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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00316849
First received: April 19, 2006
Last updated: April 9, 2013
Last verified: April 2013
  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: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Time to progression [ Time Frame: From registration to documentation of progression, up to 5 years ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
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
Iowa Lutheran Hospital
Des Moines, Iowa, United States, 50316
Mercy Capitol
Des Moines, Iowa, United States, 50307
Mercy Medical Center - Des Moines
Des Moines, Iowa, United States, 50314
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
Investigators
Principal Investigator: Jann Sarkaria North Central Cancer Treatment Group
  More Information

No publications provided

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
Study First Received: April 19, 2006
Last Updated: April 9, 2013
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on August 21, 2014