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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
32
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).
UCSF Medical Center at Parnassus
San Francisco, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States
Maximum tolerated dose
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.
Time frame: First 28 days of therapy
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
Pharmacokinetics
Blood samples for pharmacokinetic studies will be drawn 3 days prior to course 1 and on day 28 of course 1.
Time frame: Three days prior to course 1 and day 28 of course 1
Toxicity
Time frame: From day 1 of therapy until 30 days after the last dose of the drug
Tumor response
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.
Time frame: Pre-treatment, 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
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
Akt pathway activity in pre-study tumor samples
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Duke Comprehensive Cancer Center
Durham, North Carolina, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh
Pittsburgh, Pennsylvania, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
Houston, Texas, United States
Time frame: Pre-treatment