AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

This study is currently recruiting participants.
Verified November 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01362803
First received: May 27, 2011
Last updated: March 14, 2014
Last verified: November 2013
  Purpose

Background:

- Plexiform neurofibromas are tumors that grow in and around nerves. The only way to treat them is with surgery. Some of these tumors cannot be completely removed. The tumors may be too large, too numerous, or in a bad location for surgery. An experimental drug called AZD6244 hydrogen sulfate may be able to prevent the tumors from growing, slow down their growth, or shrink them. This drug has been tested in adults with cancer and in children with some types of brain cancer. This study will test how well this drug works with these types of tumors.

Objectives:

- To study the safety and effectiveness of AZD6244 hydrogen sulfate in children and young adults with plexiform neurofibromas that cannot be completely removed by surgery.

Eligibility:

- Children and young adults between 12 and 18 years of age who have plexiform neurofibromas that cannot be completely removed by surgery.

Design:

  • Patients will be screened with a physical exam, medical history, blood tests, and imaging studies.
  • They will take the study drug twice a day with 8 ounces of water, every day for 28-day cycles of treatment. During study visits, participants will have blood and urine tests and physical exams. They will also have imaging studies to examine the tumor sizes and locations. They will answer questions about their health. They may have other tests as needed.
  • Participants will continue to receive the study drug as long as they have no severe side effects and the disease is not getting worse.

Condition Intervention Phase
Neurofibromatosis 1
Neurofibromatosis Type 1
NF 1
Neurofibroma, Plexiform
Drug: AZD6244 hyd sulfate
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor AZD6244 Hydrogen Sulfate (Selumetinib Sulfate) in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To determine the maximum tolerated dose (MTD), tolerability, and recommended Phase II dose AZD6244 hyd sulfate administered PO Q 12H daily for 28 days/cycle with no rest period between cycles.
  • To study plasma PK at baseline and steady state

Secondary Outcome Measures:
  • To determine effect of AZD6244hyd sulfate on growth rate of PN using MRI
  • Study pharmacodynamics in PBMC's by evaluating ERK phosphorylation
  • Measure adherence of dosing, and define toxicities of chronic dosing in pediatric patients.

Estimated Enrollment: 30
Study Start Date: May 2011
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: AZD6244 hyd sulfate
    N/A
Detailed Description:

Background

Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. PN may be congenital and appear to have the fastest growth rate in young children. There are no standard treatment options for PN other than surgery, which is often difficult due to the encasement of vital structures, and extensive and invasive growth.

PN are composed of neoplastic Schwann cells that lack NF1 gene expression resulting in upregulation of Ras, which initiates several signaling cascades regulating cell proliferation.

AZD6244 hyd sulfate, a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1, which is currently undergoing evaluation in adult cancers and children with brain tumors, and may mediate anti-tumor effects in PN by inhibition of downstream signaling of Ras.

Objectives

To determine the maximum tolerated dose (MTD) of oral AZD6244 hyd sulfate administered daily to pediatric patients with NF1 and inoperable PN. Based on the results of the dose escalation in this study, the current MTD has been determined as 20 mg/m2/dose. To be consistent in pedriatric dosing, an additional dose level of 25mg.m2/dose was added, which is the MTD recently determined in a study conducted by the Pediatric Brain Tumor Consortium (PBTC).

To define the acute and chronic toxicities, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD6244 hyd sulfate.

To determine the effect of AZD6244 hyd sulfate on the growth rate of PN.

Eligibility

Pediatric Patients (3 to less than or equal to 18 years) who are able to swallow intact capsules, with NF1 and inoperable measurable PN that have the potential to cause significant morbidity.

Design

AZD6244 hyd sulfate will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment cycle). Limited dose escalations will be performed to define the MTD based on tolerability of AZD6244 hyd sulfate during the first three treatment cycles.

Disease status will be evaluated using volumetric MRI analysis at regular intervals.

The plasma PK and PD of AZD6244 hyd sulfate will be evaluated.

  Eligibility

Ages Eligible for Study:   3 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-INCLUSION CRITERIA:

  1. Age: greater than or equal to 3 years and less than or equal to 18 years of age at the time of study enrollment, if able to swallow whole capsules. The age limits including young children were chosen because early childhood and puberty are considered to be the greatest risk for disease progression, and AZD6244 hyd sulfate may provide the most benefit to this young group of patients. In addition, an important objective of this study is to characterize the pharmacokinetics of AZD6244 hyd sulfate in the pediatric population since it has been well studied in adults.
  2. Diagnosis: Patients with NF1 and inoperable PNs that have the potential to cause significant morbidity, such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions.

    Histiologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a PN is clinically suspected.

