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Early-Phase Study to Assess Inhibitor Ribociclib in Patients With Recurrent Glioblastoma or Anaplastic Glioma

NCT02345824

Description:

This is a single-institution, open-label, early-phase study to assess the ability of ribociclib (LEE011) to inhibit CDK4/CDK6/Rb/E2F signaling and cell proliferation/viability in core and infiltrating tumor tissues obtained from patients with recurrent glioblastoma or anaplastic glioma compared to the baseline/primary pathologic tumor specimen. Abundant preclinical evidence indicates that Rb-deficient cancer cells are resistant to CDK4/6 inhibition and ongoing trials with CDK4/6 inhibitors exclude patients with Rb-deficient tumors. The investigators will evaluate 10 patients with Rb-positive glioblastoma or anaplastic glioma in this study. Given that a minority of glioblastomas ha Rb loss the investigators anticipate enrolling a maximum of 20 patients, to meet our goal of 10 patients with Rb-positive tumors.

Related Conditions:
  • Glioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Early-Phase Study to Assess Inhibitor <span class="go-doc-concept go-doc-intervention">Ribociclib</span> in Patients With Recurrent <span class="go-doc-concept go-doc-disease">Glioblastoma</span> or Anaplastic <span class="go-doc-concept go-doc-disease">Glioma</span>

Title

  • Brief Title: Early-Phase Study to Assess Inhibitor Ribociclib in Patients With Recurrent Glioblastoma or Anaplastic Glioma
  • Official Title: Early-Phase Study to Assess Tumor Pharmacokinetics and Efficacy of the CDK4/6 Inhibitor Ribociclib (LEE011) in Patients With Recurrent Glioblastoma or Anaplastic Glioma
  • Clinical Trial IDs

    NCT ID: NCT02345824

    ORG ID: D13223

    NCI ID: 18729

    Trial Conditions

    Glioblastoma

    Glioma

    Trial Interventions

    Drug Synonyms Arms
    Ribociclib LEE011 Ribociclib (LEE011) Treatment

    Trial Purpose

    This is a single-institution, open-label, early-phase study to assess the ability of
    ribociclib (LEE011) to inhibit CDK4/CDK6/Rb/E2F signaling and cell proliferation/viability
    in core and infiltrating tumor tissues obtained from patients with recurrent glioblastoma or
    anaplastic glioma compared to the baseline/primary pathologic tumor specimen. Abundant
    preclinical evidence indicates that Rb-deficient cancer cells are resistant to CDK4/6
    inhibition and ongoing trials with CDK4/6 inhibitors exclude patients with Rb-deficient
    tumors. The investigators will evaluate 10 patients with Rb-positive glioblastoma or
    anaplastic glioma in this study. Given that a minority of glioblastomas ha Rb loss the
    investigators anticipate enrolling a maximum of 20 patients, to meet our goal of 10 patients
    with Rb-positive tumors.

    Detailed Description

    Preliminary evaluation of efficacy and determination of the ribociclib safety profile in
    patients with brain tumors will be studied. All patients will be treated with ribociclib
    (600 mg/day) for 8-21 days before surgical resection of the recurrent tumor. Rb status of
    the recurrent tumor will be determined by immunohistochemistry within 2 weeks after surgery.
    Patients with Rb-positive tumors will continue treatment with ribociclib (21 days on, 7 days
    off) after surgery. Patients will be treated until unacceptable toxicity is observed, or
    until disease progression as assessed by radiographic or clinical metrics. We will determine
    whether molecular markers associated with changes induced by ribociclib treatment in tumors
    (matching initial vs. recurrent tumors) correlate with progression-free survival.

    Approximately 20% of patients with recurrent high-grade glioma will undergo surgical
    resection of their tumor typically at the time of first recurrence. These patients will be
    eligible for this study. An extra 10 mL of blood will be collected during a routine clinical
    procedure prior to initiation of ribociclib treatment (i.e., baseline blood sample),
    separated into plasma and buffy coat fractions, and frozen for pharmacokinetic (PK)
    analysis. Patients will be treated with ribociclib for 8-21 days prior to surgery to
    identify drug effects on tumor cells, and to determine drug PK. The last presurgical dose of
    ribociclib will be administered on the day of surgery at 4-8 hours prior to surgery to allow
    sufficient time for the drug to enter tumor cells, inhibit CDK4/6, and modulate downstream
    effectors. Blood will be acquired within 1 hour before surgery (as close to the time of
    surgery as possible). Blood will be separated into plasma and buffy coat fractions, and
    frozen. During surgery, samples of brain tumor core and infiltrating brain tumor will be
    acquired. Tissue samples will be frozen or fixed in paraffin embedded blocks and histology
    for PK and molecular analyses.

