AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

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Brief Title

AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors

Official Title

A Phase I/II Study of the Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor Selumetinib (AZD6244; Hydrogen Sulfate in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)

Brief Summary

      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.
    

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.
           Surgery is the only standard treatment option available for PN. However, this is often
           difficult due to the encasement of vital structures, and extensive and invasive PN
           growth.

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

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

        -  In this phase I study of selumetinib directed at NF1 PN, we have observed a degree of

      activity which has not been observed previously; therefore a phase II evaluation will be
      conducted

      Objectives

      Phase I:

        -  To determine the maximum tolerated dose (MTD) of oral selumetinib 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 pediatric dosing, an additional dose level of 25 mg/m2/dose was added,
           which is the MTD recently determined in a study conducted by the Pediatric Brain Tumor
           Consortium (PBTC). Amendment H (November 2014): The MTD has been determined to be 25
           mg/m(2)/dose.

        -  To define the acute and chronic toxicities and pharmacokinetics (PK) of selumetinib.
           Completed with amendment H.

      Phase II:

      -Primary objectives: To evaluate the confirmed partial and complete response rate of
      selumetinib using volumetric MRI analysis in children and young adults with NF1 and
      inoperable PN with PN related morbidity at the time of enrollment.

      Eligibility

      Pediatric Patients (greater than or equal to 2 and 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

        -  Selumetinib will be administered orally BID on a continuous dosing schedule (28 days = 1
           treatment cycle). In the phase I portion, limited dose escalations will be performed to
           define the MTD based on tolerability of selumetinib during the first three treatment
           cycles. In the phase II portion, the recommended phase II dose level (RP2D) will be
           administered.

        -  Phase II: Patients will be enrolled on one of two strata:

             -  Stratum 1: PN related morbidity present at enrollment

                ---PN related pain, disfigurement, or difficulty in physical functioning

             -  Stratum 2: No significant PN related morbidity present at enrollment, but potential
                for development of PN morbidity

        -  Patient reported and functional outcomes will be evaluated at regular intervals.

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

        -  The day 1 and steady state plasma PK and PD of selumetinib will be evaluated.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Ph1:Determine MTD and extended tolerability

Secondary Outcome

 Determine effect on growth rate of PN

Condition

Neurofibromatosis 1

Intervention

AZD6244

Study Arms / Comparison Groups

 Arm 1
Description:  Phase 1: AZD6244 PO BID x 28 DAYS

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

99

Start Date

September 21, 2011

Completion Date

January 1, 2030

Primary Completion Date

January 1, 2025

Eligibility Criteria

        -INCLUSION CRITERIA:

          1. Age Phase I: greater than 3 years and less than or equal to 18 years 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 selumetinib 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 selumetinib in the pediatric population since it
             has been well studied in adults.

             Age Phase II: geater than 2 years of age and less than or equal to 18 years of age.
             BSA greater than or equal to 0.55 m(2), and able to swallow whole capsules.

          2. Diagnosis: Patients with NF1 and inoperable PN, defined as PN that cannot be
             surgically completely removed without risk for substantial morbidity due to encasement
             of, or close proximity to, vital structures, invasiveness, or high vascularity of the
             PN. The PN has to cause (stratum 1) or have the potential to cause (stratum 2)
             significant morbidity, such as (but not limited to) head and neck lesions that could
             compromise the airway or great vessels, paraspinal lesions that can cause myelopathy
             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 are
             significantly disfiguring, lesions of the extremity that cause limb hypertrophy or
             loss of function, and painful lesions. Patients will be enrolled into stratum 1 or 2
             based on PN related morbidity.

             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: (NIH Consensus conference):

               -  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.

             Phase II: Measurability and suitability for volumetric MRI analysis of the target PN
             must be confirmed with the NCI POB prior to enrolling a patient. The target PN will be
             defined as the clinically most relevant PN, which has to be amenable to volumetric MRI
             analysis. PN will be classified as typical PN versus nodular PN versus solitary
             nodular PN prior to enrollment

          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.

               -  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 selumetinib 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, imatinib or other
                  targeted therapies are eligible for enrollment. At least 4 weeks must have
                  elapsed since receiving medical therapy directed at the PN. Patients who received
                  prior medical therapy for their PN must have recovered from the acute toxic
                  effects of all prior therapy to less than or equal to grade 1 before entering
                  this study.

               -  Growth factors that support platelet or white cell number or function must not
                  have been administered within 7 days prior to enrollment.

               -  At least 6 weeks must have elapsed prior to enrollment since the patient received
                  any prior radiation therapy.

               -  At least 4 weeks must have elapsed since any surgeries, with evidence of good
                  wound healing.

          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%. Patients who are
             wheelchair bound because of paralysis secondary to a plexiform neurofibroma should be
             considered ambulatory when they are up in their wheelchair. Similarly, patients with
             limited mobility secondary to need for mechanical support (such as an airway PN
             requiring tracheostomy or CPAP) will also be considered ambulatory for the purpose of
             the study.

          6. Hematologic Function: Patients must have an absolute neutrophil count greater than or
             equal to 1500/(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 AST/ ALT within less than
             or equal to 3 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 greater than 5 to less than or equal to 10/ Maximum Serum Creatinine 1.0 mg/dL

             Age greater than 10 to 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 or cardiac MRI) greater than or equal
             to 53% (or the institutional normal; if a range is given then the upper value of the
             range will be used); QTcF less than or equal to 450 msec.

         10. Adequate Blood Pressure defined as:

             A blood pressure (BP) less than or equal to the 95th percentile for age, height, and
             gender measured as described in (Appendix IB). Adequate blood pressure can be achieved
             using medication for treatment of hypertension.

         11. 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.

         12. Willingness to avoid excessive sun exposure and use adequate sunscreen protection if
             sun exposure is anticipated.

         13. Willingness to avoid the ingestion of grapefruit and Seville oranges (as well as other
             products containing these fruits, e.g. grapefruit juice or marmalade) during the
             study, as these may affect selumetinib metabolism.

        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 for all females of childbearing potential as per
             institutional standards (at NIH subjects 9 years and older or those showing pubertal
             development). 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. Phase I: 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. Use of an investigational agent within the past 30 days.

          4. Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor,
             immunotherapy, or biologic therapy.

          5. Any evidence of severe or uncontrolled systemic disease, active infection, active
             bleeding diatheses, or renal transplant, including any patient known to have hepatitis
             C, or human immunodeficiency virus (HIV) will be excluded. Patients with HIV who have
             adequate CD4 count, not requiring antiretroviral medication, may be enrolled.

          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. Refractory nausea and vomiting, chronic grastointestinal disease (e.g., inflammatory
             bowel disease), or significant bowel resection that would preclude adequate
             absorption.

         10. Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the
             subject meets criteria for re-treatment.

         11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath
             tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.

         12. Supplementation with vitamin E greater than 100% of the daily recommended dose. Any
             multivitamin containing vitamin E must be stopped prior to initiation of therapy.

         13. Patients not achieving adequate blood pressure in spite of antihypertensive therapy
             for control of blood pressure.

         14. Cardiac Function: a) known inherited coronary disease, b) Symptomatic heart failure
             (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease),
             c) Prior or current cardiomyopathy, d) Sever valvular heart disease, 3) History of
             atrial fibrillation

         15. Ophthalmologic conditions:

               1. Current or past history of central serous retinopathy

               2. Current or past history of retinal vein occlusion

               3. Known intraocular pression (IOP) greater than 21 mmHg (or ULN adjusted by age) or
                  uncontrolled glaucoma (irrespective of IOP); Patients with known glaucoma and
                  increased IOP who do not have meaningful vision (light perception only or no
                  light perception) and are not experiencing pain related to the glaucoma, may be
                  eligible after discussion with the study chair.

               4. Subjects with any other significant abnormality on ophthalmic examination should
                  be discussed with the Study Chair for potential eligibility

               5. Ophthalmological f ndings secondary to long-standing optic pathway glioma (such
                  as visual loss, optic nerve pallor or strabismus) or long-standing
                  orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a
                  significant abnormality for the purposes of the study

         16. Known severe hypersensitivity to selumetinib or any excipient of selumetinib or
             history of allergic reactions attributed to compounds of similar chemical or biologic
             composition to selumetinib.

         17. Recent major surgery within a minimum of 4 weeks prior to starting study treatment,
             with the exception of surgical placement for vascular access.

         18. Any unresolved chronic toxicity with CTC AE grade greater than or equal to 2 from
             anti-NF1 therapy, except for alopecia.

         19. Clinical judgement by the investigator that the patient should not participate in the
             study.

         20. While not an exclusion criterion, unless considered clinically indicated, patients
             should avoid taking other additional non-study medications that may interfere with the
             study medications. In particular, patients should avoid medications that are known to
             either induce or inhibit the activity of hepatic mircrosomal isoenzymes CYP1A2,
             CYP2C19 and CYP3A4, as this may interfere with the metabolism of selumetinib.
      

Gender

All

Ages

2 Years - 18 Years

Accepts Healthy Volunteers

No

Contacts

Brigitte C Widemann, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01362803

Organization ID

110161

Secondary IDs

11-C-0161

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Brigitte C Widemann, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

August 31, 2021