Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioblastoma

Glioma

Brain Neoplasms

Gliosarcoma

Astrocytoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Anticonvulsants

Amino Acids

Sirolimus

Erlotinib Hydrochloride

Temsirolimus

MTOR Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Tyrosine

Erlotinib \& sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of erlotinib and 5mg of sirolimus for patients not on concurrent Cytochrome P450, family 3 (CY3PA)-inducing anti-epileptics (EIAEDS) and 400 mg of erlotinib and 10 mg of sirolimus for patients on concurrent EIAEDS.

Erlotinib \& sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of oral erlotinib and 5mg of oral sirolimus for patients not on concurrent CY3PA-inducing anti-epileptics (EIAEDS) and 400 mg of oral erlotinib and 10 mg of oral sirolimus for patients on concurrent EIAEDS.

Erlotinib + sirolimus

David Reardon, MD

Primary objective:

To determine the 6-month progression free survival of patients with recurrent glioblastoma multiforme (GBM) treated with Erlotinib plus Sirolimus.

Secondary objectives:

To further define the safety and tolerability of Erlotinib plus Sirolimus when administered to patients with recurrent GBM; and to evaluate progression free survival, radiographic response and overall survival of patients with recurrent GBM treated with Erlotinib plus Sirolimus.

The primary objective of this study will be to determine the 6-month progression free survival of patients with recurrent GBM treated with Erlotinib plus Sirolimus.

This is an exploratory, single-arm, phase II study designed to assess the anti-tumor activity of a combinatorial regimen consisting of Erlotinib plus Sirolimus among patients with recurrent GBM. The combinatorial regimen of Erlotinib plus Sirolimus is rationally designed to simultaneously inhibit upstream (EGFR) and downstream (mTOR) mediators of Phosphatidylinositide 3-kinase/Protein Kinase B (PI3/AKT) signaling. In a recently completed phase I study, we determined that an EGFR inhibitor (Gefitinib) can be safely combined with Sirolimus at dose levels that are routinely used in the monotherapy setting. Therefore, the primary endpoint of this study is the probability of progression-free survival at 6 months among recurrent GBM patients treated with standard doses of Erlotinib plus Sirolimus. An important secondary objective is to further assess the safety of Erlotinib and Sirolimus for patients with recurrent GBM.

Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme

Phase II Trial of Erlotinib Plus Sirolimus for Patients With Recurrent Malignant Glioma Multiforme

Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or death due to any cause. Progression based on Macdonald criteria is defined as a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration.

Time in weeks from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. Progression based on Macdonald criteria is defined as a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration.

Time in weeks from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Best radiographic response per modified Macdonald criteria. Complete response: disappearance of all enhancing tumor, no new lesions, and no steroids or only maintenance doses. Partial response: ≥ 50% reduction in the products of the perpendicular diameters of all enhancing lesions, no new lesions, \& steroids must be at a stable/decreasing dose. Stable disease: does not qualify for complete or partial response or progression \& is stable clinically. Progression: ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.

Number of participants experiencing a ≥ grade 3, treatment-related, non-hematologic toxicity.

Genentech, Inc.

OSI Pharmaceuticals

Duke University

All adverse events were entered using Common Toxicology Criteria (CTC) v. 3.0, but were converted to CTC v. 4.0 for entry into ClinicalTrials.gov

Tarceva and Rapamycin

Erlotinib \& sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of erlotinib and 5mg of sirolimus for patients not on concurrent CY3PA-inducing anti-epileptics (EIAEDS) and 400 mg of erlotinib and 10 mg of sirolimus for patients on concurrent EIAEDS.

Erlotinib + Sirolimus

Age, Categorical

Age, Customized

Sex: Female, Male

Karnofsky Performance Scores (KPS) range from 0-100 (100=Normal, no complaints; no evidence of disease; 90=Able to carry on normal activity; minor signs or symptoms of disease; 80=Normal activity with efforts; some signs or symptoms of disease; 70=Cares for self; unable to carry on normal activity or to do active work. Scores between intervals are possible.

Karnofsky Performance Scale (KPS)

Received prior bevacizumab

Not receiving EIAEDs

Receiving EIAEDs

Enzyme-inducing anti-epileptic drug (EIAED) status

David A. Reardon, MD

6-month Progression-free Survival (PFS)

Median Progression Free Survival (PFS)

Median Overall Survival (OS)

Complete Response

Partial Response

Stable Disease

Progressive Disease

Not evaluable

Best Radiographic Response

Number of Participants Experiencing a ≥ Grade 3, Treatment-related, Non-hematologic Toxicity.

Erlotinib \& sirolimus on a daily dosing schedule on a 28-day cycle. Dosing was 150 mg of erlotinib and 5mg of sirolimus for patients not on concurrent Cytochrome P450, family 3, subfamily A (CY3PA)-inducing anti-epileptics (EIAEDS) and 400 mg of erlotinib and 10 mg of sirolimus for patients on concurrent EIAEDS.

Overall Study

Epilepsy

Central Nervous System Neoplasms

Nervous System Neoplasms

Oligodendroglioma

Brain Tumor, Adult

Anaplastic Astrocytoma

Anaplastic Oligodendroglioma

Diffuse Astrocytoma

Pilocytic Astrocytoma

Subependymal Giant Cell Astrocytoma

This is an open-label,phase I single-arm dose-escalation and phase II study of continuous, once daily doses of erlotinib administered orally in combination with sirolimus in adult patients with malignant glioma at first, second or third recurrence

In arm I of dose escalation phase,starting dose of erlotinib is 150 mg daily. Starting dose of sirolimus includes a 15 mg loading dose, followed by continuous dosing at 5 mg daily.Dose escalation will proceed according to protocol Phase II of the study was not conducted only Phase I

Timothy F. Cloughesy, MD

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.

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.

Erlotinib and Sirolimus in Treating Patients With Recurrent Malignant Glioma

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

Jonsson Comprehensive Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme	NCT00672243	Glioblastoma Gliosarcoma	Erlotinib + sir...	18 Years -	Duke University
Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme	NCT00672243	Glioblastoma Gliosarcoma	Erlotinib + sir...	18 Years -	Duke University
Erlotinib and Sirolimus in Treating Patients With Recurrent Malignant Glioma	NCT00509431	Brain and Centr...	Erlotinib + Sir...	18 Years -	Jonsson Comprehensive Cancer Center

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