Binimetinib in Treating Younger Patients with Progressive or Recurrent Solid Tumors or Low-Grade Gliomas

Status: Active

Description

This phase I / II trial studies the side effects and best of dose binimetinib and to see how well it works in treating younger patients with solid tumors or low-grade gliomas that are growing, spreading, or getting worse (progressive) or have come back (recurrent). Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • PHASE I: Patients with recurrent, refractory, or progressive non-hematologic malignancies (central nervous system [CNS] or solid tumors) associated with activation of the RAS/RAF/ERK pathway, including any LGG, any tumor in a patient with NF1, or any tumor with a documented activating BRAF, NRAS, or KRAS mutation, will be eligible; LGG is defined as any World Health Organization (WHO) grade I or II (or equivalent) astrocytic, oligodendroglial, and/or glioneuronal tumor
  • PHASE II: Patients with recurrent or progressive disease, as defined in the following three strata below, will be eligible; for eligibility determination, tumor imaging from at least two time-points must be available to document radiographic progression or recurrence; patients with non-progressive refractory tumors will not be eligible * Stratum 1: patients with LGG with a BRAF truncated fusion that is measurable in at least two dimensions on imaging * Stratum 2: patients with NF1 and LGG that is measurable in at least two dimensions on imaging * Stratum 3: pediatric patients with a recurrent or progressive tumor thought to involve the Ras/Raf/ERK pathway but not included in strata 1 or 2 that is measurable in at least two dimensions on imaging; this includes any LGG not included in strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), any tumor other than LGG in a patient with NF1, and any other tumor with a documented activating BRAF, NRAS, or KRAS mutation * Stratum 4 (surgical arm, target validation): patients who meet criteria for stratum 1, 2, or 3 for whom tumor biopsy and/or resection is clinically indicated
  • PHASE II: Tumor tissue for correlative studies is required for all patients except those with NF1 and LGG (stratum 2) or any patient with optic pathway glioma (stratum 2 or 3), for whom tumor tissue is optional
  • PHASE II: Patients must have received at least one prior chemotherapy or radiation regimen prior to progression
  • PHASE II: At the time of enrollment, at least 6 weeks must have elapsed since the last dose of any nitrosourea, and the longer of 2 weeks or 3 half-lives must have elapsed since the last dose of any other tumor-directed medication, or biologic therapy
  • PHASE II: At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) at the time of enrollment
  • Performance score using the Karnofsky performance scale (patients > 12 years old) or Lansky Play - performance scale (patients =< 12 years old) must be >= 60 assessed within two weeks prior to enrollment
  • Within two weeks prior to enrollment: Absolute neutrophil count >= 1,000/mcL
  • Within two weeks prior to enrollment: Platelets >= 75,000/mcL and > 7 days since last platelet transfusion
  • Within two weeks prior to enrollment: Hemoglobin >= 9 gm/dL and > 7 days since last red blood cell transfusion
  • Within two weeks prior to enrollment: Not refractory to red cell or platelet transfusions
  • Within two weeks prior to enrollment: Total bilirubin =< 1.5 times the upper limit of normal
  • Within two weeks prior to enrollment: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 times the institutional upper limit of normal
  • Within two weeks prior to enrollment: Serum creatinine which is less than 1.5 times the upper limit of institutional normal for age or glomerular filtration rate (GFR) > 70 ml/min/1.73m^2
  • Within two weeks prior to enrollment: Corrected QT (QTc) interval =< 450 ms
  • Within two weeks prior to enrollment: Left ventricular ejection fraction (LVEF) >= 50% as determined an echocardiogram
  • Female patients of childbearing potential must have negative serum or urine pregnancy test within 72 hours of the first dose of MEK162; patient must not be pregnant or breast-feeding; patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study and for 30 days following cessation of treatment
  • Patient must be able to take oral/enteral medication
  • Patient, parent, or legal guardian must be able to understand and willing to provide informed consent
  • Patients must have recovered from the effects of prior therapy

Exclusion Criteria

  • Patients for whom other curative or established standard-of-care therapeutic options with acceptable morbidity exist
  • Patients with any significant medical illnesses that in the investigator’s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this therapy
  • History of Gilbert’s syndrome
  • Patients receiving any other anticancer or experimental drug therapy
  • Use of hematopoietic growth factors within 2 weeks prior to initiation of therapy
  • Any other investigational agents within 2 weeks or =< 3 x half-lives (whichever is longer) before start of study therapy
  • Patients who have undergone surgery =< 3 weeks or who have not recovered from side effects of this procedure prior to receiving study drug
  • Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, impaired gastrointestinal function, or psychiatric illness/social situations that would limit compliance with study requirements
  • History or current evidence of retinal vein occlusion (RVO) or predisposing factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
  • History of retinal degenerative disease
  • Prior therapy with a MEK inhibitor
  • Impairment of gastrointestinal function (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
  • Patients who have a neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Patients with uncontrolled hypertension

Locations & Contacts

Alabama

Birmingham
Children's Hospital of Alabama
Status: Active
Contact: Elizabeth Duncan Alva
Email: ealva@peds.uab.edu

California

Los Angeles
Children's Hospital Los Angeles
Status: Active
Contact: Nathan John Robison
Phone: 323-361-8147
Email: nrobison@chla.usc.edu

Colorado

Aurora
Children's Hospital Colorado
Status: Active
Contact: Kathleen M. O'Toole Dorris
Email: Kathleen.Dorris@childrenscolorado.org

District of Columbia

Washington
Children's National Medical Center
Status: Active
Contact: Lindsay Baker Kilburn
Email: lkilburn@childrensnational.org

Florida

Miami
Nicklaus Children's Hospital
Status: Active
Contact: Ziad Ahmad Khatib
Phone: 305-662-8360ext4960
Email: ziad.khatib@mch.com

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: Active
Contact: Tobey John MacDonald
Email: tobey.macdonald@emory.edu

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: In review
Contact: Stewart Goldman
Phone: 312-227-4844
Email: SGoldman@luriechildrens.org

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Kenneth J. Cohen
Phone: 410-614-5055
Email: kcohen@jhmi.edu

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: Active
Contact: Karen Denise Wright
Email: karend_wright@dfci.harvard.edu

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: Active
Contact: Anne Elizabeth Bendel
Email: anne.bendel@childrensmn.org

Missouri

Saint Louis
Washington University School of Medicine
Status: Active
Contact: Karen M. Gauvain
Email: Gauvain_K@kids.wustl.edu

New York

New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: Active
Contact: Sharon Leigh Gardner
Email: Sharon.Gardner@nyumc.org

Oregon

Portland
Oregon Health and Science University
Status: Active
Contact: Rebecca Marie Loret de Mola
Email: loretdem@ohsu.edu

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: In review
Contact: Michael J. Fisher
Phone: 215-590-2800
Email: fisherm@email.chop.edu

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: Active
Contact: Daniel Charles Bowers
Email: Daniel.Bowers@utsouthwestern.edu
Houston
Texas Children's Hospital
Status: Active
Contact: Patricia Ann Baxter
Email: pabaxter@txch.org

Washington

Seattle
Seattle Children's Hospital
Status: Active
Contact: Sarah E. S. Leary
Email: sarah.leary@seattlechildrens.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) (or proposed phase II dose) of MEK162 (binimetinib) administered on a continuous, twice daily dosing schedule in children with tumors that are recurrent, progressive, or refractory after standard therapy. (PHASE I)

II. To assess preliminary efficacy of MEK162 in pediatric low-grade glioma (LGG) characterized by a B-Raf proto-oncogene, serine/threonine kinase (BRAF) truncated fusion lesion. (PHASE II)

III. To assess preliminary efficacy of MEK162 in LGG in children with neurofibromatosis type 1 (NF1). (PHASE II)

SECONDARY OBJECTIVES:

I. To characterize the safety and tolerability of MEK162 in children with advanced solid tumors. (PHASE I)

II. To assess pharmacokinetic profile of MEK162 and its metabolite (AR00426032) when administered as an oral suspension in children and adolescents with recurrent, refractory or progressive tumors. (PHASE I)

III. To assess any preliminary antitumor activity of MEK162 in children with advanced solid tumors. (PHASE I)

IV. To determine the 12-month progression-free and overall survival in pediatric patients with a recurrent or progressive LGG characterized by a BRAF truncated fusion lesion (KIAA1549 and similar translocations) (Stratum 1). (PHASE II)

V. To determine the 12-month progression-free and overall survival in pediatric patients with NF1 and recurrent or progressive LGG (Stratum 2). (PHASE II)

TERTIARY OBJECTIVES:

I. To explore the pharmacodynamic (PD) effects of MEK162 on biomarkers of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway activity in peripheral blood lymphocytes (PBL) and tumor tissue (if available). (PHASE I)

II. To assess response rate and 12-month progression free and overall survival in pediatric patients with a recurrent or progressive tumor with known or presumed signaling through the Ras/Raf/ERK pathway not included in strata 1 or 2, including tumors positive for BRAF V600E or activating neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, any LGG not eligible for strata 1 or 2 (i.e., any LGG without a BRAF truncated fusion in a patient without NF1), and any tumor other than LGG in a patient with NF1 (Stratum 3). (PHASE II)

III. To correlate treatment response with molecular phenotype. (PHASE II)

IV. To quantify the intra-tumoral concentration of MEK162 after 7-21 days of twice-daily administration, and correlate with plasma pharmacokinetic (PK) assessment. (PHASE II)

V. To assess downstream Ras/Raf/MEK/ERK pathway inhibition, as measured by ERK phosphorylation, after treatment with MEK162 suspension for 7-21 days, and correlate with blood PD assessment. (PHASE II)

VI. To describe patient and parent-reported quality of life outcomes in children with LGG and other Ras/Raf/ERK pathway-activated tumors undergoing treatment with MEK162. (PHASE II)

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive binimetinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients may continue 12 additional courses at the discretion of the treating physician.

OPTIONAL TARGET VALIDATION PHASE: Patients undergoing surgery receive binimetinib PO BID for 7-21 days pre-operatively. After surgery, patients with measurable disease resume study treatment with binimetinib; patients with no measurable residual disease resume treatment at the discretion of the local investigator in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 1 year, and then annually thereafter.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Children's Hospital Los Angeles

Principal Investigator
Nathan John Robison

Trial IDs

Primary ID ChildrensHLA
Secondary IDs NCI-2014-02168, s17-00228
Clinicaltrials.gov ID NCT02285439