Erlotinib and Sirolimus in Treating Patients With Recurrent Malignant Glioma - Full Text View

Sponsors and Collaborators:	Jonsson Comprehensive Cancer Center National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00509431

Purpose

RATIONALE: Erlotinib and sirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with sirolimus and to see how well they work in treating patients with recurrent malignant glioma.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: erlotinib hydrochloride Drug: sirolimus Procedure: biopsy Procedure: gene expression analysis Procedure: high performance liquid chromatography Procedure: immunohistochemistry staining method Procedure: mutation analysis Procedure: pharmacological study Procedure: polymerase chain reaction Procedure: polymorphism analysis	Phase I Phase II

Genetics Home Reference related topics: pyridoxal 5'-phosphate-dependent epilepsy

MedlinePlus related topics: Cancer

Drug Information available for: Erlotinib Erlotinib hydrochloride Sirolimus

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	A Phase I/II, Dual-Center, Open-Label Trial of the Safety and Efficacy of Tarceva™ (Erlotinib Hydrochloride) Plus Sirolimus in Patients With Recurrent Malignant Glioma Not on P450-Inducing Anti-Epileptics

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose (phase I) [ Designated as safety issue: Yes ]
Dose-limiting toxicity (phase I) [ Designated as safety issue: Yes ]
Response rate (phase II) [ Designated as safety issue: No ]
Progression-free survival (phase II) [ Designated as safety issue: No ]
Overall survival (phase II) [ Designated as safety issue: No ]
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) [ Designated as safety issue: No ]

Secondary Outcome Measures:

Safety and tolerability [ Designated as safety issue: Yes ]
Characterization of the single-dose and repeated-dose pharmacokinetic (PK) profiles of erlotinib hydrochloride (in serum) and sirolimus (in whole blood) combination therapy [ Designated as safety issue: No ]
Expression levels of total and activated/phosphorylated proteins relevant to the EGFR, VEGFR and PI3K/mTOR signaling pathways [ Designated as safety issue: No ]
Expression levels of total and activated/phosphorylated proteins relevant to relevant downstream signaling network components [ Designated as safety issue: No ]
Expression levels of total and activated/phosphorylated proteins relevant to EGFR and VEGFR related ligands [ Designated as safety issue: No ]
Expression levels of total and activated/phosphorylated proteins relevant to apoptosis by TUNEL [ Designated as safety issue: No ]
Expression levels of total and activated/phosphorylated proteins relevant to cell cycle control and proliferation [ Designated as safety issue: No ]
DNA-based changes (e.e., EGFR [DNA] amplification, EGFR and EGFRvIII mutations, and mutations/deletions in the PTEN gene) relevant to the molecular biology of GBM [ Designated as safety issue: No ]

Estimated Enrollment:	99
Study Start Date:	June 2007
Estimated Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

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
For 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

PATIENT CHARACTERISTICS:

Inclusion Criteria:

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

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 CONCURRENT THERAPY:

Inclusion Criteria:

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:

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
Also see Disease Characteristics

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00509431

Locations

United States, California
Jonsson Comprehensive Cancer Center at UCLA	Recruiting
Los Angeles, California, United States, 90095-1781
Contact: Clinical Trials Office - Jonsson Comprehensive Cancer Center a 888-798-0719

Sponsors and Collaborators

Jonsson Comprehensive Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Timothy F. Cloughesy, MD

Jonsson Comprehensive Cancer Center

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000557423, UCLA-0604104
Study First Received:	July 30, 2007
Last Updated:	December 2, 2008
ClinicalTrials.gov Identifier:	NCT00509431
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

adult giant cell glioblastoma
adult gliosarcoma
adult anaplastic astrocytoma
adult anaplastic oligodendroglioma
adult mixed glioma
recurrent adult brain tumor

adult glioblastoma
adult pilocytic astrocytoma
adult diffuse astrocytoma
adult subependymal giant cell astrocytoma
adult oligodendroglioma

Study placed in the following topic categories:

Erlotinib
Sirolimus
Glioblastoma
Astrocytoma
Clotrimazole
Miconazole
Tioconazole
Central Nervous System Neoplasms
Recurrence
Brain Neoplasms

Neuroectodermal Tumors
Epilepsy
Neoplasms, Germ Cell and Embryonal
Neuroepithelioma
Oligodendroglioma
Glioma
Gliosarcoma
Nervous System Neoplasms
Neoplasms, Glandular and Epithelial

Additional relevant MeSH terms:

Anti-Infective Agents
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Neoplasms, Nerve Tissue
Nervous System Diseases
Enzyme Inhibitors
Antibiotics, Antineoplastic

Protein Kinase Inhibitors
Immunosuppressive Agents
Pharmacologic Actions
Anti-Bacterial Agents
Neoplasms
Neoplasms by Site
Therapeutic Uses
Antifungal Agents
Neoplasms, Neuroepithelial

ClinicalTrials.gov processed this record on January 16, 2009