Clinical Trials /

A Phase I/II Study of Ribociclib,a CDK4/6 Inhibitor, Following Radiation Therapy

NCT02607124

Description:

In this research study the investigators want to learn more about the effects, both good and bad, when the study drug Ribociclib is given after radiation therapy. The investigators are asking people to be in this research study that have been newly diagnosed with a high grade glioma, and the tumor has been screened for the Rb1 protein, and have recently finished radiation therapy. Patients with a DIPG or a Bi-thalamic high grade glioma do not need to have 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 called cyclin-dependent kinases (CDK 4 and 6) that control cell division. Another protein Rb1 also controls cell division and works to stop cells from dividing so they do not become cancer cells. But in cancer, the CDK 4 and 6 proteins are out of control making the cells divide and grow quickly. The study drug, ribociclib stops the CDK 4 and 6 proteins. When the CDK 4 and 6 proteins are stopped, the normal Rb1 protein can now work to slow cell growth. For patients with HGG, to be in this study tumor tissue must have a normal Rb1 protein. The researchers think that if the study drug is given soon after radiation therapy, it may help improve the effect of the radiation in stopping the tumor from growing. The study drug, Ribociclib is considered investigational as it has not yet been approved by the United States Food and Drug Administration. The study drug has been tested in children and adults with cancer in prior research studies.

Related Conditions:
  • Glioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Administration of <span class="go-doc-concept go-doc-intervention">Ribociclib</span> Following <span class="go-doc-concept go-doc-intervention">Radiation</span> Therapy in Children With Newly Diagnosed Non-biopsied Diffuse Pontine Gliomas (DIPG) and <span class="go-doc-concept go-doc-biomarker">RB</span>+ Biopsied DIPG and High Grade Gliomas (HGG)

Title

  • Brief Title: Administration of Ribociclib 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/II Study of Ribociclib, a CDK4/6 Inhibitor, 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

    NCT ID: NCT02607124

    ORG ID: CLEE011XUS17T

    Trial Conditions

    High Grade Glioma

    Diffuse Intrinsic Pontine Glioma

    Bithalamic High Grade Glioma

    Trial Interventions

    Drug Synonyms Arms
    Ribociclib LEE011 RB+ High Grade Glioma, Non-Biopsied Diffuse Instrinsic Pontine Glioma

    Trial Purpose

    In this research study the investigators want to learn more about the effects, both good and
    bad, when the study drug Ribociclib is given after radiation therapy.

    The investigators are asking people to be in this research study that have been newly
    diagnosed with a high grade glioma, and the tumor has been screened for the Rb1 protein, and
    have recently finished radiation therapy. Patients with a DIPG or a Bi-thalamic high grade
    glioma do not need to have 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 called
    cyclin-dependent kinases (CDK 4 and 6) that control cell division. Another protein Rb1 also
    controls cell division and works to stop cells from dividing so they do not become cancer
    cells. But in cancer, the CDK 4 and 6 proteins are out of control making the cells divide
    and grow quickly. The study drug, ribociclib stops the CDK 4 and 6 proteins. When the CDK 4
    and 6 proteins are stopped, the normal Rb1 protein can now work to slow cell growth. For
    patients with HGG, to be in this study tumor tissue must have a normal Rb1 protein. The
    researchers think that if the study drug is given soon after radiation therapy, it may help
    improve the effect of the radiation in stopping the tumor from growing.

    The study drug, Ribociclib is considered investigational as it has not yet been approved by
    the United States Food and Drug Administration. The study drug has been tested in children
    and adults with cancer in prior research studies.

    Detailed Description

    Ribociclib has shown an acceptable toxicity profile in adults and pediatrics. Available data
    suggests that over 70% of DIPG patient have an intact RB and 90% HGG patients have
    expression of RB, therefore CDK4/6 inhibition is a suitable target. Given the dismal
    prognosis for children with DIPG and HGG, it is appropriate to evaluate the long term
    feasibility and early efficacy of Ribociclib following radiation therapy in patients with
    RB+ tumors. The aim of the upfront biopsy molecular studies proposed is to identify
    subgroups of patients who will benefit from the use of checkpoint inhibitors in the setting
    of intact RB pathway. This study will play a major role in moving the field of DIPG/HGG
    research forward as the investigators intend to reveal feasibility of upfront stereotactic
    biopsy and specific pathway directed therapy following radiation therapy with the ultimate
    goal to add additional targeted therapy in combination with Ribociclib resulting in
    improving the outcome for patients diagnosed with these fatal tumors.

    The current proposal will be a novel pediatric study to obtain biopsy in DIPG prior to
    therapy and administer molecularly targeted therapy following radiation therapy in children
    with newly diagnosed DIPG and HGG. In this study, the investigators will assess the assess
    long-term feasibility and early efficacy of Ribociclib administered daily for 3 weeks and
    off one week every 28 days following radiation therapy for at least 6 courses and up to 12
    courses in patients with newly-diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG.
    Moreover, the investigators will approach this devastating disease with a multi-disciplinary
    team and evaluate the quality of life and functional outcome resulting in effective
    interventions.

