Pilot Efficacy Study of vemurafenib, an oral inhibitor of BRAFV600E, in Children with Recurrent/Refractory BRAFV600E-mutant gliomas

Trial Requirements and Treatment

Patients will receive vemurafenib once daily by mouth. One course is 28 days. Subsequent courses will immediately follow, with no break in the administration of the drug. Clinical assessment will be required every 2 months for the first 6 months, then every 3 months for the next 6 months.

Rationale for Study

This trial is testing the drug vemurafenib (also called PLX4032) in children with pediatric astrocytomas that have the BRAFV600E mutation. Vemurafenib works by blocking the activity of BRAF, a key protein in the RAS/RAF/MAPK pathway that is overactive in these tumors. In normal cells, the molecules in this pathway deliver signals to one another that regulate important processes such as cell proliferation, natural cell death (also called apoptosis) and cell growth. A significant fraction of pediatric astrocytomas contain the BRAFV600E mutation, and this mutation is thought to be vital to tumor maintenance.

Subsequently, the study will attempt to document vemurafenib drug levels within surgically resected tumor samples. If drug levels are found to be meet our goals, an expanded cohort will be opened to measure efficacy of this drug in children with recurrent tumors.

Primary Objectives

The primary objectives of this study are:

  1. To characterize the pharmacokinetics of vemurafenib in pediatric patients
  2. During the pilot efficacy study, to document antitumor activity of treatment with vemurafenib, as measured by objective responses.

Secondary Objectives

  1. To document intra-tumoral drug concentration in patients treated with vemurafenib and compare them to serum drug levels pre-surgery
  2. To describe progression-free survival of patients treated on vemurafenib

Inclusion Criteria

    1. Patients with histologically confirmed diagnosis of a primary central nervous system tumor will be eligible. Patient tumors must test positive for the BRAFV600E or the BRAF Ins T mutation at a CLIA-approved laboratory. If either mutation cannot be confirmed from a prior test, and archival tumor is not available to confirm presence of either mutation, patients must have tumor biopsy to collect tumor sample for mutation confirmation
    2. Patients must be ≤ 25 years of age.
    3. Specific BSA criteria depending on enrolling dose level: no restrictions for dose level 0, BSA ≥ 0.75 required for dose levels -1 and -2, BSA >0.90 required for dose levels -3 and -4
    4. Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
    5. Patients must be able to swallow tablets (or applesauce, if part of bioavailability “crushed” six patient cohort).
    6. Patient must have MRI confirming progressive disease.
    7. Karnofsky Performance Scale (KPS for > 16 yrs of age) or Lansky Performance Score (LPS for ≤ 16 years of age) ≥ 60 assessed within 14 days prior to registration.
    8. Patient must have failed at least one prior therapy besides surgery — radiation or chemotherapy (either cytotoxic or biologic agent) — prior to study registration. Patient must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
      • Myelosuppresive chemotherapy: Patients must have received their last dose of known myelosuppresive chemotherapy at least 3 weeks prior to study registration or six weeks if therapy was a nitrosourea.
      • Biologic agent: Patient must be 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 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 3 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 psuedo-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
      • Corticosteriods: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
      • Growth factors: Patients must be 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.
    9. Organ Function: Documented within 14 days of registration and within 7 days of the start of treatment.
    10. Adequate bone marrow function:
      • Absolute neutrophil count ≥ 1000/µl (unsupported)
      • Platelets ≥ 75,000/µl (unsupported)
      • Hemoglobin ≥ 8 g/dL (may be supported)
    11. 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
    12. Adequate renal function:
      • Creatinine clearance or Radioisotope GFR ≥ 70 ml/min/1.73m2 or a serum creatinine based on age as follows:
      Age (years) Maximum Serum Creatinine (mg/dL)
      ≤5 0.8
      > 5 but ≤ 10 1
      >10 but ≤15 1.2
      >15 1.5


      • Sodium: ≥ 130 and ≤ 145 mmol/L
      • Potassium: 3.4- 4.8 mmol/L
      • Calcium: ≥ 7 mg/dL
      • Magnesium: ≥ 0.7 mmol/L
      • Albumin ≥ 3 g/dL


      • QTc interval <450 msec on EKG.
    13. 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.

Specific Inclusion Criteria for Pre-Surgical Cohort

  1. 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.
  2. 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

  1. 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).
  2. Patients under 25 years of age will be eligible for the expansion cohort.
  3. Patients between 18 and 25 years of age will take adult dose of 960 mg BID.
  4. Patients less than 18 years of age will take the MTD defined in the safety cohort.

Exclusion Criteria

  1. 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.
  2. Patients with active lesions suspicious for keratoacanthomas/cSCC; patients who have excision of keratocanthomas/cSCC, with dermatologic confirmation of the absence of active disease may become eligible
  3. All patients with known diagnosis of Neurofibromatosis Type 1 or other known RAS-opathies are excluded.
  4. Patients receiving any other anticancer or investigational drug therapy.
  5. Patients with uncontrolled seizures are not eligible for the study.
  6. Previous BRAF inhibitor use such as vemurafenib, GSK2118436 or sorafenib.
  7. Patients with QTc interval >450 msecs or other factors that increase the risk of QT prolongation 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 (see Appendix 4) are excluded.
  8. Required use of a concomitant medication that can prolong the QT interval. See Appendix 5 for a table of medications with the potential to prolong the QTc interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at AZCERT
  9. Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
  10. History of allergic reactions attributed to compounds of similar chemical or biologic composition to vemurafenib.
  11. Negative result of BRAFV600E screening test performed at UCSF.