

Interventions

DrugSynonymsArms
ribociclibKisqaliDose level 1 (starting dose level) (participants </= 21yrs)
EverolimusAfinitorDose level 1 (starting dose level) (participants </= 21yrs)

Purpose

In this research study, we want to learn about the safety of the study drugs, ribociclib and everolimus, when given together at different doses after radiation therapy. We also want to learn about the effects, if any, these drugs have on children and young adults with brain tumors. We are asking people to be in this research study who have been diagnosed with a high grade glioma, their tumor has been screened for the Rb1 protein, and they have recently finished radiation therapy. If a patient has DIPG or a Bi-thalamic high grade glioma, they do not need to have the tumor tissue screened for the Rb1 protein, but do need to have finished radiation therapy. Tumor cells grow and divide quickly. In normal cells, there are proteins that control how fast cells grow but in cancer cells these proteins no longer work correctly making tumor cells grow quickly. Both study drugs work in different ways to slow down the growth of tumor cells. The researchers think that if the study drugs are given together soon after radiation therapy, it may help improve the effect of the radiation in stopping or slowing down tumor growth. The study drugs, ribociclib and everolimus, have been approved by the United States Food and Drug Administration (FDA). Ribociclib is approved to treat adults with breast cancer and everolimus is approved for use in adults and children who have other types of cancers. The combination of ribociclib and everolimus has not been tested in children or in people with brain tumors and is considered investigational. The goals of this study are: - Find the safest dose of ribociclib and everolimus that can be given together after radiation. - Learn the side effects (both good and bad) the study drugs have on the body and tumor. - Measure the levels of study drug in the blood over time. - Study the changes in the endocrine system that may be caused by the tumor, surgery or radiation.

Detailed Description

      This is a phase I study to determine: 1) the MTD and/or the recommended phase II dose (RP2D)
      of ribociclib and everolimus which can be safely administered during maintenance therapy for
      up to 24 courses following completion of radiation therapy with newly diagnosed non-biopsied
      DIPG and RB+ biopsied DIPG and HGG, 2) characterization of the pharmacokinetic profile of
      ribociclib and everolimus as combination maintenance therapy following completion of
      radiation therapy with newly diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG.

      Patients with RB+ tumors and non-biopsied DIPG will receive standard radiation therapy prior
      to enrollment followed by ribociclib and everolimus as maintenance therapy. Upon completion
      of radiation therapy, a 2 - 4 week break will occur and then ribociclib will be given orally
      daily for 21 days followed by a 7 day break every 28 days at 70% of the adult RP2D (300 mg)
      in combination with everolimus at 80% of the adult RP2D (2.5 mg) given orally once daily
      continuously for up to 24 courses. One course is equivalent to 28 days. Due to dosing
      concerns with the limited dosing capsules (50 mg and 200 mg are only available), dose
      escalations will have BSA restrictions to accommodate for variations from target doses and
      BSA adjusted actual dose. Two intra-patient dose-de-escalations will be allowed if dose
      limiting toxicities arise and may continue study treatment for up to 24 courses in the
      absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Dose level 1 (starting dose level) (participants </= 21yrs)ExperimentalRibociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (>21 yrs of age 300mg daily (DIPG only); </=21 yrs of age 120 mg/m2/day) Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; dose calculation age dependent (>21yrs 2.5mg/day (DIPG only); </=21yr 1.2 mg/m2/day) BSA >/=0.75m2
  • ribociclib
  • Everolimus
Dose level 2 (participants </= 21yrs)ExperimentalRibociclib administered orally; daily on days 1-21 each 28 day cycle; 170 mg/m2/day Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; 1.2 mg/m2/day BSA >/=0.45m2
  • ribociclib
  • Everolimus
Dose level 3 (participants </= 21yrs)ExperimentalRibociclib administered orally; daily on days 1-21 each 28 day cycle; 170 mg/m2/day Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; 1.5 mg/m2/day BSA >/=0.45m2
  • ribociclib
  • Everolimus
Dose level 1 (DIPG participants > 21yrs)ExperimentalRibociclib administered orally; daily on days 1-21 each 28 day cycle; 300mg daily Everolimus administered orally; daily on days 1 - 28 each 28 day cycle; 2.5mg/day
  • ribociclib
  • Everolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Age Patients must be ≥ 12 months of age and ≤ 30 years of age at the time of study
             entry for patients diagnosed with DIPG.

        Patients must be ≥ 12 months of age and ≤ 21 years of age at the time of study entry for
        patients diagnosed with HGG.