    Trial Arms

    Name Type Description Interventions
    RB+ High Grade Glioma Experimental Ribociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (>21 yrs of age 600mg daily (DIPG); <21 yrs of age 350 mg/m2/day) Ribociclib
    Non-Biopsied Diffuse Instrinsic Pontine Glioma Experimental Ribociclib administered orally; daily on days 1-21 each 28 day cycle; dose calculation age dependent (>21 yrs of age 600mg daily (DIPG); <21 yrs of age 350 mg/m2/day) Ribociclib

    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.

    - RB status

    - Diagnostic stereotactic biopsy: Patients diagnosed with DIPG may choose to have
    a stereotactic biopsy prior to starting radiation therapy.

    - Toxicities related to biopsy must have resolved prior to proceeding with
    radiation therapy.

    - Screening for Rb applies to all patients with available tissue except for
    patients diagnosed with DIPG and bi-thalamic tumors.

    - If resection occurred at an outside institution, eligibility and treatment MRI
    evaluations in addition to Rb testing must be completed at CCHMC.

    - Tumor

    - Diffuse Intrinsic Pontine Glioma (DIPG) Patients with newly diagnosed diffuse
    intrinsic pontine gliomas (DIPGs), defined 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 be an anaplastic astrocytoma, glioblastoma multiforme,
    gliosarcoma, anaplastic mixed glioma or fibrillary astrocytoma.

    - Note: Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma,
    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.

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

    - Patients with disseminated disease are not eligible, and MRI of spine must be
    performed prior to enrollment if the treating physician suspects disseminated
    disease.

    - High-grade Glioma (HGG)

    - Patients must have had histologically verified anaplastic astrocytoma,
    glioblastoma multiforme, high grade glioma, NOS or gliosarcoma AND RB positive
    noted on immunohistochemistry. Patients with primary spinal cord tumors are
    eligible.

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

    - 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 and/or steroids.

    - Radiation therapy requirements

    - Patients with DIPG who received radiation therapy should have received radiation
    therapy at the current standard dose of 54 Gy total. Radiation therapy will be
    interrupted for acute toxicities per the treating physician.

    - Patients diagnosed with HGG will receive radiation therapy at the current
    standard dose of 59.4 Gy total. Radiation therapy will be interrupted for acute
    toxicities per the treating physician.

    - Timing of Radiation

    - Non-biopsied DIPG or bi-thalamic tumors 30 days post radiographic diagnosis

    - DIPG with stereotactic biopsy 37 days post radiographic diagnosis and at least
    14 days post biopsy

    - HGG 37 days post surgery and at least 14 days post biopsy or resection.

    - Organ Function

    - Patients must have normal organ and marrow function documented within 14 days of
    study entry and within 7 days of the start of treatment of Ribociclib as defined
    below:

    - Absolute neutrophil count 1000mm3

    - Platelets 75,000/mm3 (unsupported for 7 days)

    - Hemoglobin 9g/dl (unsupported) for 7 days

    - Total bilirubin 3 times upper limit of normal (ULN) for age

    - ALT (SGPT) 2.5 X ULN for age

    - Albumin 2 g/dl

    - Creatinine clearance or radioisotope GFR 70mL/min/1.73m2 or serum creatinine
    based on age/gender.

    - 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 Patients of childbearing or child fathering potential must use a
    highly effective method of contraception throughout the study while taking the drug
    and for 21 days after stopping treatment

    - 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 or any additional adjuvant therapy during radiation
    therapy.

    - 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.

    - 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 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 known to cause Torsades de Pointe that cannot be discontinued (within 5
    half-lives or 7 days prior to starting study drug) or replaced by safe
    alternative medication

    - Hypertension defined below:

    - Patients 2-17 years of age must have a blood pressure that is 95th percentile
    for age, height and gender at the time of enrollment.

    - Patients who are 18 years of age must have 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 is above the 95th percentile for age,
    height and gender, it is to be rechecked and documented to be 95th percentile
    for age, height and gender prior to patient enrollment.

    - Inability to determine the QTcF interval on the ECG (i.e. unreadable or not
    interpretable) or QTcF > 450 msec (using Fridericia's correction). All as determined
    by screening ECG (using the mean QTcF of triplicate ECGs)

    - Patient is currently receiving any of the following medications and cannot be
    discontinued 7 days prior to starting study drug Ribociclib:

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

    - 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, dietary supplements.

    - 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

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

    - Known need for major surgery within 14 days of the first dose of Ribociclib.
    Gastrostomy, insertion of a G tube, Ventriculo-peritoneal shunt, endoscopic
    ventriculostomy and central venous access are NOT considered major surgery. (Tumor
    biopsy is not considered as a major surgery).

    - Patients with diagnostic imaging consistent with DIPG and evidence of hemorrhage on
    MRI will be excluded from the option to have a biopsy obtained, however may proceed
    with eligibility for the non-biopsy arm.

    Minimum Eligible Age: 12 Months

    Maximum Eligible Age: 30 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Number of adverse events

    Number of patients alive at one year

    Secondary Outcome Measures

    Time from initiation of treatment to the earliest date of failure - progression free survival

    Number of patients with observed pseudoprogression

    Trial Keywords