Erlotinib Hydrochloride and Isotretinoin in Treating Patients With Recurrent Malignant Glioma
Erlotinib Hydrochloride and Isotretinoin in Treating Patients With Recurrent Malignant Glioma
This phase I trial is studying the side effects and best dose of erlotinib hydrochloride when
 given with isotretinoin in treating patients with recurrent malignant glioma. Erlotinib
 hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for
 cell growth. Isotretinoin may help cells that are involved in the body's immune response to
 work better. Giving erlotinib hydrochloride together with isotretinoin may kill more tumor
 cells
PRIMARY OBJECTIVES:

 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).

 SECONDARY OBJECTIVES:

 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