          -  BSA restrictions for patients ≤ 21 years of age at the time of study entry

               -  Patients enrolled on dose level -1 must have BSA≥0.55m2

               -  Patients enrolled on dose level 0* must have BSA≥0.75m2

               -  Patients enrolled on dose level 0 must have BSA≥0.55m2

               -  Patients enrolled on dose level 1 must have BSA≥0.75m2

               -  Patients enrolled on dose level 2 and 3 must have BSA≥ 0.45m2

          -  RB status Screening for RB applies to all patients with pre-trial tumor tissue except
             for patients diagnosed with DIPG and bi-thalamic tumors who do not have available
             tissue.

        RB testing must be evaluated centrally at CCHMC prior to enrollment or report from CLIA
        certified lab must be reviewed centrally at CCHMC.

          -  Tumor Diffuse Intrinsic Pontine Glioma (DIPG) Patients with newly diagnosed diffuse
             intrinsic pontine gliomas (DIPGs), defined on neuroimaging as tumors with a pontine
             epicenter and diffuse intrinsic involvement of the pons, are eligible without
             histologic confirmation.

        Patients with brainstem tumors that do not meet these criteria or not considered to be
        typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and
        proven to have + RB and be the following according to the 2016 World Health Organization
        Classification of Tumors of the Central Nervous System 30:

        Anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS) Glioblastoma (IDH mutant, IDH
        wildtype or NOS) Diffuse midline glioma, H3 K27M mutant or H3 K27M negative Diffuse
        astrocytoma (IDH mutant, IDH wildtype, or NOS)

        Note: Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, pleomorphic
        xanthoastrocytoma with or without anaplasia, gangliogliomas, or other mixed gliomas without
        anaplasia are not eligible.

        Patients with diffuse intrinsic brain stem glioma (DIPG) can be enrolled without the need
        for available tumor tissue for RB protein status confirmation. If DIPG or bi-thalamic
        patients have been biopsied and if available tissue, RB status will be tested. These must
        be RB+ to be eligible for enrollment.

        Bi-thalamic tumors, biopsied and noted to have intact RB are eligible. Bi-thalamic tumors
        that are not biopsied will be eligible to enroll on the DIPG non-biopsied arm. 107

        High-grade Glioma (HGG)

        Patients must have had histologically verified the following according to the 2016 World
        Health Organization Classification of Tumors of the Central Nervous System 30:

        Anaplastic astrocytoma (IDH mutant, IDH wildtype, or NOS) Glioblastoma (IDH mutant, IDH
        wildtype or NOS) Diffuse astrocytoma (IDH mutant, IDH wildtype, or NOS) AND RB+ noted on
        immunohistochemistry.

        Patients with primary spinal cord tumors are eligible. Patients with multi-focal disease
        within the cerebrum are eligible.

        Patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not eligible.

          -  MRI of spine must be performed prior to enrollment if the treating physician suspects
             disseminated disease as a baseline evaluation. If leptomeningeal disease develops post
             radiation therapy and prior to enrollment, patients may be considered eligible if
             craniospinal irradiation was not received prior to enrollment.

          -  Performance Status Karnofsky ≥ 50% for patients >16 years of age or Lansky ≥50 for
             patients >16 years of age. 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.

          -  Prior Therapy Patients must have not received any prior therapy other than surgery,
             radiation (focal to disease) and/or steroids (maximum dose dexamethasone 16 mg/day).

          -  Radiation therapy requirements

               -  Patients diagnosed with DIPG: any variances in the radiotherapy dose within 10%
                  of the current standard dose (54 Gy) will be discussed with the
                  Sponsor-Investigator to confirm eligibility prior to study enrollment.

               -  Patients diagnosed with HGG: any variances in the radiotherapy dose within 10% of
                  the current standard dose (59.4 Gy) will be discussed with the
                  Sponsor-Investigator to confirm eligibility prior to study enrollment.

               -  Patients diagnosed with primary spinal tumors any variances in the radiotherapy
                  dose within 10% of the current standard dose (54 Gy) will be discussed with the
                  Sponsor-Investigator to confirm eligibility prior to study enrollment.

               -  Timing of Radiation Radiation therapy must have begun no later than 30 days after
                  the date of radiographic diagnosis or definitive surgery, whichever is the later
                  date.

          -  Organ Function Patients must have normal organ and marrow function documented within 7
             days of study enrollment

          -  All patients must have recovered from all acute RT-related toxicities to ≤ grade 2
             prior to initiating the use of ribociclib and everolimus.

          -  Pregnancy Status Female patients of childbearing potential, must not be pregnant or
             breast-feeding. Female patients of childbearing potential must have a negative serum
             or urine pregnancy test.

