A Phase I Trial of Enzastaurin (LY317615) in Combination With Carboplatin in Adults With Recurrent 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).
Interventional
Primary Purpose: Treatment
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 (EIAED) and for patients on EIAEDs.
Joohee Sul, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
070053
NCT01445119
January 2007
July 2013
Name | Location |
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National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |