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Temsirolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00316849
First Posted: April 21, 2006
Last Update Posted: April 10, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
This phase I trial is studying the side effects and best dose of temsirolimus when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma multiforme. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving temsirolimus together with temozolomide and radiation therapy may kill more tumor cells.

Condition Intervention Phase
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Other: pharmacological study Procedure: adjuvant therapy Radiation: 3-dimensional conformal radiation therapy Radiation: intensity-modulated radiation therapy Drug: temsirolimus Drug: temozolomide Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of CCI-779, and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximally tolerated dose (MTD), determined according to dose-limiting toxicities (DLTs) graded using Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) [ Time Frame: Up to 24 weeks ]
  • Time to treatment related toxicity as assessed by hematologic measures and CTCAE v3.0 [ Time Frame: From registration to documentation of toxicity, up to 5 years ]
  • Time to treatment related toxicity greater than grade 3, assessed by CTCAE v3.0 [ Time Frame: From registration to documentation of toxicity, up to 5 years ]
  • Time to progression [ Time Frame: From registration to documentation of progression, up to 5 years ]
  • Time to treatment failure [ Time Frame: From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by patient, up to 5 years ]
    Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals.The effect of dose and ancillary dichotomized covariates such as gender or age (<50 years versus 50+ years) will be explored using logrank testing involving one covariate at a time.

  • Response to therapy associated with patient outcome, as assessed by automated morphological MRI change detector and physiological MRI techniques, including diffusion-weighted imaging, perfusion-weighted imaging, and chemical shift imaging [ Time Frame: Up to 5 years ]
    Logistic regression and Cox proportional hazards models will be used to determine the association between changes in tumor volume (as assessed by a software package) and tumor response and 12-month survival (logistic regression) and progression-free and overall survival (Cox proportional hazards models).


Enrollment: 56
Study Start Date: May 2006
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (temsirolimus, temozolomide, radiation therapy)
GROUP 1: (temsirolimus with radiation and temozolomide) Patients receive temsirolimus IV over 30 minutes once weekly. Beginning 7-10 days later, patients also receive oral temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days a week, for 6 weeks. Patients with stable or responding disease proceed to adjuvant therapy. GROUP 2: (radiation and temozolomide) Patients receive oral temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days a week, for 6 weeks. Patients with stable or responding disease proceed to adjuvant therapy. ADJUVANT THERAPY: Beginning 4-6 weeks after the completion of chemoradiotherapy patients receive oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Other: pharmacological study
Other Name: pharmacological studies
Procedure: adjuvant therapy Radiation: 3-dimensional conformal radiation therapy
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: intensity-modulated radiation therapy
Other Name: IMRT
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
Drug: temozolomide
Given orally
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of temsirolimus when administered with temozolomide in combination with radiotherapy followed by adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

II. Assess and describe the adverse events associated with this regimen in these patients.

III. Evaluate the early response to therapy in these patients using an automated morphological MRI change detector and physiological MRI techniques, including diffusion-weighted imaging, perfusion-weighted imaging, and chemical shift imaging.

SECONDARY OBJECTIVES:

I. Determine the inhibition status of mTOR signaling pathways in peripheral blood mononuclear cells in patients treated with this regimen.

II. Identify potential pharmacokinetic interactions between temozolomide and temsirolimus.

III. Correlate, preliminarily, survival, progression-free survival, and response with pre-treatment tumor tissue molecular markers in these patients.

OUTLINE: This is a multicenter, dose-escalation study of temsirolimus. Patients are assigned to 1 of 2 treatment groups.

GROUP 1: (temsirolimus with radiation and temozolomide) Patients receive temsirolimus IV over 30 minutes once weekly. Beginning 7-10 days later, patients also receive oral temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days a week, for 6 weeks. Patients are evaluated 4-6 weeks after completion of chemoradiotherapy. Patients with stable or responding disease proceed to adjuvant therapy. Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity. At least 6 patients are treated at the MTD.

