Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01089101
First received: March 17, 2010
Last updated: June 30, 2014
Last verified: May 2014
  Purpose

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating young patients with recurrent or refractory low grade glioma. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Childhood Low-grade Cerebellar Astrocytoma
Childhood Low-grade Cerebral Astrocytoma
Childhood Mixed Glioma
Childhood Pilocytic Astrocytoma
Neurofibromatosis Type 1
Recurrent Childhood Anaplastic Oligodendroglioma
Recurrent Childhood Brain Stem Glioma
Recurrent Childhood Cerebellar Astrocytoma
Recurrent Childhood Cerebral Astrocytoma
Recurrent Childhood Oligodendroglioma
Recurrent Childhood Pilocytic Astrocytoma
Recurrent Childhood Visual Pathway and Hypothalamic Glioma
Recurrent Childhood Visual Pathway Glioma
Drug: selumetinib
Other: laboratory biomarker analysis
Other: pharmacological study
Other: pharmacogenomic studies
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 and Phase II Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities (phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

  • Stratum-specific objective response (complete response [CR]+partial response [PR]) rate sustained for 8 weeks (phase II) [ Time Frame: First 10 courses ] [ Designated as safety issue: No ]
    For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. In addition, the confirmed sustained objective response rate observed during treatment by cumulative incidence functions will be estimated. This provides not only an overall estimate of the response rate but also an estimate of the timing of responses as a function of number of months of treatment.


Secondary Outcome Measures:
  • Plasma drug concentrations and pharmacokinetic parameters volume of the central compartment (Vc/F), elimination rate constant (Ke), half-life (t1/2), apparent oral clearance (CL/F), and area under the plasma concentration time curve (AUC) (phase I) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
  • Progression-free survival (PFS) (phase II) [ Time Frame: From the date of initial treatment to the earliest date of disease progression, second malignancy or death for subjects who fail; and to the date of last contact for subjects who remain at risk for failure assessed for up to 4 years ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates of distributions of PFS for all eligible subjects who received at least one dose of selumetinib will be provided separately for each stratum. It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.

  • Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion as assessed by IHC and FISH, respectively (phase II) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Frequency tables summarizing the presence and absence of BRAF aberrations in all patients from whom tissue is available will be provided. The association of presence/absence and type of BRAF aberrations vs. PFS will be explored via Kaplan-Meier (KM)-plots. Log-rank tests and/or Cox regression models may also be used to assess statistical associations between BRAF and PFS provided more than 10 events are observed in a given strata to make such assessments meaningful.


Estimated Enrollment: 135
Study Start Date: April 2010
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (selumetinib)
Patients receive selumetinib PO BID on days 1-28. Courses repeat every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.
Drug: selumetinib
Given PO
Other Names:
  • ARRY-142886
  • AZD6244
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) or recommend a Phase II dose of AZD6244 (selumetinib) in children with recurrent or refractory low-grade glioma (phase I completed as of April 29, 2013). (Phase I) II. To describe the toxicity profile and define the dose limiting toxicity of AZD6244 in children with recurrent or refractory low-grade glioma (phase I completed as of April 29, 2013). (Phase I) III. To study the safety of the maximum tolerated dose (MTD) or recommended a Phase II dose (RP2D) of AZD6244 as determined based on safety data from children >= 12 years of age in children < 12 years of age; if the MTD/RP2D of the older children is too toxic for the younger children, we will de-escalate to one dose level below and study the safety of that dose in the younger age cohort (phase I completed as of April 29, 2013). (Phase I) IV. To assess the sustained response rate of AZD6244 administered at 25 mg/m^2/dose twice daily (BID), in a single arm Phase II setting in patients assigned to strata based on neurofibromatosis (NF)-1 status and presence or absence of v-raf murine sarcoma viral oncogene homolog B (BRAF) aberrations, specifically BRAF V600E mutations and/or BRAF KIAA1549 fusion identified by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. (Phase II)

SECONDARY OBJECTIVES:

I. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics administered on this schedule and to assess the influence of patient specific covariates (including concomitant drug therapy) on AZD6244 pharmacokinetics (phase I completed as of April 29, 2013). (Phase I) II. To evaluate the feasibility of collecting pre-trial tumor samples and the feasibility of using in situ hybridization assay to identify BRAF aberrations in available tumor specimens (phase I completed as of April 29, 2013). (Phase I) III. To determine if pre-trial tumor samples show the biochemical signature that indicates activation of the mitogen-activated protein kinase (MAPK) pathway (phase I completed as of April 29, 2013). (Phase I) IV. To describe magnetic resonance imaging (MRI) characteristics of the tumors before and after treatment and to explore the diffusion changes in the tumors before and after treatment to determine if there is an early diffusion indicator of response (phase I completed as of April 29, 2013). (Phase I) V. Within the constraints of a Phase I trial, to document antitumor activity of treatment with AZD6244, as measured by objective responses and progression-free survival (PFS) (phase I completed as of April 29, 2013). (Phase I) VI. To explore the pharmacogenetic polymorphisms in AZD6244 metabolizing enzymes and transporters and relate these polymorphisms to AZD6244 pharmacokinetics (phase I completed as of April 29, 2013). (Phase I) VII. To estimate the PFS distributions associated with AZD6244 treatment separately in patients assigned to the six strata as well as for various other subsets e.g. histology and tumor grade across strata. (Phase II) VIII. To explore correlations between BRAF aberrations and treatment response and PFS in patients for whom relevant biology data are available. (Phase II) IX. To assess MAPK aberrations by a combination of whole-exome and ribonucleic acid (RNA) sequencing. (Phase II) X. To characterize the inter- and intra-patient variability in AZD6244 pharmacokinetics administered on this schedule at the MTD/RP2D. (Phase II)

OUTLINE: This is a phase I dose-escalation study (completed as of April 29, 2013) followed by a phase II study.

Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

  Eligibility

Ages Eligible for Study:   3 Years to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant is willing to sign a screening consent and provide pre-trial tumor material for BRAF testing

    • All patients who are candidates for enrollment in stratum 5 based on their tumor histology must be pre-screened
    • Screening may be applied to potential stratum 1 and 2 patients when patient accrual is close to pre-specified interim analysis or final sample size thresholds in either stratum; the Operations and Biostatistics Center (OBC) will notify sites when/if it becomes necessary to screen patients for BRAF aberrations for stratum 1 and 2
  • Patients whose prior BRAF testing was performed at another lab (Clinical Laboratory Improvement Amendments [CLIA]/College of American Pathologist [CAP] certified or otherwise) must send additional tumor material to Brigham and Women's Hospital (BWH) for confirmation; however, to preserve available tumor material, patients whose tumor material has previously undergone BRAF analysis at the Lindeman and Ligon Labs at Brigham and Women's Hospital using the same procedures as described in this protocol, will not be required to submit additional tumor material for analysis; these patients must have both the BRAFV600E mutation and BRAF KIAA1549 fusion assessments done and if only one test was previously conducted; additional tissue will be required for the second test
  • Patient must have one of the following:

    • For stratum 5: non NF-1 associated low grade glioma (LGG) (other than pilocytic astrocytoma or optic pathway glioma)
    • For stratum 1 or 2: non NF-1, non-optic pathway pilocytic astrocytoma; note: all patients with non NF-1 associated optic pathway glioma with or without tissue must be enrolled on stratum 4
  • Imaging evaluations necessary to establish eligibility for study entry must be done within three (3) weeks prior to registration
  • All other evaluations necessary to establish eligibility for study entry must be done within two (2) weeks prior to registration
  • Patients must start therapy within 7 calendar days of registration and may begin treatment prior to stratification
  • Laboratory values must be no older than seven (7) days prior to the start of therapy; if a test that is repeated after registration and prior to therapy is outside the limits for eligibility, it must be rechecked within 48 hours prior to the start of therapy; if laboratory values still fail to meet eligibility criteria, the patient may not receive protocol therapy
  • All patients must meet the following inclusion and exclusion criteria; NO EXCEPTIONS WILL BE GIVEN
  • Patients with sporadic (non NF-1 associated), histologically diagnosed progressive, recurrent or refractory non-optic pathway pilocytic astrocytoma who have pre- treatment tumor tissue available for BRAF analysis
  • NF-1 patients with radiographic evidence of a progressive, recurrent or refractory low grade glioma, with or without pre-treatment tumor tissue
  • Patients with progressive, recurrent or refractory optic pathway glioma, with or without pre-treatment tumor tissue
  • Patients with histologically diagnosed progressive, recurrent or refractory non NF-1 associated LGG (other than pilocytic astrocytoma or optic pathway glioma); these patients must have BRAF aberrations as documented by the Lindeman and Ligon Labs at Brigham and Women's Hospital using the same procedures
  • Patients will be assigned to one of 6 strata following enrollment; all BRAF assessments used for stratification below must be done at the Lindeman and Ligon Labs at Brigham and Women's Hospital using the same procedures as described in this protocol;

    • Stratum 1: patients with non NF-1 associated progressive, recurrent or refractory pilocytic astrocytoma with pre-trial tumor material available and with a BRAF aberration i.e. BRAFV600E mutation and/or BRAF KIAA1549 fusion as determined by IHC and FISH, respectively; patients with optic pathway glioma are excluded
    • Stratum 2: patients with non NF-1 associated progressive, recurrent or refractory pilocytic astrocytoma with pre-trial tumor material available and without a BRAF aberration i.e. BRAFV600E mutation and/or BRAF KIAA1549 fusion as determined by IHC and FISH, respectively; patients with optic pathway glioma are excluded
    • Stratum 3: patients with neuro-fibromatosis 1 (NF-1) associated progressive, recurrent or refractory low grade glioma (World Health Organization [WHO] grade I & II), with or without tissue
    • Stratum 4: patients with non-NF1 associated progressive, recurrent or refractory optic pathway glioma with or without tissue available for BRAF evaluation
    • Stratum 5: patients with non NF-1 associated progressive, recurrent or refractory low grade glioma other than pilocytic astrocytoma or optic pathway glioma with a documented BRAF aberration identified in pre-trial tumor material
    • Stratum 6: patients with non-NF-1 associated progressive, recurrent or refractory low grade glioma (other than optic pathway glioma [OPG]) with tissue available for BRAF analyses who cannot be classified into stratum 1, 2 or 5 due to inadequate tissue quality, assay failure, etc
  • Patients must have bi-dimensionally measurable disease defined as at least one lesion that can be accurately measured in at least two planes in order to be eligible for this study
  • Patients must have received prior therapy other than surgery and must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, biologic therapy or radiotherapy prior to study entry
  • 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
  • Patient must have received their last dose of the biologic agent >= 7 days prior to study registration

    • For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration
  • Monoclonal antibody treatment: at least three half-lives must have elapsed prior to registration
  • Radiation: patients must have:

    • Had their last fraction of local irradiation to primary tumor >= 12 months prior to registration; investigators are reminded to review potentially eligible cases to avoid confusion with pseudo-progression
    • Had their last fraction of craniospinal irradiation (> 24Gy) > 3 months 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
  • 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
  • Patients must have a body surface area (BSA) >= 0.55 m^2
  • 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 capsules
  • 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
  • Absolute neutrophil count >= 1,000/uL (unsupported)
  • Platelets >= 100,000/L (unsupported)
  • Hemoglobin >= 8 g/dL (may be supported)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal for age
  • Total bilirubin < 1.5 times upper limit of normal for age
  • Albumin >= 3g/dL
  • Serum sodium and potassium within the institutional limits of normal
  • Serum calcium and magnesium above the institutional lower limit of normal
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73m^2 or a serum creatinine based on age as follows:

    • =< 5 years: 0.8 mg/dL
    • > 5 years but =< 10 years: 1 mg/dL
    • > 10 years but =< 15 years: 1.2 mg/dL
    • > 15 years: 1.5 mg/dL
  • Left ventricular ejection fraction (LVEF) >= 50%
  • Corrected QT (QTc) interval =< 450 msecs
  • Hypertension:

    • Patients, 3-17 years of age must have a blood pressure that is =< 95th percentile for age, height and gender at the time of registration
    • Patients who are >= 18 years of age must have a blood pressure that is < 140/90 mm of Hg at the time of registration
    • Note: if a blood pressure (BP) reading prior to registration is above the 95th percentile for age, height and gender it must be rechecked and documented to be =< the 95th percentile for age, height and gender prior to patient registration
  • 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
  • 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 AZD6244 ceases; women of child-bearing potential must have a negative pregnancy test prior to entry; 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; please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle
  • Ability to understand and the willingness to sign a written informed consent document according to institutional guidelines

Exclusion Criteria:

  • Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), likely interfere with the study procedures or results
  • Patients who are receiving any other anticancer or investigational agents
  • Patients with uncontrolled seizures
  • Previous mitogen-activated protein kinase kinase (MEK) inhibitor use such as PD-0325901; CI1040; AS73026; GDC 0973; ARRY43182; GSK110212
  • Prior treatment with a BRAF inhibitor such as vemurafenib or dabrafenib
  • Patients with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) that meets New York Heart Association (NYHA) class II or above
  • Required use of a concomitant medication that can prolong the QT interval
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01089101

Locations
United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Girish Dhall    323-361-4629    gdhall@chla.usc.edu   
Principal Investigator: Girish Dhall         
Lucile Packard Children's Hospital Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Paul G. Fisher    650-721-5889    pfisher@stanford.edu   
Principal Investigator: Paul G. Fisher         
University of California San Francisco Medical Center-Parnassus Recruiting
San Francisco, California, United States, 94143
Contact: Anuradha Banerjee    415-476-3831    banerjee@neurosurg.ucsf.edu   
Principal Investigator: Anuradha Banerjee         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Roger J. Packer    202-884-2120    rpacker@cnmc.org   
Principal Investigator: Roger J. Packer         
United States, Illinois
Lurie Children's Hospital-Chicago Recruiting
Chicago, Illinois, United States, 60614
Contact: Stewart Goldman    773-880-4562    sgoldman@northwestern.edu   
Principal Investigator: Stewart Goldman         
United States, Maryland
Mark O Hatfield-Warren Grant Magnuson Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: Katherine E. Warren    301-435-4683    warrenk@mail.nih.gov   
Principal Investigator: Katherine E. Warren         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ira J. Dunkel    212-639-2153    dunkeli@mskcc.org   
Principal Investigator: Ira J. Dunkel         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Sridharan Gururangan    919-684-3506    gurur002@mc.duke.edu   
Principal Investigator: Sridharan Gururangan         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maryam Fouladi    513-803-0721    maryam.fouladi@cchmc.org   
Principal Investigator: Maryam Fouladi         
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15224
Contact: Regina I. Jakacki    412-692-7056    regina.jakacki@chp.edu   
Principal Investigator: Regina I. Jakacki         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Alberto Broniscer    901-595-4925    alberto.broniscer@stjude.org   
Principal Investigator: Alberto Broniscer         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Murali M. Chintagumpala    832-822-4266    mxchinta@txch.org   
Principal Investigator: Murali M. Chintagumpala         
Sponsors and Collaborators
Investigators
Principal Investigator: Anuradha Banerjee Pediatric Brain Tumor Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01089101     History of Changes
Other Study ID Numbers: NCI-2012-03173, NCI-2012-03173, CDR667932, PBTC-029B, PBTC-029, U01CA081457
Study First Received: March 17, 2010
Last Updated: June 30, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Oligodendroglioma
Astrocytoma
Glioma
Neurofibromatoses
Neurofibromatosis 1
Osteitis Fibrosa Cystica
Optic Nerve Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neurofibroma
Nerve Sheath Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases
Optic Nerve Neoplasms
Cranial Nerve Neoplasms
Nervous System Neoplasms

ClinicalTrials.gov processed this record on July 23, 2014