Clinical Trials /

Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E (BRAFV600E)-Mutant Gliomas

NCT01748149

Description:

This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory gliomas containing the BRAFV600E or BRAF Ins T mutation.

Related Conditions:
  • Glioma
Recruiting Status:

Active, not recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Vemurafenib in Children With Recurrent/Refractory <span class="go-doc-concept go-doc-biomarker">BRAFV600E</span>-<span class="go-doc-concept go-doc-keyword">mutant</span> Gliomas

Title

  • Brief Title: Vemurafenib in Children With Recurrent/Refractory BRAFV600E-mutant Gliomas
  • Official Title: PNOC 002: Safety, Phase 0, and Pilot Efficacy Study of Vemurafenib, an Oral Inhibitor of BRAFV600E, in Children With Recurrent/Refractory BRAFV600E-mutant Gliomas
  • Clinical Trial IDs

    NCT ID: NCT01748149

    ORG ID: CC#120819

    Trial Conditions

    Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas

    Trial Interventions

    Drug Synonyms Arms
    Vemurafenib RO5185426, PLX4032 Vemurafenib

    Trial Purpose

    This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a
    recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory
    gliomas containing the BRAFV600E mutation.

    Detailed Description

    This is a multicenter, safety and pharmacokinetic trial to determine the MTD and/or select a
    recommended phase 2 dose (RP2D) of vemurafenib in children with recurrent or refractory
    gliomas containing the BRAFV600E mutation. Using the RP2D, the study team will then conduct
    a Phase 0 study in a pre-surgical cohort of 10 patients requiring debulking surgery at the
    time of recurrence. These patients will receive neo-adjuvant vemurafenib, thus allowing the
    study team to measure intra-tumoral drug concentrations and target inhibition. An expansion
    cohort will then be enrolled to allow the study team to preliminarily estimate efficacy.

    Trial Arms

    Name Type Description Interventions
    Vemurafenib Experimental Vemurafenib should be swallowed whole with 8 oz (1 cup) of water. Pharmacokinetic studies will determine if vemurafenib can be "crushed". If patients receiving "crushed" tablets are felt to receive adequate exposure, then they will be allowed to participate in the expansion cohort. [Patients approved to take "crushed" tablets should use a pill crusher and mix pill with 3-5 ml apple sauce]. If not, then only patients able to swallow whole pills will be eligible. The patient will be requested to maintain a medication diary of each dose of medication. The medication diary will be returned to clinic staff at the end of each cycle. Vemurafenib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients with histologically confirmed diagnosis of glioma (WHO Grades I-IV) will be
    eligible. Patient tumors must test positive for the BRAFV600E mutation at UCSF
    Molecular Pathology central laboratory. If mutation cannot be confirmed from a prior
    test and archival tumor is not available to confirm presence of BRAFV600E mutation,
    patients must have tumor biopsy to collect tumor sample for mutation confirmation.

    - Patient must be less than 18 years of age at registration for the safety study.
    Patients must be < 25 years of age for Phase 0 and Efficacy Cohorts.

    - Patients with neurological deficits should have deficits that are stable for a
    minimum of 1 week prior to registration.

    - Patients must be able to swallow tablets (or applesauce, if part of bioavailability
    "crushed" six patient cohort).

    - Patient must have MR imaging performed within two weeks of first dose of drug.

    - Karnofsky Performance Scale (KPS for > 16 yrs of age) or Lansky Performance Score(LPS
    for 16 years of age) 60 assessed within two weeks prior to registration.

    - The patient must have failed at least one prior therapy besides surgery- radiation or
    chemotherapy (either cytotoxic or biologic agent)- prior to study registration.
    Patients must have fully recovered from the acute toxic effects of all prior
    chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

    - Myelosuppressive chemotherapy: Patients must have received their last dose of known
    myelosuppressive anticancer chemotherapy at least three weeks prior to study
    registration or at least six weeks if nitrosourea.

    - Biologic agent: Patient must have recovered from any toxicity potentially related to
    the agent and received their last dose of the biologic agent 7 days prior to study
    registration.

    - For agents that have known adverse events occurring beyond 7 days after
    administration, this period must be extended beyond the time during which adverse
    events are known to occur. The duration of this interval should be discussed with the
    study chair.

    - For biologic agents that have a prolonged half-life, the appropriate interval since
    last treatment should be discussed with the study chair prior to registration.

    - Monoclonal antibody treatment: At least three half-lives must have elapsed prior to
    registration. Such patients should be discussed with the study chair prior to
    registration.

    - Radiation: Patients must have:

    - Had their last fraction of local irradiation to primary tumor 12 weeks prior to
    registration; investigators are reminded to review potentially eligible cases to
    avoid confusion with pseudo-progression.

    - Had their last fraction of craniospinal irradiation or total body irradiation > 12
    weeks prior to registration

    - Bone Marrow Transplant: Patient must be:

    - 6 months since allogeneic bone marrow transplant prior to registration

    - 3 months since autologous bone marrow/stem cell prior to registration

    - Corticosteroids: Patients who are receiving dexamethasone must be on a stable or
    decreasing dose for at least 1 week prior to registration.

