Clinical trial NCT01748149: Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E (BRAFV600E)-Mutant Gliomas
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Pediatric Recurrent/Refractory BRAFV600E-mutant Gliomas
Keywords: recurrent/refractory BRAFV600E-mutant gliomas
pediatrics
children
neo-adjuvant vemurafenib
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2012-12-12
Enrollment: 40
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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 or BRAF Ins T 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 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. Participants are followed up for adverse events while receiving study treatment until resolution.

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 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. Women must refrain from donating eggs during this same period. 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.

Primary outcomes:
measure: Maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D)
timeFrame: Up to 4 weeks
measure: Proportion of participants with dose limiting toxicities
timeFrame: Up to 4 weeks
measure: Median concentrations of vemurafenib in the blood found through pharmacokinetic (PK) samples
timeFrame: Up to 4 weeks
measure: Objective Response Rate
timeFrame: Up to 4 weeks
Secondary outcomes:
measure: Median Intra-tumoral drug level concentration
timeFrame: Up to 4 weeks
measure: Progression-free survival
timeFrame: Up to 6 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Mattel Children's Hospital UCLA
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Parnassus
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Children's Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis Children's Hospital
state: Missouri
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of California, San Francisco
name: Sabine Mueller, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nicolaides T, Nazemi KJ, Crawford J, Kilburn L, Minturn J, Gajjar A, Gauvain K, Leary S, Dhall G, Aboian M, Robinson G, Long-Boyle J, Wang H, Molinaro AM, Mueller S, Prados M. Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). Oncotarget. 2020 May 26;11(21):1942-1952. doi: 10.18632/oncotarget.27600. eCollection 2020 May 26.