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

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase II, Phase IBiomarker/Laboratory analysis, Treatment12 to 21PBTC-029B
NCI-2012-03173, CDR667932, PBTC-029, NCT01089101

Trial Description

Summary

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 or does not respond to treatment. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Further Study Information

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. Courses repeat every 28 days for up to 26 courses 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.

Eligibility Criteria

Inclusion Criteria:

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

Albumin >= 3 g/dL

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

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

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 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

ELIGIBILITY CRITERIA FOR ENROLLMENT ON THE RE-TREATMENT STUDY

Ability to understand and the willingness to sign a written informed consent document according to institutional guidelines

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

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

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

Corrected QT (QTc) interval =< 450 msecs

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

Serum calcium and magnesium above the institutional lower limit of normal

Serum sodium and potassium within the institutional limits of normal

Total bilirubin < 1.5 times upper limit of normal for age

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

Hemoglobin >= 8 g/dL (may be supported)

Platelets >= 100,000/L (unsupported)

Absolute neutrophil count >= 1,000/uL (unsupported)

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

Patients must be able to swallow capsules

Patients with neurological deficits should have deficits that are stable for a minimum of 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

Corticosteroids: patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration

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

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

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 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 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; 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

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 with progressive, recurrent or refractory optic pathway glioma, with or without pre-treatment tumor tissue

NF-1 patients with radiographic evidence of a progressive, recurrent or refractory low grade glioma, with or without pre-treatment tumor tissue

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

All patients must meet the following inclusion and exclusion criteria; NO EXCEPTIONS WILL BE GIVEN

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

Patients must start therapy within 7 calendar days of registration and may begin treatment prior to stratification

All other evaluations necessary to establish eligibility for study entry must be done within two (2) weeks prior to registration

Imaging evaluations necessary to establish eligibility for study entry must be done within three (3) weeks prior to registration

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 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

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 when patient accrual is close to pre-specified interim analysis or final sample size thresholds in either stratum; the Operations and Biostatistics Data Management Center (OBDMC) will notify sites when it becomes necessary to screen patients for BRAF aberrations for stratum 1 and 2

Patients must have a body surface area (BSA) >= 0.55 m^2

Left ventricular ejection fraction (LVEF) >= 55%

Monoclonal antibody treatment: at least three half-lives must have elapsed prior to registration

Exclusion Criteria:

Previous mitogen-activated protein kinase kinase (MEK) inhibitor use such as PD-0325901; CI1040; AS73026; GDC 0973; ARRY43182; GSK110212

History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244

Required use of a concomitant medication that can prolong the QT interval

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

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

Patients with uncontrolled seizures

Patients who are receiving any other anticancer or investigational agents

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
Jason R. Fangusaro, Principal Investigator

Trial Sites

U.S.A.

California
Los Angeles

Children's Hospital Los Angeles

Girish Dhall
Ph: 323-361-4629
Email: gdhall@chla.usc.edu

Girish Dhall
Principal Investigator

Palo Alto

Lucile Packard Children's Hospital Stanford University

Paul Graham Fisher
Ph: 650-721-5889
Email: pfisher@stanford.edu

Paul Graham Fisher
Principal Investigator

San Francisco

UCSF Medical Center-Mount Zion

Anuradha Banerjee
Ph: 415-476-3831
Email: banerjee@neurosurg.ucsf.edu

Anuradha Banerjee
Principal Investigator

UCSF Medical Center-Parnassus

Anuradha Banerjee
Ph: 415-476-3831
Email: banerjee@neurosurg.ucsf.edu

Anuradha Banerjee
Principal Investigator

District of Columbia
Washington

Children's National Medical Center

Roger Joseph Packer
Ph: 202-884-2120
Email: rpacker@cnmc.org

Roger Joseph Packer
Principal Investigator

Illinois
Chicago

Children's Memorial Outpatient Center in Lincoln Park

Stewart Goldman
Ph: 773-880-4562
Email: sgoldman@northwestern.edu

Stewart Goldman
Principal Investigator

Lurie Children's Hospital-Chicago

Jason R. Fangusaro
Ph: 312-227-4846
Email: jfangusaro@luriechildrens.org

Jason R. Fangusaro
Principal Investigator

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

Katherine Elizabeth Warren
Ph: 301-435-4683
Email: warrenk@mail.nih.gov

Katherine Elizabeth Warren
Principal Investigator

New York
New York

Memorial Sloan-Kettering Cancer Center

Ira J. Dunkel
Ph: 212-639-2153
Email: dunkeli@mskcc.org

Ira J. Dunkel
Principal Investigator

North Carolina
Durham

Duke University Medical Center

Sridharan Gururangan
Ph: 919-684-3506
Email: gurur002@mc.duke.edu

Sridharan Gururangan
Principal Investigator

Ohio
Cincinnati

Cincinnati Children's Hospital Medical Center

Maryam Fouladi
Ph: 513-803-0721
Email: maryam.fouladi@cchmc.org

Maryam Fouladi
Principal Investigator

Pennsylvania
Pittsburgh

Children's Hospital of Pittsburgh of UPMC

Ian F. Pollack
Ph: 412-692-5881
Email: ian.pollack@chp.edu

Ian F. Pollack
Principal Investigator

Tennessee
Memphis

St. Jude Children's Research Hospital

Alberto Broniscer
Ph: 901-595-4925
Email: alberto.broniscer@stjude.org

Alberto Broniscer
Principal Investigator

Texas
Houston

Baylor College of Medicine

Murali Mohan Chintagumpala
Ph: 832-822-4266
Email: mxchinta@txch.org

Murali Mohan Chintagumpala
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01089101

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.