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A Phase I Single Arm Open Label Study of Erlotinib and 13-cis-Retinoic Acid (CRA) in Patients With Recurrent Malignant Gliomas

Phase 1
18 Years
Not Enrolling
Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Diffuse Astrocytoma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Adult Oligodendroglioma, Recurrent Adult Brain Tumor

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Trial Information

A Phase I Single Arm Open Label Study of Erlotinib and 13-cis-Retinoic Acid (CRA) in Patients With Recurrent Malignant Gliomas


I. To determine the recommended phase II doses of erlotinib (erlotinib hydrochloride) and
13-cis-retinoic acid (CRA) when administered to adults with recurrent malignant glioma who
are not receiving cytochrome P450 enzyme-inducing antiepileptic drugs (EIAEDs).


I. To assess dose-related toxicities. II. To measure 6 month progression-free survival and
overall survival. III. To estimate response rates in those patients with measurable disease.
IV. To evaluate for epidermal growth factor receptor (EGFR)vIII, phosphatase and tensin
homolog (PTEN), cyclin D1, cyclin E, and RARbeta1 expression in tumor samples from enrolled
patients as predictors of clinical benefit from this combination.

OUTLINE: This is a dose-escalation study.

Patients receive isotretinoin orally (PO) once daily (QD) on days 1-21 and erlotinib
hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed for up to 2 years.

Inclusion Criteria:

Histologically proven malignant glioma (glioblastoma multiforme, anaplastic astrocytoma,
anaplastic oligodendroglioma, or anaplastic mixed oligoastrocytoma) which is progressive
or recurrent after radiation therapy +/- chemotherapy; patients with previous low grade
glioma who progressed after radiotherapy +/- chemotherapy and are biopsied and found to
have a high grade glioma are eligible Karnofsky performance status of >= 60% Patients -
both males and females - with reproductive potential (i.e., premenopausal or menopausal
for less than 1 year and not surgically sterilized) must practice at least 2 contraceptive
measures throughout the study Patients must be registered and meet all the requirements of
iPLEDGE in order to receive 13-cis-Retinoic Acid (CRA) Patients must provide verbal and
written informed consent to participate in the study Patients must have a Mini Mental
Status Exam score >= 15 Patients must have a 12-lead electrocardiogram (EKG) without
evidence of any clinically significant abnormalities Absolute neutrophil count (ANC) >=
1,500/mm^3 Platelets >= 100,000/mm^3 Aspartate aminotransferase (AST) =< 2.5 upper limit
of normal (ULN) (ULN = 50 U/L) Alanine aminotransferase (ALT) =< 2.5 ULN (ULN = 50 U/L)
Total Bilirubin =< 1.5 mg/dL Alkaline phosphatase (Alk. Phos) =< 5X ULN (ULN = 125 U/dL)
Estimated (Estim.) creatinine (Cr) Clearance > 50 ml/min Fasting total cholesterol < 300
mg/dL Fasting triglycerides < 250 mg/dL Two separate, laboratory pregnancy tests within 14
days of registration (for women of childbearing potential) Patients must have recovered
from the toxicity of prior therapy; specifically, there must be at least a 3 month
interval from the completion of the most recent course of radiation therapy, at least a 3
month interval from the implantation of Gliadel wafer(s), at least a 3 week interval from
the completion of a non-nitrosourea-containing chemotherapy regimen, and at least a 6 week
interval from the completion of a nitrosourea-containing chemo-regimen

Exclusion Criteria:

Pregnant or breast-feeding women Uncontrolled intercurrent illness including, but not
limited to, ongoing or active infection, severe cardiovascular disease including recent (<
6 months) myocardial infarction, severe psychiatric illness that would limit compliance
with study requirements, or any other disorder that would be incompatible with the study
therapy Any history of inflammatory bowel disease Any history of uncontrolled depression,
any history of hospitalization for depression, or any history of suicidal thoughts or
attempt(s) Patients receiving concurrent therapy for their tumor (with the exception of
steroids) Must have at least a 10 day interval from last dose of vitamin A, tetracyclines,
micro-dosed progesterone preparations, norethindrone/ethinyl estradiol, St. John's Wort,
fish oil supplements, or phenytoin or other P450 enzyme inducing antiepileptic drugs
Current smokers (Smoking >= 11 cigarettes per day), as smoking increases metabolism and
decreases serum levels of erlotinib Participants may not have received prior EGFR
inhibitors for any disease Patients with a history of allergic reactions to
13-cis-retinoic acid (CRA) or compounds of similar biologic or chemical composition to CRA
Known allergy to proton pump inhibitors

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recommended phase II doses of erlotinib hydrochloride and isotretinoin

Outcome Description:

At least 3 patients will be treated at each dose level and the maximum tolerated dose (MTD) will be determined. Patients will be evaluated for dose-limiting toxicity (DLT) in the first 3 weeks on protocol.

Outcome Time Frame:

3 weeks

Safety Issue:


Principal Investigator

Glenn Lesser

Investigator Role:

Principal Investigator

Investigator Affiliation:

Comprehensive Cancer Center of Wake Forest University


United States: Institutional Review Board

Study ID:

CCCWFU 91209



Start Date:

May 2010

Completion Date:

June 2013

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Anaplastic Oligodendroglioma
  • Adult Diffuse Astrocytoma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Adult Oligodendroglioma
  • Recurrent Adult Brain Tumor
  • Astrocytoma
  • Brain Neoplasms
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma



Wake Forest University Health SciencesWinston-Salem, North Carolina  27157