Erlotinib and Sirolimus in Treating Patients With Recurrent Malignant Glioma

OBJECTIVES:

Primary

- Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of
escalating doses of erlotinib hydrochloride in combination with sirolimus in adult
patients with malignant glioma, who are not receiving enzyme-inducing anti-epileptic
drugs (EIAED). (Phase I)

- Evaluate preliminary efficacy (response rate [RR], progression-free survival [PFS], and
overall survival [OS]) of erlotinib hydrochloride and sirolimus combination therapy in
glioblastoma multiforme (GMB)/gliosarcoma (GS) patients who are not undergoing surgery
at the time of recurrence or relapse (dose-expansion arm). (Phase II)

- Evaluate molecular determinants of response to the combination of erlotinib
hydrochloride and sirolimus, especially the roles of the mutation of EGFR (e.g., vIII
mutant, other somatic mutations of vIII, and mutation/deletion of PTEN).

Secondary

- To characterize the safety and tolerability of erlotinib hydrochloride and sirolimus
combination therapy in these patient populations.

- To characterize the single-dose and repeated-dose pharmacokinetic (PK) profiles of
erlotinib hydrochloride (in serum) and sirolimus (in whole blood) combination therapy
in these patient populations.

- To characterize, in pre- and/or post-treatment tumor samples, when available,
expression levels of total and activated phosphorylated proteins relevant to the EGFR,
VEGFR, and PI3K/mTOR signaling pathways, relevant downstream signaling network
components, EGFR and VEGFR-related ligands, apoptosis (TUNEL), cell cycle control, and
proliferation.

- To assess pre- and/or post-treatment tumor samples, when available, for DNA-based
changes (e.g., EGFR [DNA] amplification, EGFR and EGFRvIII mutations, and
mutations/deletions in the PTEN gene) relevant to the molecular biology in GBM.

OUTLINE: Patients receive oral erlotinib hydrochloride and sirolimus once daily on days
1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.

Patients undergo tumor tissue and blood sample collection periodically for pharmacological
and biological studies. Samples are analyzed for concentrations of erlotinib hydrochloride
and trough serum levels of sirolimus via HPLC, EGFR, EGFRvIII, PTEN and the phospho-specific
antibodies associated with the MAPK and PI3K pathways via IHC, and EGFRvIII and sequencing
of EGFR, PTEN and other critical genes via PCR, gene expression, and SNP analysis. Germline
DNA will also be used to distinguish polymorphisms from somatic mutations in gene sequenced.

After completion of study treatment, patients are followed periodically.

Inclusion Criteria:

- Histologically confirmed malignant glioma, including any of the following:

- Glioblastoma multiforme (GBM)

- Gliosarcoma (GS)

- Anaplastic astrocytoma (AA)

- Anaplastic oligodendroglioma (AO)

- Anaplastic mixed oligoastrocytomas (AMA)

- Malignant astrocytoma not otherwise specified (NOS)

- Prior low-grade glioma allowed provided there is histologic evidence of progression
to a malignant glioma

- Must meet the following criteria for phase I:

- All types of malignant gliomas allowed

- No limitations on the number of relapses

- Must meet the following criteria for phase II:

- Only patients with GBM or GS are allowed

- Must be in first, second, or third relapse

- patients who had prior therapy (must include external beam radiotherapy) for a
low-grade glioma that is considered standard, non-surgical treatment for a high-grade
glioma, the surgical diagnosis of high-grade glioma will be considered the first
relapse

- Must have shown unequivocal radiographic evidence for tumor progression by MRI or CT
scan and have either measurable or evaluable disease

- Measurable disease is defined as bidimensionally measurable lesions with clearly
defined margins by MRI scan

- Evaluable disease is defined as unidimensionally measurable lesions or masses with
margins not clearly defined

- Karnofsky performance status ≥ 60%

- Life expectancy > 8 weeks

- Absolute neutrophil count ≥ 1,500/μL

- Platelets ≥ 100,000/μL

- Total bilirubin < 2.0 x upper limit of institutional normal (ULN)

- AST < 2.0 x ULN

- Creatinine < 1.5 x ULN

- Fasting serum triglycerides < 2.5 x ULN

- Fasting serum cholesterol < 350 mg/dL

- Women of child-bearing potential and men must agree to use adequate contraception
(i.e., hormonal or barrier method of birth control) prior to study entry and for the
duration of study participation

- Recovered from all toxicities associated with prior surgery, radiotherapy, or
chemotherapy

- At least 1 week since prior surgery

- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)

- At least 12 weeks since prior radiation therapy

- Must not receive any P450-enzyme-inducing anticonvulsants (EIAC) for at least 2 weeks
prior to and during participation in this trial

Exclusion Criteria:

- Women who are pregnant or lactating

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to erlotinib hydrochloride or sirolimus

- Uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection requiring IV antibiotics

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Hyperlipidemia (e.g., grade 3 or greater hypercholesterolemia or
hypertriglyceridemia) not controlled with medication

- Psychiatric illness or social situations that would limit compliance with study
requirements

- Disorders associated with significant immunocompromise (e.g., HIV or systemic lupus
erythematosus [SLE])

- Patients with another primary malignancy that has required treatment other than
surgery within the past year (except for nonmelanoma skin cancer or carcinoma in
situ)

- Patients with the inability to comply with the protocol requirements in the opinion
of the investigator including those who can not take oral medications

- Patients who are unable to undergo routine imaging evaluations with magnetic
resonance imaging scans

- Prior EGFR-directed or mTOR-directed therapies including sirolimus or sirolimus
analogs

- Patients taking concurrent immunosuppressive agents other than prescribed
corticosteroids

- Concurrent antineoplastic or antitumor agents that are not part of the study therapy
including chemotherapy, radiation therapy, immunotherapy, and hormonal anticancer
therapy

- Blood products during cycle 1 unless a patient experiences hematologic DLT or if it
is medically imperative to administer a transfusion

- Concurrent grapefruit or grapefruit juice

- Other concurrent investigational agents

- Receiving concurrent enzyme-inducing antiepileptic drugs