          -  Pregnancy Prevention Women of child-bearing potential are 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.

          -  Female patients with infants must agree not to breastfeed their infants while on this
             study.

          -  Informed Consent Signed informed consent according to institutional guidelines must be
             obtained. Assent, when appropriate, will be obtained according to institutional
             guidelines.

        Exclusion Criteria:

          -  Concurrent Illness 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
             or would likely interfere with the study procedures or results.

          -  Inability to Participate Patients with inability to return for follow-up visits or
             obtain follow-up studies required to assess toxicity to therapy.

          -  Received a radiosensitizer, craniospinal irradiation therapy, investigational agent or
             any additional adjuvant therapy during radiation therapy.

          -  Received prior therapy with CDK4/6 inhibitor and/or mTOR inhibitor.

          -  Seizures Patients who are currently receiving enzyme inducing anti-epileptic drugs
             that are known strong inducers or inhibitors of CYP3A4/5 (EIAEDs). Patients with a
             history of seizures and maintained on an anti-epileptic drug that is not a strong
             inducers or inhibitor of CYP3A4/5 are eligible.

          -  Patient has a known hypersensitivity to ribociclib or any of its excipients as
             described below:

               -  The capsules contain only the drug substance without any excipients.

               -  The film-coated tablets consist of drug substance and compendial quality
                  colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, magnesium
                  stearate and microcrystalline cellulose. The film-coating is a mix of compendial
                  quality iron oxides, lecithin, polyvinyl alcohol, talc, titanium dioxide, and
                  xanthan gum.

               -  The oral solution consists of ribociclib succinate in water with an orange
                  flavoring agent and common excipients such as preservatives, sweetener and pH
                  modifier

          -  Clinically significant active cardiac disease, uncontrolled heart disease and/or
             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
                  Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening

               -  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 for 7 days prior to starting study drug(s) or replaced by safe
                       alternative medication.

               -  Hypertension defined below:

        Patients1-17 years of age with blood pressure that is ≥ 95th percentile for age, height and
        gender at the time of enrollment

        Patients who are ≥ 18 years of age with a systolic blood pressure that is >160 or diastolic
        > 90 mm of Hg at the time of enrollment.

        * Note: If a BP reading prior to enrollment does not meet parameters, blood pressure should
        be rechecked and documented to be within eligibility range prior to patient enrollment.

          -  Inability to determine the QTc interval on the ECG (i.e.: unreadable or not
             interpretable) or QTc >480 msec as determined by screening ECG.

          -  Patient is currently receiving any of the following medications and cannot be
             discontinued 7 days prior to starting study drugs ribociclib and everolimus

               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
                  hybrids, pummelos, star-fruit, and Seville oranges

               -  Strong and moderate inhibitors or inducers of CYP3A4/5

               -  Substrates of CYP3A4/5 with a narrow therapeutic index

               -  Other investigational and anti-neoplastic therapies, including chemotherapy,
                  immunotherapy, target therapy, biological response modifiers

               -  Medications that have a narrow therapeutic window and are predominantly
                  metabolized through CYP3A4/5

               -  Medications that have a known risk to prolong the QT interval or induce Torsades
                  de Pointes

               -  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 first dose of study treatment.

          -  Bleeding Disorder Patient is currently receiving warfarin or other coumadin-derived
             anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low
             molecular weight heparin (LMWH) or fondaparinux is allowed as long as patient has
             adequate coagulation defined as: aPTT INR≤1.5 x upper limit of normal.

          -  Patient has a history of non-compliance to medical regimen.

          -  Known need for major surgery within 14 days of the first dose of ribociclib and
             everolimus. Gastrostomy, insertion of a G tube, Ventriculo-peritoneal shunt,
             endoscopic ventriculostomy and central venous access are NOT considered major surgery.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of adverse events
Time Frame:6 months
Safety Issue:
Description:Number of individual toxicities and incidence of significant delays

Secondary Outcome Measures

Measure:Time from diagnosis to death - overall survival
Time Frame:48 months
Safety Issue:
Description:Overall survival is defined as the time from diagnosis to death.
Measure:Number of patients with observed pseudoprogression
Time Frame:12 months
Safety Issue:
Description:the assessment of true vs. pseudoprogression will be based on the tumor measurements from subsequent scans
Measure:Whole exome sequencing to explore biology of DIPG and HGG tumors
Time Frame:24 months
Safety Issue:
Description:Genetic sequence analysis

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Hospital Medical Center, Cincinnati

Trial Keywords

  • DIPG
  • High Grade Glioma
  • ribociclib
  • everolimus

Last Updated

November 27, 2017