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



Status:Active, not recruiting
Conditions:Brain Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:Any - 25
Updated:11/14/2018
Start Date:February 2014
End Date:June 2020

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Pediatric Neuro-Oncology Consortium (PNOC)-002: Safety, Phase 0, and Pilot Efficacy Study of Vemurafenib, an Oral Inhibitor of BRAFV600E, in Children and Young Adults With Recurrent/Refractory BRAFV600E- or BRAF Ins T Mutant Brain Tumors

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.

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. 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.

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 University
of California, San Francisco (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 magnetic resonance (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/μl (unsupported)

- Platelets ≥ 75,000/μl (unsupported)

- Hemoglobin ≥ 8 g/dL (may be supported)

- Adequate hepatic function:

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

- serum glutamate pyruvate transaminase (SGPT)/serum glutamate oxaloacetate transaminase
(SGOT) (ALT/AST) ≤ 2.5 times institutional upper limit of normal for age

- Adequate renal function:

- Creatinine clearance or Radioisotope glomerular filtration rate (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:

- Corrected QT (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/cutaneous squamous cell carcinoma
(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.
We found this trial at
21
sites
700 Childrens Drive
Columbus, Ohio 43205
(616) 722-2000
Principal Investigator: Mohamed S. AbdelBaki
Phone: 614-722-4087
Nationwide Children's Hospital At Nationwide Children’s, we are creating the future of pediatric health care....
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4650 Sunset Blvd
Los Angeles, California 90027
 (323) 660-2450
Principal Investigator: Ashley S. Margol
Phone: 323-361-8147
Childrens Hospital Los Angeles Children's Hospital Los Angeles is a 501(c)(3) nonprofit hospital for pediatric...
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262 Danny Thomas Pl
Memphis, Tennessee 38105
(901) 495-3300
Principal Investigator: Amar Gajjar
Phone: 901-595-2615
St. Jude Children's Research Hospital St. Jude is unlike any other pediatric treatment and research...
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747 52nd St
Oakland, California 94609
(510) 428-3000
Principal Investigator: Joseph C. Torkildson
Phone: 510-428-3272
Children's Hospital and Research Center Oakland For nearly 100 years, Children's Hospital & Research Center...
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South 34th Street
Philadelphia, Pennsylvania 19104
 215-590-1000
Principal Investigator: Jane E. Minturn
Phone: 267-426-5026
Children's Hospital of Philadelphia Since its start in 1855 as the nation's first hospital devoted...
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3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
503 494-8311
Principal Investigator: Kellie J. Nazemi
Phone: 503-494-1543
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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3020 Childrens way
San Diego, California 92123
(858) 576-1700
Principal Investigator: John R. Crawford
Phone: 858-966-4930
Rady Children's Hospital - San Diego Rady Children's Hospital-San Diego is the region’s pediatric medical...
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401 North Broadway
Baltimore, Maryland 21287
410-955-5000
Principal Investigator: Kenneth J. Cohen
Phone: 410-614-5055
Johns Hopkins University-Sidney Kimmel Cancer Center The name Johns Hopkins has become synonymous with excellence...
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450 Brookline Ave
Boston, Massachusetts 2215
617-632-3000
Principal Investigator: Susan N. Chi
Phone: 617-632-2291
Dana-Farber Cancer Institute Since it’s founding in 1947, Dana-Farber has been committed to providing adults...
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Chicago, Illinois 60614
Principal Investigator: Stewart Goldman
Phone: 312-227-4873
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1600 Southwest Archer Road
Gainesville, Florida 32610
Principal Investigator: Sridharan Gururangan
Phone: 352-294-8347
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6621 Fannin St
Houston, Texas 77030
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Principal Investigator: Patricia A. Baxter
Texas Children's Hospital Texas Children's Hospital, located in Houston, Texas, is a not-for-profit organization whose...
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Los Angeles, California 90095
Principal Investigator: Tom B. Davidson
Phone: 310-825-6708
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2450 Riverside Avenue
Minneapolis, Minnesota 55454
Principal Investigator: Christopher L. Moertel
Phone: 612-626-2778
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Saint Louis, Missouri 63110
Principal Investigator: Karen M. Gauvain
Phone: 314-286-2790
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2000 Circle of Hope Dr
Salt Lake City, Utah 84112
(801) 585-0303
Principal Investigator: Nicholas S. Whipple
Phone: 801-662-4700
Huntsman Cancer Institute at University of Utah Huntsman Cancer Institute (HCI) is part of the...
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San Francisco, California 94115
Principal Investigator: Theodore P. Nicolaides
Phone: 415-476-3831
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San Francisco, California 94143
Principal Investigator: Sabine Mueller
Phone: 415-476-3831
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4800 Sand Point Way NE
Seattle, Washington 98105
(206) 987-2000
Principal Investigator: Sarah E. Leary
Phone: 206-667-7955
Seattle Children's Hospital Seattle Children’s Hospital specializes in meeting the unique physical, emotional and developmental...
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555 University Avenue
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111 Michigan Ave NW
Washington, District of Columbia
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Principal Investigator: Lindsay B. Kilburn
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Childrens National Medical Center As the nation’s children’s hospital, the mission of Children’s National Medical...
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