Clinical Trials /

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

NCT01089101

Description:

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Low Grade Glioma
  • Optic Nerve Glioma
  • Pilocytic Astrocytoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma
  • Official Title: A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2012-03173
  • SECONDARY ID: NCI-2012-03173
  • SECONDARY ID: PBTC-029B
  • SECONDARY ID: CDR667932
  • SECONDARY ID: PBTC-029
  • SECONDARY ID: PBTC-029
  • SECONDARY ID: U01CA081457
  • SECONDARY ID: UM1CA081457
  • NCT ID: NCT01089101
  • NCT ALIAS: NCT01386450

Conditions

  • Low Grade Glioma
  • Recurrent Childhood Pilocytic Astrocytoma
  • Recurrent Neurofibromatosis Type 1
  • Recurrent Visual Pathway Glioma
  • Refractory Neurofibromatosis Type 1
  • Refractory Visual Pathway Glioma

Interventions

DrugSynonymsArms
SelumetinibARRY-142886, AZD6244, MEK Inhibitor AZD6244Treatment (selumetinib)

Purpose

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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) 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) 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) 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) V. To estimate the sustained response rate and
      prolonged disease stabilization rate (defined as lack of disease progression for >= 12
      courses) associated with AZD6244 in patients with recurrent and/or progressive low-grade
      gliomas who previously received treatment on PBTC-029 or PBTC-029B for a minimum of 12
      courses, with at least stable disease or patients who had a sustained response but remained
      on treatment < 12 courses. (Re-treatment Study)

      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) 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) 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) 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) 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) VI. To explore the
      pharmacogenetic polymorphisms in AZD6244 metabolizing enzymes and transporters and relate
      these polymorphisms to AZD6244 pharmacokinetics. (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) XI. To determine progression-free
      survival following re-treatment with AZD6244 for progressive, recurrent low-grade gliomas and
      to evaluate the impact of variables such as previous response, interval treatment regimens,
      BRAF status and previous dose of AZD6244. (Re-treatment Study) XII. To evaluate the toxicity
      profile of re-treatment with AZD6244 and correlate with toxicities seen during initial
      treatment. (Re-treatment Study) XIII. To evaluate the toxicity profile of re-treatment with
      AZD6244 beyond 2 years for those patients who continue to show benefit from the drug, i.e. at
      least stable disease (SD). (Re-treatment Study)

      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. Cycles repeat every
      28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
      Patients who experience a sustained objective response from selumetinib on the phase I or
      phase II portions of the trial, and who have completed 2 years of treatment and stopped study
      drug may be enrolled on the re-treatment study after progression/recurrence. Patients in the
      re-treatment study may continue treatment indefinitely in the absence of disease progression
      or unacceptable toxicities.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (selumetinib)ExperimentalPatients receive selumetinib PO BID on days 1-28. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience a sustained objective response from selumetinib on the phase I or phase II portions of the trial, and who have completed 2 years of treatment and stopped study drug may be enrolled on the re-treatment study after progression/recurrence. Patients in the re-treatment study may continue treatment indefinitely in the absence of disease progression or unacceptable toxicities.
  • Selumetinib

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  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

          -  Participant is willing to sign a screening consent and provide pre-trial tumor
             material for BRAF testing (both for BRAF V^600E mutation and BRAF KIAA1549 fusion
             assessments)

               -  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

          -  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

          -  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 prior to 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;
             assessments for both BRAF V^600E mutation and BRAF KIAA1549 fusion are required for
             patients who will enroll on strata 1, 2 and 5

               -  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. BRAFV^600E 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. BRAF^V600E 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

                    -  Clarification: Stratum 4 was specifically designed for patients with
                       hypothalamic/optic pathway gliomas; the intent is that if there is any optic
                       chiasm invasion regardless of where the tumor is originating from (chiasm
                       vs. hypothalamus vs. other location), the patient should be enrolled on
                       Stratum 4, regardless of whether the tumor has been biopsied or not;
                       obviously, there are some tumors that include part of the hypothalamus and
                       clearly do NOT include the chiasm at all; in these situations, and if the
                       tumor is a biopsy proven pilocytic astrocytoma, these patients should be
                       enrolled on Stratum 1 or 2 (depending upon BRAF status)

          -  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 (> 24 Gy) > 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 years [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) (within 14 days of registration
             and within 7 days of the start of treatment)

