Enzastaurin to Treat Recurrent Brain Tumor
This study will examine the safety of a twice-a-day dosing regimen of the experimental drug Enzastaurin in patients with malignant glioma (a cancerous brain tumor) who are and who are not taking certain anti-seizure medicines. Enzastaurin may prevent the formation of new blood vessels that tumors need to grow. It has shown some effect against brain tumors in animals and in some patients with recurrent gliomas. This study will see if the drug can help patients with gliomas and how much drug they should be given.
Patients 18 years of age and older with malignant glioma that has recurred after standard therapy may be eligible for this study. Candidates are screened with a physical examination, blood and urine tests, magnetic resonance imaging (MRI) or computed tomography (CT) scans, and an electrocardiogram.
Participants are divided into two groups of patients-those who are and those who are not taking certain anti-seizure medications-in order to determine if the anti-seizure medication alters the way the body handles Enzastaurin. Patients in both groups are further divided into different dosing regimens: some in each group take Enzastaurin once a day for 3 weeks, followed by twice a day for 3 weeks; others in the group take the drug twice a day for 3 weeks followed by once a day for 3 weeks. The medication is taken by mouth every day. Treatment is given in 6-week cycles and may continue for 1 year unless the tumor grows or the patient develops unacceptable drug side effects. In addition to drug treatment, patients have the following tests and procedures:
- Medical history, physical, and neurological examinations every 3 weeks during the first cycle and then every 6 weeks.
- MRI or CT scan of the head before starting each new cycle. MRI uses a magnetic field and radio waves to produce images of body tissues and organs. CT uses x-rays to provide 3-dimensional views of the part of the body being studied. For both procedures, the patient lies on a table that slides into the cylindrical scanner.
- Routine blood tests every week during the first cycle and every 3 weeks after that.
- Electrocardiogram on days 21 and 42 of the first cycle, just before taking the drug and 30 minutes and 4 hours after taking the drug.
- Pharmacokinetic studies within 3 days of day 21 of the first cycle. Several blood samples are drawn to measure levels of Enzastaurin. Patients taking the drug once a day have blood samples drawn before the morning dose and 1, 2, 4, 6 and 24 hours after the dose. Patients taking the drug twice a day have samples drawn before the morning dose, at 1, 2, 4, 6 and 12 hours after the dose, and then 12 hours after the evening dose. In addition, on day 1 an extra tube of blood is drawn at the time of the Enzastaurin dose and 4 hours later.
- Dynamic MRI with spectroscopy or PET. These tests are done to help distinguish live tumor from dying tumor. The experience of dynamic MRI with spectroscopy is the same as standard MRI and is done at the same time as the standard procedure. PET uses a radioactive substance to show cellular activity in specific tissues of the body. The patient is given an injection of a sugar solution in which a radioactive isotope has been attached to the sugar molecule. A special camera detects the radiation emitted by the radioisotope, and the resulting images show how much glucose is being used in various parts of the body. Because rapidly growing cells, such as tumors, take up and use more glucose than normal cells do, this test can be used to show active tumors.
|Study Design:||Primary Purpose: Treatment|
|Official Title:||A Phase I Trial of Enzastaurin (LY317615) in Patients With Recurrent Gliomas|
- To establish the maximally tolerated dose of enzastaurin in patients with refractory primary brain tumors not on any enzyme-inducing anti-epileptic drugs (EIAED) and for patients on EIAEDs.
|Study Start Date:||April 7, 2005|
|Study Completion Date:||April 1, 2014|
|Primary Completion Date:||April 1, 2014 (Final data collection date for primary outcome measure)|
Enzastaurin is a macrocyclic bisindolylmaleimide which disrupts the intrinsic phosphotransferase activity of conventional and novel PKC isoforms via an interaction at the ATP binding site, displays selectivity in inhibiting the isoforms.
Preclinical studies demonstrate potent anti-angiogenic activity of enzastaurin and studies in normal volunteers and solid tumor patients demonstrate the drug is very well tolerated at doses that achieve a biologically active serum concentration.
To establish the maximally tolerated dose of enzastaurin in patients with refractory primary brain tumors not on any enzyme-inducing anti-epileptic drugs (EIAED) and for patients on EIAEDs.
To determine if twice a day dosing results in higher systemic exposure of enzastaurin and its metabolites than once a day dosing in patients not on EIAEDs and those on EIAEDs.
To obtain exploratory data regarding the relationship between the activity of the PKC-b pathway (specifically GSK3-b activation) in peripheral blood mononuclear cells of treated patients and clinical outcome.
To obtain exploratory information about the anti-tumor activity of enzastaurin at the higher doses specified in this protocol.
Patients with histologically proven malignant glioma will be eligible for this protocol.
Patients will be stratified into Group A or Group B based on their concomitant medications. Patients who are on enzyme inducing anti-epileptic drugs such as phenytoin, carbamazepine or trileptal will be enrolled into Group B while patients who meet the eligibility criteria and are not on any enzyme inducers, will be entered into Group A.
As of December 2005, three DLT's were observed at dose level 1 and it was determined that this was not a tolerable dose. A third dose level has been added using a lower dose for Group A patients only. Twelve patients will be entered at the third dose level in Group A only.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00108056
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Teri N Kreisl, M.D.||National Cancer Institute (NCI)|