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

Adult Glioblastoma Clinical Trial

Official title:

A Phase I Study of CCI-779, and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00316849
• Other study ID #: NCI-2009-00642
• Secondary ID: N027DCDR00004672
• Status: Completed
• Phase: Phase 1
• First received: April 19, 2006
• Last updated: April 9, 2013
• Start date: May 2006

Study information

• Verified date: April 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Glioblastoma
• Gliosarcoma

Intervention

Other:
• pharmacological study

Procedure:
• adjuvant therapy

Radiation:
• 3-dimensional conformal radiation therapy

• intensity-modulated radiation therapy

Drug:
• temsirolimus
Given IV
• temozolomide
Given orally

Locations

Country	Name	City	State
United States	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa
United States	Iowa Lutheran Hospital	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Iowa Oncology Research Association CCOP	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Mercy Capitol	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Altru Cancer Center	Grand Forks	North Dakota
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)		Up to 24 weeks	Yes
Primary	Time to treatment related toxicity as assessed by hematologic measures and CTCAE v3.0		From registration to documentation of toxicity, up to 5 years	Yes
Primary	Time to treatment related toxicity greater than grade 3, assessed by CTCAE v3.0		From registration to documentation of toxicity, up to 5 years	Yes
Primary	Time to progression		From registration to documentation of progression, up to 5 years	No
Primary	Time to treatment failure	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.	From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by patient, up to 5 years	No
Primary	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	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).	Up to 5 years	No