Enzastaurin to Treat Recurrent Brain Tumor
Status: | Terminated |
---|---|
Conditions: | Brain Cancer |
Therapuetic Areas: | Oncology |
Healthy: | No |
Age Range: | 18 - Any |
Updated: | 4/6/2019 |
Start Date: | April 7, 2005 |
End Date: | April 1, 2014 |
A Phase I Trial of Enzastaurin (LY317615) in Patients With Recurrent Gliomas
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.
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.
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.
OBJECTIVES:
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.
ELIGIBILITY:
Patients with histologically proven malignant glioma will be eligible for this protocol.
DESIGN:
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.
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.
OBJECTIVES:
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.
ELIGIBILITY:
Patients with histologically proven malignant glioma will be eligible for this protocol.
DESIGN:
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.
- INCLUSION CRITERIA:
Patients with histologically proven malignant glioma 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 refractory to standard treatment will be
eligible.
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, i.e., MRI
or CT must be used throughout the period of protocol treatment for tumor measurement.
Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:
1.
2.
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.
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.
All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study.
Patients must be greater than or equal to 18 years old, and with a life expectancy
greater than 8 weeks.
Patients must have a Karnofsky performance status of greater than or equal to 60.
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, e.g., 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.
Patients must have adequate bone marrow function (WBC greater than or equal to
3,000/micro l, 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 to10 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.
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 patients' ability to tolerate this therapy
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. Minorities
will actively be recruited to participate.
Patients must practice adequate contraception.
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:
Patients who, in the view of the treating physician, have significant active cardiac,
hepatic, or renal diseases are ineligible.
No concurrent use of other standard chemotherapeutics or investigative agents.
Patients known to have an active malignancy (except non-melanoma skin cancer or
carcinoma in-situ of the cervix).
Patients who have an active infection requiring IV antibiotics.
Patients who are pregnant or breast feeding.
Patients who have any disease that will obscure toxicity or dangerously alter drug
metabolism.
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.
EKG demonstrating clincically 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.
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 (i.e. echocardiogram, stress test).
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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