A Phase I Trial of Enzastaurin (LY317615) in Combination With Carboplatin in Adults With Recurrent Gliomas
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).
-INCLUSION CRITERIA:

 1. Patients with histologically proven malignant glioma who have progressive disease
 following standard treatment will be eligible for this protocol. Malignant glioma
 include glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), anaplastic
 oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant glioma
 NOS (not otherwise specified). Additionally, patients with primitive neuroectodermal
 tumors (PNETs) of the central nervous system, progressive low-grade gliomas and
 radiographically diagnosed brain stem gliomas will be eligible.

 2. Patients must have unequivocal evidence for tumor progression by MRI or CT scan. This
 scan should be performed within 14 days prior to registration and on a steroid dosage
 that has been stable for at least 5 days. If the steroid dose is increased between the
 date of imaging and registration a new baseline MR/CT is required. The same type of
 scan, that is., MRI or CT must be used throughout the period of protocol treatment for
 tumor measurement.

 3. Patients having undergone recent resection of recurrent or progressive tumor will be
 eligible as long as all of the following conditions apply:

 A. They have recovered from the effects of surgery.

 B. Residual disease following resection of recurrent tumor is not mandated for
 eligibility into the study. To best assess the extent of residual disease
 post-operatively, a CT/ MRI should be done:

 -  no later than 96 hours in the immediate post-operative period or

 -  at least 4 weeks post-operatively, and

 -  within 14 days of registration, and

 -  on a steroid dosage that has been stable for at least 5 days.

 If the 96 hour scan is more than 14 days before registration, the scan needs to be
 repeated. If the steroid dose is increased between the date of imaging and
 registration, a new baseline MRI/CT is required on a stable steroid dosage for at
 least 5 days.

 4. Patients must have failed prior radiation therapy and must have an interval of greater
 than or equal to 4 weeks from the completion of radiation therapy to study entry.

 5. All patients or their previously designated LAR (Legally Authorized Representative)
 (if the patient is deemed by the treating physician to be cognitively impaired or
 questionably impaired in such a way that the ability of the patient to give informed
 consent is questionable) must sign an informed consent indicating that they are aware
 of the investigational nature of this study. Patients will be registered prior to
 starting the study.

 6. Patients must be greater than or equal to 18 years old, and with a life expectancy
 greater than 8 weeks.

 7. Patients must have a Karnofsky performance status of greater than or equal to 60.

 8. Patients must have recovered from the toxic effects of prior therapy: 2 weeks from any
 noncytotoxic investigational agent, 4 weeks from prior cytotoxic therapy, two weeks
 from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration,
 and 1 week for non-cytotoxic agents, for example., interferon, tamoxifen, thalidomide,
 cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the
 definition of non-cytotoxic agents should be directed to the Study Chair.

 9. Patients must have adequate bone marrow function (WBC greater than or equal to
 3,000/microl, ANC greater than or equal to 1,500/mm(3), platelet count of greater than
 or equal to 100,000/mm(3), and hemoglobin greater than or equal to 10 gm/dl), adequate
 liver function (SGOT and bilirubin less than or equal to 2 times ULN), and adequate
 renal function (creatinine less than or equal to 1.5 mg/dL and/or creatinine clearance
 greater than or equal to 60 cc/min) before starting therapy. These tests must be
 performed within 14 days prior to registration. Eligibility level for hemoglobin may
 be reached by transfusion.

 10. Patients must not have any significant medical illnesses that in the investigator's
 opinion cannot be adequately controlled with appropriate therapy or would compromise
 the patient's ability to tolerate this therapy.

 11. This study was designed to include women and minorities, but was not designed to
 measure differences of intervention effects. Males and females will be recruited with
 no preference to gender. No exclusion to this study will be based on race.

 12. Patients must practice adequate contraception.

 13. Prior treatment with an enzyme inducing antiepileptic drug must have been discontinued
 at least 14 days prior to study entry for Group A patients.

 EXCLUSION CRITERIA:

 1. Patients who, in the view of the treating physician, have significant active cardiac,
 hepatic, or renal diseases are ineligible.

 2. No concurrent use of other standard chemotherapeutics or investigative agents.

 3. Prior treatment with platinum-based therapy.

 4. Patients known to have an allergic response to mannitol.

 5. Patients known to have an active malignancy other than their malignant glioma (except
 non-melanoma skin cancer or carcinoma in-situ of the cervix).

 6. Patients who have an active infection requiring IV antibiotics.

 7. Patients who are pregnant or breast feeding.

 8. Patients who have any disease that will obscure toxicity or dangerously alter drug
 metabolism.

 9. QTc with Bazett's correction that is unmeasurable, or greater than or equal to 460
 msec on screening ECG. If a patient has QTc greater than or equal to 460 msec on
 screening ECG, a second screen ECG may be repeated at least 24 hours apart. The
 average QTc from the 2 screening ECGs must be less than 460 msec in order for the
 patient to be eligible for the study.

 10. EKG demonstrating clinically significant arrythmia (multifocal premature ventricular
 contraction [PVC], bigeminy, trigeminy, ventricular tachycardia, bradycardia) that is
 symptomatic or requires treatment (CTCAE Grade 3), or asymptomatic sustained
 ventricular tachycardia.

 11. Patients who have baseline EKGs suggestive of past or present cardiac ischemia will
 not be eligible unless they have an appropriate (as defined by the P.I. of this trial)
 negative cardiac work up (that is, echocardiogram, stress test).

 12. Patients may not be on systemic anti-coagulants (that is, heparin, warfarin, small
 heparin fragments).