Clinical trial NCT00316849: Temsirolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme
Official title: A Phase I Study of CCI-779, and Temozolomide in Combination With Radiation Therapy in Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-04-21
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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 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

Primary outcomes:
measure: 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)
timeFrame: Up to 24 weeks
measure: Time to treatment related toxicity as assessed by hematologic measures and CTCAE v3.0
timeFrame: From registration to documentation of toxicity, up to 5 years
measure: Time to treatment related toxicity greater than grade 3, assessed by CTCAE v3.0
timeFrame: From registration to documentation of toxicity, up to 5 years
measure: Time to progression
timeFrame: From registration to documentation of progression, up to 5 years
measure: Time to treatment failure
timeFrame: From registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by patient, up to 5 years
measure: 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
timeFrame: Up to 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Clive
country: United States
facility: Medical Oncology and Hematology Associates-West Des Moines
state: Iowa
city: Des Moines
country: United States
facility: Mercy Capitol
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Iowa Oncology Research Association CCOP
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates-Des Moines
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates
state: Iowa
city: Des Moines
country: United States
facility: Mercy Medical Center - Des Moines
state: Iowa
city: Des Moines
country: United States
facility: Iowa Lutheran Hospital
state: Iowa
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Grand Forks
country: United States
facility: Altru Cancer Center
state: North Dakota
Study officials:
affiliation: North Central Cancer Treatment Group
name: Jann Sarkaria
role: PRINCIPAL_INVESTIGATOR
References: