Enzastaurin in Treating Young Patients With Refractory Primary CNS Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:
NCT00503724
First received: July 17, 2007
Last updated: March 2, 2012
Last verified: March 2012
  Purpose

RATIONALE: Enzastaurin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of enzastaurin in treating young patients with refractory primary brain tumors.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Neuroblastoma
Drug: enzastaurin hydrochloride
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I and Pharmacokinetic Study of Enzastaurin (LY317615) in Children and Adolescents With Refractory Primary CNS Tumors

Resource links provided by NLM:


Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: First 28 days of therapy ] [ Designated as safety issue: Yes ]
    The maximum tolerated dose or recommended phase II dose will be based on the dose-limiting toxicities observed during the first 28 days of therapy in those participants receiving enzastaurin on a once per day dosing schedule.

  • Number of participants treated with the maximum tolerated dose or phase II recommended dose on a twice daily dosage schedule with dose-limiting toxicities [ Time Frame: First 28 days of therapy ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetics [ Time Frame: Three days prior to course 1 and day 28 of course 1 ] [ Designated as safety issue: No ]
    Blood samples for pharmacokinetic studies will be drawn 3 days prior to course 1 and on day 28 of course 1.

  • Toxicity [ Time Frame: From day 1 of therapy until 30 days after the last dose of the drug ] [ Designated as safety issue: Yes ]
  • Tumor response [ Time Frame: Pre-treatment, day 15 of course 1, and at the end of courses 3, 5, 8, 11, and 13. ] [ Designated as safety issue: No ]
    Brain images to assess tumor response (complete response, partial response, or stable disease) are taken pre-treatment, at day 15 of course 1, and at the end of courses 3, 5, 8, 11, and 13.

  • Change in MR perfusion parameters obtained within 15 ± 2 days after initiation of enzastaurin hydrochloride therapy as compared to baseline [ Time Frame: Baseline and day 15 of course 1 ] [ Designated as safety issue: No ]
  • Change from baseline in the inhibition of Akt cell signaling at day 14 and day 28 [ Time Frame: Pre-treatment and at days 14 and 28 of course 1 ] [ Designated as safety issue: No ]
  • Akt pathway activity in pre-study tumor samples [ Time Frame: Pre-treatment ] [ Designated as safety issue: No ]

Enrollment: 32
Study Start Date: June 2007
Study Completion Date: May 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: enzastaurin hydrochloride
    Participants receive 200, 260, 340, or 440 mg/m2/day of enzastaurin orally once daily for 28 days (one course) during the dose escalation phase of the study. To study the toxicity profile of the MTD or phase II recommended dose established during the dose escalation phase, participants receive twice daily doses of enzastaurin orally at the phase II recommended dose for 28 days (one course). In the absence of unacceptable toxicity or disease progression, treatment may continue for 13 courses (approximately one year).
    Other Name: LY317615 monohydrochloride
Detailed Description:

OBJECTIVES:

Primary

  • To estimate the maximum tolerated dose (MTD) and/or recommend a phase II dose of enzastaurin hydrochloride in children with recurrent or refractory CNS tumors who are not receiving enzyme-inducing anticonvulsants.
  • To further characterize the pharmacokinetics and toxicity of the recommended phase II dose of enzastaurin hydrochloride given twice daily in these patients.

Secondary

  • To characterize the pharmacokinetics of enzastaurin hydrochloride at the recommended phase II dose given once a day or twice a day in children.
  • To document and describe toxicities associated with enzastaurin hydrochloride.
  • To document antitumor activity in children with recurrent or refractory CNS tumors.
  • To explore changes in MR perfusion scans obtained within 15 ± 2 days after initiation of enzastaurin hydrochloride therapy as compared to baseline and to correlate these changes with clinical outcome.
  • To evaluate a panel of biological surrogate markers in this patient population at baseline and following enzastaurin hydrochloride administration.

OUTLINE: This is a multicenter study.

Patients receive oral enzastaurin hydrochloride once daily until the maximum tolerated dose (MTD) is determined. Patients then receive enzastaurin hydrochloride at the MTD twice daily on days 1-28. Treatment repeats every 28 days for 13 courses in the absence of disease progression or unacceptable toxicity. Patients may receive 13 additional courses (for a total of 26 courses) of oral enzastaurin hydrochloride if the patient is benefitting from the treatment and the investigator and subject agree to continue treatment.

Patients undergo blood sample collection periodically for pharmacokinetic studies.

After completion of study treatment, patients are followed periodically.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Histologically confirmed primary CNS malignancy including low-grade glioma

    • All tumors, except intrinsic brain stem and diffuse optic pathway tumors, must have histological verification at either the time of diagnosis or recurrence

      • Patients with intrinsic brain stem or diffuse optic pathway tumors must have clinical and/or radiographic evidence of progression
  • Recurrent or progressive disease or disease refractory to standard therapy and for which there is no known curative therapy

PATIENT CHARACTERISTICS:

Inclusion Criteria:

  • Karnofsky performance scale (for > 16 years of age) or Lansky performance score (for ≤ 16 years of age) ≥ 60% assessed within two weeks prior to registration
  • Peripheral absolute neutrophil count (ANC) ≥ 1,000/μL
  • Platelet count ≥ 100,000/μL (transfusion independent)
  • Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR maximum serum creatinine based on age as follows:

    • 0.8 mg/dL (≤ 5 years of age)
    • 1.0 mg/dL (6 to 10 years of age)
    • 1.2 mg/dL (11 to 15 years of age)
    • 1.5 mg/dL (≥ 16 years of age)
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age
  • ALT ≤ 5 x ULN for age
  • Serum albumin ≥ 2.5 g/dL
  • Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
  • Negative pregnancy test
  • Patients must have a normal QTc for age and no evidence of a clinically significant arrhythmia on ECG
  • No evidence of active graft-versus-host disease

Exclusion Criteria:

  • Pregnant or lactating
  • Body surface area < 0.5 m^2
  • Clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results
  • Known hypersensitivity to enzastaurin hydrochloride or its components
  • Inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy

PRIOR CONCURRENT THERAPY:

Inclusion Criteria:

  • Must have recovered from the acute toxic effects (grade ≤ 2) of all prior therapy before entering this study
  • Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (6 weeks for prior nitrosourea)
  • At least 7 days since the completion of therapy with a hematopoietic growth agent (i.e., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin)

    • At least 14 days since long-acting formulations
    • Therapeutic use of myeloid growth factors in patients with serious neutropenic conditions, such as sepsis, may be considered at the investigator's discretion
  • At least 7 days since the completion of therapy with a biologic agent
  • At least 2 weeks since prior local palliative radiotherapy (small port)
  • At least 6 months must have elapsed after prior total body irradiation (TBI) or craniospinal radiotherapy
  • At least 6 weeks must have elapsed after other substantial bone marrow irradiation
  • At least 6 months since prior allogeneic bone marrow transplantation
  • At least 3 months since prior autologous bone marrow or stem cell transplantation
  • Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration

    • Corticosteroids should be used at the lowest dose to control symptoms of edema and mass effect

Exclusion Criteria:

  • Routine concurrent use of growth factors (i.e., G-CSF, GM-CSF, or erythropoietin)
  • Any other concurrent anticancer or investigational drug therapy
  • Concurrent enzyme-inducing anticonvulsants (EIACDs)
  • Concurrent gents that prolong the QTc
  • Concurrent drugs that are substrates or inhibitors of CYP3A4 or CYP2C9
  • Other concurrent drugs that are sensitive substrates of CYP2C8, CYP2C9, or CYP2C19 and/or have a narrow therapeutic window
  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: NCT00503724

Locations
United States, California
UCSF Medical Center at Parnassus
San Francisco, California, United States, 94143-0372
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010-2970
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
United States, North Carolina
Duke Comprehensive Cancer Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
Houston, Texas, United States, 77030-2399
Sponsors and Collaborators
Pediatric Brain Tumor Consortium
Investigators
Study Chair: Susan M. Blaney, MD Texas Children's Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier: NCT00503724     History of Changes
Other Study ID Numbers: CDR0000557572, U01CA081457, PBTC-023
Study First Received: July 17, 2007
Last Updated: March 2, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Pediatric Brain Tumor Consortium:
recurrent childhood brain stem glioma
childhood central nervous system germ cell tumor
recurrent childhood cerebellar astrocytoma
recurrent childhood cerebral astrocytoma
childhood choroid plexus tumor
childhood craniopharyngioma
childhood infratentorial ependymoma
childhood supratentorial ependymoma
recurrent childhood ependymoma
recurrent childhood medulloblastoma
childhood oligodendroglioma
recurrent childhood supratentorial primitive neuroectodermal tumor
recurrent childhood visual pathway and hypothalamic glioma
recurrent childhood visual pathway glioma
childhood grade I meningioma
childhood grade II meningioma
childhood grade III meningioma
recurrent childhood subependymal giant cell astrocytoma
recurrent childhood pineoblastoma
recurrent childhood brain tumor
disseminated neuroblastoma
recurrent neuroblastoma

Additional relevant MeSH terms:
Neuroblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases

ClinicalTrials.gov processed this record on September 22, 2014