    A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below:

    • Six or more caf(SqrRoot)(Copyright)-au-lait macules (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal subjects)
    • Freckling in axilla or groin
    • Optic glioma
    • Two or more Lisch nodules
    • A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
    • A first-degree relative with NF1
  3. Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable as per criteria above.
  4. Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not considered to be feasible without substantial risk or morbidity, or if a patient with a surgical option refuses surgery.

    • Since there is no standard effective chemotherapy for patients with NF1 and PN, patients may be treated on this trial without having received prior medical therapy directed at their PN.
    • Since AZD6244 hyd sulfate is not expected to cause substantial myelosuppression, there will be no limit to number of prior myelosuppressive regimen for PN or other tumor manifestations associated with NF1 such as optic glioma.
    • Patients who have received previous investigational agents or biologic therapy, such as tipifarnib, pirfenidone, Peg-Intron, sorafenib, or other VEGFR inhibitors are eligible for enrollment.
    • Growth factors that support platelet or white cell number or function must not have been administered within the past 7 days.
    • Patients who received prior medical therapy for their PN must have recovered from the toxic effects of all prior therapy before entering this study.
    • At least 6 weeks must have elapsed prior to enrollment since the patient received any prior radiation therapy.
  5. Performance status: Patients greater than or equal to 16 years of age must have a Karnofsky performance level of greater than or equal to70%, and children < 16 years old must have a Lansky performance of greater than or equal to 70%.
  6. Hematologic Function: Patients must have an absolute neutrophil count greater than or equal to 1000/(micro)l, hemoglobin greater than or equal to 9g/dl, and platelet greater than or equal to 100,000/(micro)l.
  7. Hepatic Function: Patients must have bilirubin within 1.5 times the upper limit of normal for age, with the exception of Gilbert syndrome, and ALT within less than or equal to 1.5 times the upper limit of normal.
  8. Renal Function: Patients must have a creatinine clearance or radioisotope GFR greater than or equal to 60ml/min/1.73 m(2) or a normal serum creatinine based on age described below.

    Age (years)/Maximum Serum Creatinine(mg/dL):

    Age less than or equal to 5/Maximum Serum Creatinine 0.8 mg/dL

    Age 5 and/or less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL

    Age 10 and/or less than or equal to 15/ Maximum Serum Creatinine 1.2 mg/dL

    Age greater than 15/ Maximum Serum Creatinine 1.5 mg/dL

  9. Cardiac Function: Normal ejection fraction (ECHO) greater than or equal to 55% (if a range is given then the upper limit of the range will be used)
  10. Informed Consent: Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be done after obtaining written informed consent from all patients or their legal guardians (if the patient is < 18 years old). When appropriate, pediatric patients will be included in all discussions. This can be accomplished through one of the following mechanisms: a) the NCI, POB screening protocol, b) an IRB-approved institutional screening protocol or c) the study-specific protocol.

    Documentation of the informed consent for screening will be maintained in the patient s research chart. Studies or procedures that were performed for clinical indications (not exclusively to determine eligibility) may be used for baseline values even if the studies were done before informed consent was obtained.

  11. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of age will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.

EXCLUSION CRITERIA:

  1. Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrollment on this study in girls, age 9 or older. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
  2. Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject inevaluable.
  3. An investigational agent within the past 30 days.
  4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
  5. Clinically significant uncontrolled unrelated systemic illness such as serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction.
  6. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
  7. Inability to swallow capsules, since capsules cannot be crushed or broken.
  8. Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
  9. Prior treatment with AZD6244 hyd sulfate.
  10. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
  11. Presence of greater than or equal to grade 1 cataract, as cataract was observed in preclinical studies with AZD6244 hyd sulfate.
  12. Supplementation with vitamin E greater than 100% of the daily recommended dose.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01362803

Contacts
Contact: Brigitte C Widemann, M.D. (301) 496-7387 widemanb@pbmac.nci.nih.gov

Locations
United States, District of Columbia
Childrens National Medical Center Recruiting
Washington, District of Columbia, United States
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-3039
Sponsors and Collaborators
Investigators
Principal Investigator: Brigitte C Widemann, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01362803     History of Changes
Other Study ID Numbers: 110161, 11-C-0161
Study First Received: May 27, 2011
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Dose Limited Toxicity
Maximum Tolerated Dose
Pharmacokinetics
Pharmacodynamics
Dose Escalation
Neurofibromatosis Type 1
NF1
Plexiform Neurofibroma

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibromatosis 1
Nervous System Neoplasms
Neurofibroma
Osteitis Fibrosa Cystica
Neurofibroma, Plexiform
Neoplasms by Site
Neoplasms
Nervous System Diseases
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Peripheral Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Bone Diseases, Endocrine
Bone Diseases
Musculoskeletal Diseases

ClinicalTrials.gov processed this record on April 17, 2014