    - Growth factors: Off all colony forming growth factor(s) for at least 1 week prior to
    registration (filgrastim, sargramostim, erythropoietin) and at least 2 weeks for
    long- acting formulations.

    - Organ Function: Documented within 14 days of registration and within 7 days of the
    start of treatment.

    - Adequate bone marrow function:

    - Absolute neutrophil count 1000/l (unsupported)

    - Platelets 75,000/l (unsupported)

    - Hemoglobin 8 g/dL (may be supported)

    - Adequate hepatic function:

    - Total bilirubin < 1.5 times upper limit of normal for age

    - SGPT/SGOT (ALT/AST) 2.5 times institutional upper limit of normal for age

    - Adequate renal function:

    - Creatinine clearance or Radioisotope GFR 70 ml/min/1.73m2 or a serum creatinine
    based on age as follows: Less than or equal to 5 years of age= Maximum Serum
    Creatinine (mg/dL)of 0.8; Older than 5 but 10 years or younger= Maximum Serum
    Creatinine (mg/dL)of 1.0; Older than 10 but 15 years or younger= Maximum Serum
    Creatinine (mg/dL)of 1.2; Older than 15 years= Maximum Serum Creatinine (mg/dL) of
    1.5

    - Electrolytes:

    - Sodium: 130 and 145 mmol/L

    - Potassium: 3.4- 4.8 mmol/L

    - Calcium: 7 mg/dL

    - Magnesium: 0.7 mmol/L

    - Nutrition:

    - Albumin 3 g/dL

    - Cardiac:

    - QTc interval <450 msec on EKG.

    - 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. The effects of Vemurafenib on the developing human fetus are unknown.
    For this reason, women of child-bearing potential and men must agree to use adequate
    contraception: (hormonal or barrier method of birth control; abstinence) prior to
    study entry and for the duration of study participation, and for four weeks after
    dosing with vemurafenib ceases. Should a woman become pregnant or suspect she is
    pregnant while she or her partner is participating in this study, she should inform
    her treating physician immediately. Men treated or enrolled on this protocol must
    also agree to use adequate contraception prior to the study, for the duration of
    study participation, and 4 weeks after completion of study drug administration.

    - All skin lesions suspicious for keratoacanthomas/cSCC found at baseline dermatology
    visit must have been excised.

    - Signed informed consent according to institutional guidelines must be obtained.

    Specific inclusion criteria for Pre-Surgical Cohort:

    - Patients under 25 years of age will be eligible for the pre-surgical cohort. Patients
    between 18-25 years of age will be treated at the adult FDA-approved dose of 960 mg
    BID and can be enrolled immediately. Patients less than 18 years of age will be
    enrolled and treated at the pediatric MTD once it is defined in the Safety Cohort.

    - Surgical patients must have tumor that needs to be removed/debulked and is accessible
    for the neurosurgeon. Need for surgery must be such that the patient can take drug
    for 10 days before surgery.

    Specific inclusion criteria for Expansion cohort:

    Expansion cohort will be open if tissue drug levels in the Pre-Surgical cohort meet
    criteria (Tumor tissue drug concentration is greater than 50 nM). Patients under 25 years
    of age will be eligible for the expansion cohort. Patients between 18 and 25 years of age
    will take adult dose of 960 mg BID. Patients less than 18 years of age will take the MTD
    defined in the safety cohort.

    Exclusion Criteria:

    - Patients with any clinically significant unrelated systemic illness (serious
    infections or significant cardiac, pulmonary, hepatic or other organ dysfunction)
    that will likely interfere with the study procedures or results.

    - All patients with known clinical diagnosis of Neurofibromatosis Type 1 are excluded.

    - Patients receiving any other anticancer or investigational drug therapy.

    - Patients with uncontrolled seizures are not eligible for the study.

    - Previous BRAF inhibitor use such as vemurafenib, GSK2118436 or sorafenib.

    - Patients with QTc interval >450 msecs or other factors that increase the risk of
    QTprolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history
    of long QT interval syndrome) including heart failure that meets New York Heart
    Association(NYHA) class III and IV definitions are excluded.

    - Required use of a concomitant medication that can prolong the QT interval. A
    comprehensive list of agents with the potential to cause QTc prolongation can be
    found at http://www.azcert.org/medical-pros/drug-lists/browse-drug-list.cfm?alpha=A

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

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to vemurafenib.

    - Negative result of BRAFV600E screening test performed at UCSF.

    Minimum Eligible Age: N/A

    Maximum Eligible Age: 25 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D)

    Toxicity Profile (dose limiting toxicities)

    Concentrations of vemurafenib in the blood found through pharmacokinetic samples

    Objective Response

    Secondary Outcome Measures

    Intra-tumoral drug concentration Comparison

    Progression-free survival

    Trial Keywords

    recurrent/refractory BRAFV600E-mutant gliomas

    pediatrics

    children

    neo-adjuvant vemurafenib