    Trial Arms

    Name Type Description Interventions
    Ribociclib (LEE011) Treatment Experimental Patients will be treated with ribociclib (LEE011) (recommended phase 2 dose of 600 mg/day) for 8-21 days prior to surgery. For preliminary evaluation of efficacy and toxicity, patients with Rb-positive tumors will resume treatment with ribociclib at 14-28 days post-surgery on a schedule of 21 days on, 7 days off in a 28-day cycle. Patients will be treated until unacceptable toxicity is observed, or until disease progression as assessed by radiographic or clinical metrics. Ribociclib

    Eligibility Criteria

    Inclusion criteria:

    - Written informed consent must be obtained prior to any screening procedures

    - Patients age 18-85 are eligible for study participation

    - History of grade III or IV glioma (GBM or AG) with archived FFPE and/or frozen tumor
    tissue available

    - Patient must be a candidate for surgical resection of recurrent high-grade glioma

    - Karnofsky Performance Scale score 70.

    - Life expectancy of 4 months or longer.

    - Received at least 1 prior systemic therapy for glioma.

    - A sufficient interval must have elapsed between the last dose of prior anti-cancer
    therapy (including cytotoxic and biological therapies and major surgery) and
    enrollment, to allow the effects of prior therapy to have abated

    - Patients must have adequate organ function

    - For continued ribociclib treatment after surgery, immunohistochemical (IHC)
    confirmation of Rb expression in 50% of malignant tumors cells in at least 1 tumor
    specimen is

    Exclusion criteria:

    - Impairment of gastro-intestinal (GI) function or GI disease that may significantly
    alter the absorption of ribociclib such as patients with a history of GI surgery
    which may result in intestinal blind loops and patients with clinically significant
    gastroparesis, unresolved nausea, vomiting, or diarrhea of CTCAE grade > 1

    - Impaired cardiac function or clinically significant cardiac diseases

    - Patients who are currently receiving treatment (within 5 days prior to starting study
    drug) with agents that are metabolized predominantly through CYP3A4 and that have a
    narrow therapeutic window. Agents including vitamins, supplements, and herbal
    supplements that are either (i) metabolized solely through CYP3A4/5, CYP1A2 or BSEP
    and have a narrow therapeutic window or (ii) are strong inhibitors of CYP3A4/5,
    CYP1A2 or BSEP. Agents that are known strong inducers or inhibitors CYP3A4 are
    prohibited. Patients must avoid consumption of grapefruit, Seville oranges or
    products containing the juice of each during the entire study and for 7 days before
    the first dose.

    - Patients with concurrent severe and/or uncontrolled concurrent medical conditions
    that the investigator believes could compromise participation in the study (e.g.,
    uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary
    disease, clinically significant neurological disorder, active or uncontrolled
    infection)

    - Pregnant or lactating women, where pregnancy is defined as the state of a female
    after conception and until the termination of gestation, confirmed by a positive hCG
    laboratory test (> 5 mIU/mL).

    - Women of childbearing potential, defined as all women physically capable of becoming
    pregnant, unless they are using effective methods of contraception during dosing of
    study treatment. Effective contraception must be used by both sexes (female patients
    and their male partners) during study treatment and for 30 days after the last dose
    of study medication

    - Fertile males must be willing to use contraception. Fertile males must use condom
    with spermicide (double barrier method). Effective contraception, as defined above,
    must be used by both sexes (male patients and their female partners) during study
    treatment and for 30 days after the last dose of study medication. A condom is
    required to be used by vasectomized men in order to prevent delivery of the study
    drug via seminal fluid.

    - Patients unwilling or unable to comply with the protocol

    - Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not
    mandatory)

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 85 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Inhibition of CDK4/CDK6 Signaling Pathway in Cell Proliferation

    Secondary Outcome Measures

    Ribociclib Concentration in Tissues

    Ribociclib Concentration in Plasma

    Tumor Progression

    Survival Outcomes

    Ribociclib Safety Profile

    Trial Keywords

    CDK4/6 Inhibitor

    LEE011

    Recurrent Glioblastoma

    Anaplastic Glioma

    Ribociclib