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Vemurafenib in Children With Recurrent/Refractory BRAFV600E-mutant Gliomas

Information source: University of California, San Francisco
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas

Intervention: Vemurafenib (Drug)

Phase: Phase 0

Status: Recruiting

Sponsored by: Theodore Nicolaides MD

Official(s) and/or principal investigator(s):
Theodore Nicolaides, MD, Principal Investigator, Affiliation: University of California, San Francisco

Overall contact:
Theodore Nicolaides, MD, Phone: 415-476-3831, Email: theodore.nicolaides@ucsf.edu

Summary

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.

Clinical Details

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

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:

Intra-tumoral drug concentration Comparison

Progression-free survival

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.

Eligibility

Minimum age: N/A. Maximum age: 25 Years. Gender(s): Both.

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/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

- 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.

Locations and Contacts

Theodore Nicolaides, MD, Phone: 415-476-3831, Email: theodore.nicolaides@ucsf.edu

Children's Hospital Los Angeles, Los Angeles, California 90027, United States; Recruiting
Ghirish Dhall, MD, Phone: 323-361-8147, Email: GDhall@chla.usc.edu
Ashley Margol, MD, Email: amargol@chla.ucs.edu
Ghirish Dhall, MD, Principal Investigator
Ashley Margol, MD, Sub-Investigator

University of California, Los Angeles, Los Angeles, California 90027, United States; Not yet recruiting
Tom B Davidson, MD, Phone: 310-825-6708, Email: tdavidson@mednet.ucla.edu
Theodore Moore, Email: tbmoore@mednet.ucla.edu
Tom B Davidson, MD, Principal Investigator
Theodore Moore, MD, Sub-Investigator

Children's Hospital Oakland, Oakland, California 94609, United States; Not yet recruiting
Joseph Torkildson, MD, Phone: 510-428-3272, Email: jtorkildson@mail.cho.org
Caroline Hastings, MD, Phone: (510) 428-3272, Email: chastings@mail.cho.org
Joseph Torkildson, MD, Principal Investigator
Caroline Hastings, MD, Sub-Investigator

University of California, San Diego Rady Children's Hospital, San Diego, California 92123, United States; Recruiting
John Crawford, MD, Phone: 858-966-4930, Email: jrcrawford@rchsd.org
Janet Yoon, MD, Email: Jyoon@rchsd.org
John Crawford, MD, Principal Investigator
Janet Yoon, MD, Sub-Investigator

University of California, San Francisco, San Francisco, California 94158, United States; Recruiting
Theodore Nicolaides, MD, Phone: 415-476-3831, Email: theodore.nicolaides@ucsf.edu
Theodore Nicolaides, MD, Principal Investigator
Sabine Mueller, MD, PhD, Sub-Investigator

Children's National Medical Center, District of Columbia, District of Columbia 20010, United States; Recruiting
Roger Packer, MD, Phone: 202-476-5973, Email: rpacker@cnmc.org
Lindsay Kilburn, MD, Phone: 202 476-4304, Email: lkilburn@cnmc.org
Roger Packer, MD, Principal Investigator
Lindsay Kilburn, MD, Sub-Investigator

Oregon Health & Science University, Portland, Oregon 97239, United States; Recruiting
Kellie Nazemi, MD, Phone: 503-494-1543, Email: nazemik@ohsu.edu
Lissa Baird, Email: bairdli@ohsu.edu
Kellie Nazemi, MD, Principal Investigator
Lissa Baird, MD, Sub-Investigator

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting
Jane Minturn, MD, Phone: 267-426-5026, Email: minturn@email.chop.edu
Michael Fisher, MD, Email: fisherm@email.chop.edu
Jane Minturn, MD, Principal Investigator
Michael Fisher, MD, Sub-Investigator

St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States; Recruiting
Amar Gajjar, MD, Phone: 901-595-2615, Email: amar.gajjar@stjude.org
Ibrahim Qaddoumi, MD, Phone: 901 595 2365, Email: ibrahim.qaddoumi@stjude.org
Amar Gajjar, MD, Principal Investigator
Ibrahim Qaddoumi, MD, Sub-Investigator

University of Utah, Salt Lake City, Utah 84112, United States; Recruiting
Richard Lemons, MD, Phone: 801-662-4700, Email: richard.lemons@intermountainmail.org
Carol Bruggers, MD, Phone: 801-662-4700, Email: carol.bruggers@imail.org
Richard Lemons, MD, Principal Investigator
Carol Bruggers, MD, Sub-Investigator

University of Washington, Seattle, Seattle, Washington 98195, United States; Recruiting
Sarah Leary, MD, Phone: 206-667-7955, Email: sarah.leary@seattlechildrens.org
Russ Geyer, MD, Phone: 206-667-7955, Email: russ.geyer@seattlechildrens.org
Russ Geyer, MD, Sub-Investigator
Sarah Leary, MD, Principal Investigator

Additional Information

Starting date: February 2014
Last updated: April 21, 2015

Page last updated: August 20, 2015

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