          -  Platelets >= 100,000/L (unsupported) (within 14 days of registration and within 7 days
             of the start of treatment)

          -  Hemoglobin >= 8 g/dL (may be supported) (within 14 days of registration and within 7
             days of the start of treatment)

          -  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 (within 14 days of registration
             and within 7 days of the start of treatment)

          -  Total bilirubin < 1.5 times upper limit of normal for age (within 14 days of
             registration and within 7 days of the start of treatment)

          -  Albumin >= 3 g/dL (within 14 days of registration and within 7 days of the start of
             treatment)

          -  Serum sodium and potassium within the institutional limits of normal (within 14 days
             of registration and within 7 days of the start of treatment)

          -  Serum calcium and magnesium above the institutional lower limit of normal (within 14
             days of registration and within 7 days of the start of treatment)

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             ml/min/1.73m^2 or a serum creatinine based on age as follows (within 14 days of
             registration and within 7 days of the start of treatment):

               -  =< 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) >= 55%

          -  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

                    -  The normal blood pressure by height, age and gender tables can be accessed
                       in the Generic Forms section of the Pediatric Brain Tumor Consortium (PBTC)
                       members' webpage

               -  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

          -  The effects of AZD6244 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 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

          -  ELIGIBILITY CRITERIA FOR ENROLLMENT ON THE RE-TREATMENT STUDY

          -  Patients must have recurrence or progression of their low-grade glioma after coming
             off treatment with AZD6244 on PBTC-029 or PBTC-029B, with or without having received
             additional anti-tumor therapy following discontinuation of AZD6244; the progression
             must be unequivocal and sufficient to warrant re-treatment in the opinion of the
             investigator; progression will be defined as either progressive disease (PD) that
             meets the study definitions of progressive disease by MRI or vision deterioration
             thought to be related to tumor in patients with optic pathway tumors

          -  Patients must have received treatment on PBTC-029 or PBTC-029B for a minimum of 12
             courses with at least stable disease, or had a sustained response (partial response
             [PR]/ complete response [CR]) but remained on treatment < 12 courses

          -  Patients must have bi-dimensionally measurable disease defined as at least one lesion
             that can be accurately measured in at least two planes

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy, immunotherapy, biologic therapy or radiotherapy prior to study entry

               -  Myelosuppressive chemotherapy: Patients must have received their last dose of
                  known myelosuppressive anticancer chemotherapy at least three weeks prior to
                  registration on the Re-treatment Study or at least six weeks if a nitrosourea

               -  Biologic agent: Patient must have received their last dose of the biologic agent
                  >= 7 days prior to study registration; for biologic agents and monoclonal
                  antibody treatment, at least three half-lives must have elapsed prior to
                  registration

               -  Other investigational agents (not fitting into one of the above specified
                  categories): patients must have received their last dose of any other
                  investigational agent greater than 28 days prior to enrollment

               -  Radiation: Patients must have:

                    -  Had their last fraction of local irradiation to the 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

               -  Growth factors: 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

        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 (MEK) inhibitor use such as PD-0325901;
             CI1040; AS73026; GDC 0973; ARRY43182; GSK110212

          -  Prior treatment with a BRAF inhibitor such as vemurafenib or dabrafenib (previous
             treatment with sorafenib is allowed)

          -  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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities (phase I)
Time Frame:28 days
Safety Issue:
Description:Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:Plasma drug concentrations and pharmacokinetic parameters (Phase I)
Time Frame:Day 1 of cycle 1
Safety Issue:
Description:Plasma drug concentrations and pharmacokinetic parameters volume of the central compartment, elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve.
Measure:Stratum-specific progression-free survival distribution (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 30 days
Safety Issue:
Description:Kaplan-Meier estimates of distributions of PFS 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.
Measure:Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion (phase II)
Time Frame:Up to 30 days
Safety Issue:
Description:Will be assessed by immunohistochemistry and fluorescence in situ hybridization, respectively. 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 versus PFS will be explored via Kaplan-Meier-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.
Measure:Progression-free survival (retreatment study)
Time Frame:From the date of re-treatment initiation to the earliest date of disease progression, second malignancy or death for patients who fail; and the last contact for patients who remain at risk for failure, assessed up to 30 days
Safety Issue:
Description:Kaplan-Meier estimates of progression-free survival distributions for all eligible patients will be provided. Exact confidence interval estimates will be provided.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

November 18, 2019