GROUP 2: (radiation and temozolomide) Patients receive oral temozolomide daily and undergo concurrent 3-D conformal radiotherapy or intensity-modulated radiotherapy once daily, 5 days a week, for 6 weeks. Patients are evaluated 4-6 weeks after completion of chemoradiotherapy. Patients with stable or responding disease proceed to adjuvant therapy.

ADJUVANT THERAPY: Beginning 4-6 weeks after the completion of chemoradiotherapy patients receive oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood collection for immune monitoring and translational/pharmacologic studies. After completion of study treatment, patients are followed periodically for 5 years.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed glioblastoma multiforme (GBM)

    • Gliosarcoma and other grade 4 astrocytoma variants (e.g., giant cell glioblastoma) allowed
  • Newly diagnosed disease

    • Has undergone surgical resection or biopsy of the tumor at least 1 week but no more than 6 weeks ago
  • ECOG performance status 0-2
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Hemoglobin ≥ 9.0 g/dL
  • Platelet count ≥ 100,000/mm^3
  • Total bilirubin ≤ 2.5 times upper limit of normal (ULN)
  • Cholesterol < 350 mg/dL
  • Triglycerides < 400 mg/dL
  • AST ≤ 2.5 times ULN
  • Creatinine ≤ 1.5 times ULN
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No history of allergy or intolerance to dacarbazine
  • No ongoing or active infection
  • No symptomatic congestive heart failure
  • No unstable angina pectoris
  • No cardiac arrhythmia
  • No psychiatric illness or social situation that would preclude study compliance
  • No other uncontrolled illness
  • No gastrointestinal tract disease affecting ability to take oral medication or requiring IV alimentation
  • No significant traumatic injury within the past 21 days
  • No active, uncontrolled peptic ulcer disease
  • No other active cancers requiring therapy
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • Willing and able to comply with antibiotic prophylaxis with either trimethoprim/sulfamethoxazole (daily or 3 times per week) or monthly IV pentamidine combined with daily levofloxacin
  • No prior chemotherapy for any brain tumor
  • No prior temozolomide or mTOR inhibitor therapies
  • No prior cranial radiotherapy
  • More than 21 days since prior major surgery (excluding neurosurgical biopsy or resection of GBM)
  • No prior surgical procedures affecting absorption
  • No concurrent enzyme-inducing anticonvulsants, including any of the following:

    • Carbamazepine
    • Phenytoin
    • Phenobarbital
    • Primidone
  • No other concurrent investigational agents
  • Not receiving warfarin prior to study registration

    • Concurrent warfarin allowed if patients develop an indication for it while enrolled on the protocol
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00316849


Locations
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Iowa
Medical Oncology and Hematology Associates-West Des Moines
Clive, Iowa, United States, 50325
Mercy Capitol
Des Moines, Iowa, United States, 50307
Iowa Methodist Medical Center
Des Moines, Iowa, United States, 50309
Iowa Oncology Research Association CCOP
Des Moines, Iowa, United States, 50309
Medical Oncology and Hematology Associates-Des Moines
Des Moines, Iowa, United States, 50309
Medical Oncology and Hematology Associates
Des Moines, Iowa, United States, 50314
Mercy Medical Center - Des Moines
Des Moines, Iowa, United States, 50314
Iowa Lutheran Hospital
Des Moines, Iowa, United States, 50316
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, North Dakota
Altru Cancer Center
Grand Forks, North Dakota, United States, 58201
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jann Sarkaria North Central Cancer Treatment Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00316849     History of Changes
Other Study ID Numbers: NCI-2009-00642
N027D
CDR0000467232
NCCTG-N027D
U10CA025224 ( U.S. NIH Grant/Contract )
First Submitted: April 19, 2006
First Posted: April 21, 2006
Last Update Posted: April 10, 2013
Last Verified: April 2013

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Everolimus
Sirolimus
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents