Recurrent Gliomas Clinical Trial
Official title:
A Phase I Trial of Enzastaurin (LY317615) in Combination With Carboplatin in Adults With Recurrent Gliomas
This study will evaluate the safety and effectiveness of Enzastaurin, an experimental drug
that may prevent the growth of tumor vessels, in combination with Carboplatin, for patients
who have a glioma, a type of brain tumor. Carboplatin is used for treating many kinds of
cancers, though not recurrent gliomas. Tumor growth involves new cancer cell formation and
accumulation, requiring a blood supply. Research shows that brain tumor cells can produce
substances that stimulate new blood vessel formation. This study will look into whether the
combination of drugs can stop that process.
Patients ages 18 and older who have recurring gliomas, who are not pregnant or breast
feeding, and who do not have serious diseases may be eligible for this study. About 96
patients will participate for 1 year. They will have a physical examination, give blood and
urine samples for analysis, and undergo magnetic resonance imaging (MRI) or computed
tomography (CT) scans regarding tumor growth, and perhaps an electrocardiogram. Patients may
also undergo a dynamic MRI with spectroscopy or PET scan (positron emission tomography), to
distinguish a live tumor from a dying one. Researchers are studying patients taking a
certain type of antiseizure medicine and patients who are not taking it because some
antiseizure medicines may change the way the body handles a drug such as Enzastaurin. There
will be two groups of participants, with 16 to 48 each. Group A is not taking
enzyme-inducing antiseizure drugs, and Group B is taking such drugs. In Groups A and B are
four dose levels, with 4 to12 patients at each level. Patients' doctors will tell them which
group they belong to and how much Enzastaurin and Carboplatin they will take. Treatment
consists of Enzastaurin every day for 5 weeks in Cycle 1 only and for 4 weeks beginning with
Cycle 2 (each 4-week period as a cycle). Patients take Enzastaurin within 30 minutes after a
meal. History, physical, and neurological examinations are repeated at the end of Cycle 1
and then every 4 weeks. Patients will have a repeat head MRI or CT scan before each cycle.
If they tolerate the drugs without serious side effects and the tumor is not growing, they
may continue with another cycle of Enzastaurin, taking the tablets every day, and
Carboplatin being infused on Day 8 of Cycle 1 and on Day 1 of each additional cycle. Routine
lab tests are done regularly. Patients will continue the 4-week cycles of treatment for as
long as they have no serious side effects and there are no signs of tumor growth. Side
effects of Enzastaurin may be fatigue, constipation, cough, and nausea. In men, there may be
a decrease in sperm count. Carboplatin can lead to low counts in blood cells and platelets,
and there may also be an allergic reaction. Vomiting is a likely side effect. At injection
sites, there may be redness, swelling, and pain.
This study may or may not have a direct benefit for participants. However, information
gained may help the sponsor of the study, Eli Lilly and Company, and may help patients in
the future who have gliomas.
Background:
- 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.
- Carboplatin has shown activity as monotherapy in the treatment of recurrent malignant
gliomas in adults and preclinical data generated in our laboratory demonstrates
additive anti-glioma activity with enzastaurin. The safety profile of carboplatin and
the preclinical and clinical data supports its use in combination with enzastaurin in
patients with malignant gliomas.
Objective:
-To establish the maximally tolerated dose of enzastaurin in combination with carboplatin in
patients with refractory primary brain tumors not on any enzyme-inducing anti-epileptic
drugs (nEIAED) and for patients on EIAEDs.
Eligibility:
-Patients with histologically proven malignant glioma are eligible for this study.
Design:
-Patients will be stratified into two groups based on their anti-epileptic medications
(nEIAEDs = Group A, EIAED = Group B)
Group A: Each cycle of therapy will consist of enzastaurin administered daily for 4 weeks
with no breaks between cycles. All patients will receive a 7-day lead-in treatment period
(Cycle 1) consisting of a loading dose of oral enzastaurin on Day 1 at 1125mg, followed by
enzastaurin administered once daily at 500mg for 6 additional days in order to achieve
steady state pharmacokinetics of enzastaurin. The first dose of carboplatin will be
administered on Day 8 of Cycle 1, which will consist of 35 days. Following the lead-in
treatment period, the first combination cycle of enzastaurin and carboplatin (Cycle 2) will
commence as a 28-day cycle. Within each combination cycle, enzastaurin will be orally
administered at 500mg once daily on Days 1 through 28 and carboplatin will be administered
as an intravenous infusion over approximately 30 minutes on Day 1 every 28 days. The
carboplatin dose will be 3 AUC for dose level one. For dose levels 2, 3, and 4, the
carboplatin dose will be 4, 5 and 6 AUC, respectively.
Group B: Each cycle of therapy will consist of enzastaurin administered daily for 4 weeks
with no breaks between cycles. All patients will receive a 7-day lead-in treatment period
(Cycle 1) consisting of a loading dose of oral enzastaurin on Day 1 at 1125mg, followed by
enzastaurin administered once daily at 875mg for 6 additional days in order to achieve
steady state pharmacokinetics of enzastaurin. The first dose of carboplatin will be
administered on Day 8 of Cycle 1, which will consist of 35 days. Following the lead-in
treatment period, the first combination cycle of enzastaurin and carboplatin (Cycle 2) will
commence as a 28-day cycle. Within each combination cycle, enzastaurin will be orally
administered once daily on Days 1 through 28 at 875mg and carboplatin will be administered
as an intravenous infusion over approximately 30 minutes on Day 1 every 28 days. The
carboplatin dose will be 3 AUC for dose level one. For dose levels 2, 3, and 4, the
carboplatin dose will be 4, 5 and 6 AUC, respectively.
National Cancer Institute (NCI) registered this trial with Eli Lilly as sponsor. NCI did not
update the record. In June 2013, NCI transferred the trial to Lilly's clinicaltrials.gov
account and Lilly updated the record with the trial status, study start date, and completion
dates. This trial is not an applicable trial under Food and Drug Administration Amendments
Act of 2007 (FDAAA).
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Primary Purpose: Treatment