Temsirolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme - Full Text View

Sponsor:	North Central Cancer Treatment Group
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00316849

Purpose

RATIONALE: 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.

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.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: temozolomide Drug: temsirolimus Other: pharmacological study Procedure: adjuvant therapy Radiation: 3-dimensional conformal radiation therapy Radiation: intensity-modulated radiation therapy	Phase I

Study Type:	Interventional
Study Design:	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:

MedlinePlus related topics: Cancer

Drug Information available for: Sirolimus Temozolomide Everolimus CCI 779

U.S. FDA Resources

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

Primary Outcome Measures:

Tolerability (maximum tolerated dose) [ Designated as safety issue: Yes ]
Time to treatment related toxicity as assessed by hematologic measures and CTC criteria [ Designated as safety issue: Yes ]
Time to treatment related ≥ grade 3 toxicity [ Designated as safety issue: Yes ]
Time to progression [ Designated as safety issue: No ]
Time to treatment failure [ Designated as safety issue: No ]
Early response as assessed by automated morphological MRI change detector and physiological MRI techniques, including diffusion-weighted imaging, perfusion-weighted imaging, and chemical shift imaging [ Designated as safety issue: No ]

Secondary Outcome Measures:

Inhibition status of mTOR signaling pathways in peripheral blood mononuclear cells [ Designated as safety issue: No ]
Potential pharmacokinetic interactions [ Designated as safety issue: No ]
Correlate survival, progression-free survival, and response with pre-treatment tumor tissue molecular markers [ Designated as safety issue: No ]

Estimated Enrollment:	56
Study Start Date:	May 2006
Estimated Primary Completion Date:	April 2008 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

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

Determine the inhibition status of mTOR signaling pathways in peripheral blood mononuclear cells in patients treated with this regimen.
Identify potential pharmacokinetic interactions between temozolomide and temsirolimus.
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.

PROJECTED ACCRUAL: A total of 46 patients will be accrued for this study.

Eligibility

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

Criteria

DISEASE CHARACTERISTICS:

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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
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
No concurrent combination antiretroviral therapy for HIV-positive patients

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00316849

Locations

United States, Florida
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

North Central Cancer Treatment Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Jann N. Sarkaria, MD	Mayo Clinic
Investigator:	Evanthia Galanis, MD	Mayo Clinic
Study Chair:	Jonathan B. Ashman, MD	Mayo Clinic
Investigator:	Jan C. Buckner, MD	Mayo Clinic
Investigator:	Paul D. Brown, MD	Mayo Clinic
Investigator:	Joon H. Uhm, MD	Mayo Clinic
Investigator:	Kurt A. Jaeckle, MD	Mayo Clinic
Investigator:	Bradley J. Erickson, MD, PhD	Mayo Clinic

More Information

Additional Information:

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

Publications:

Sarkaria JN, Galanis E, Wu W, Dietz AB, Kaufmann TJ, Gustafson MP, Brown PD, Uhm J, Rao RD, Doyle L, Giannini C, Jaeckle K, Buckner JC. Combination of temsirolimus (CCI-779) with chemo-radiation in newly diagnosed GBM (NCCTG trial N027D) is associated with increased infectious risks. Clin Cancer Res. 2010 Oct 4; [Epub ahead of print]

Sarkaria JN, Galanis E, Wu W, et al.: NCCTG phase I trial of temsirolimus (CCI-779) and temozolomide (TMZ) in combination with radiation therapy (RT) in newly diagnosed glioblastoma multiforme (GBM) patients. [Abstract] J Clin Oncol 27 (Suppl 15): A-2019, 2009.

ClinicalTrials.gov Identifier:	NCT00316849 History of Changes
Other Study ID Numbers:	CDR0000467232, NCCTG-N027D
Study First Received:	April 19, 2006
Last Updated:	October 8, 2010
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

adult glioblastoma
adult giant cell glioblastoma
adult gliosarcoma

Additional relevant MeSH terms:

Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Sirolimus

Everolimus
Temozolomide
Dacarbazine
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on February 09, 2012