Clinical trial NCT00503724: Enzastaurin in Treating Young Patients With Refractory Primary CNS Tumors
Official title: Phase I and Pharmacokinetic Study of Enzastaurin (LY317615) in Children and Adolescents With Refractory Primary CNS Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Neuroblastoma
Keywords: 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
Lead sponsor: Pediatric Brain Tumor Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-07-19
Enrollment: 32
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: First 28 days of therapy
measure: Number of participants treated with the maximum tolerated dose or phase II recommended dose on a twice daily dosage schedule with dose-limiting toxicities
timeFrame: First 28 days of therapy
Secondary outcomes:
measure: Pharmacokinetics
timeFrame: Three days prior to course 1 and day 28 of course 1
measure: Toxicity
timeFrame: From day 1 of therapy until 30 days after the last dose of the drug
measure: Tumor response
timeFrame: Pre-treatment, day 15 of course 1, and at the end of courses 3, 5, 8, 11, and 13.
measure: Change in MR perfusion parameters obtained within 15 ± 2 days after initiation of enzastaurin hydrochloride therapy as compared to baseline
timeFrame: Baseline and day 15 of course 1
measure: Change from baseline in the inhibition of Akt cell signaling at day 14 and day 28
timeFrame: Pre-treatment and at days 14 and 28 of course 1
measure: Akt pathway activity in pre-study tumor samples
timeFrame: Pre-treatment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center at Parnassus
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
state: Texas
Study officials:
affiliation: Texas Children's Cancer Center
name: Susan M. Blaney, MD
role: STUDY_CHAIR
References: