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A Phase I Trial of Enzastaurin (LY317615) in Patients With Recurrent Gliomas


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Glioma

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Trial Information

A Phase I Trial of Enzastaurin (LY317615) in Patients 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.

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


- 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. They have recovered from the effects of surgery.

2. 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.

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).

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

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.

Principal Investigator

Teri N Kreisl, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

050136

NCT ID:

NCT00108056

Start Date:

April 2005

Completion Date:

Related Keywords:

  • Glioma
  • Brain
  • Tumor
  • Malignant
  • Therapy
  • Progression
  • Malignant Brain Tumor
  • Malignant Glioma
  • Glioma
  • Brain Neoplasms
  • Glioma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892