Temozolomide Plus Irinotecan in Treating Patients With Recurrent Malignant Glioma

Johns Hopkins Medicine

Status and phase: Completed; Phase 1

Conditions: Brain and Central Nervous System Tumors

Treatments: Drug: irinotecan hydrochloride; Drug: temozolomide

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00006025

CDR0000068037 (Registry Identifier)

NCI-2012-02353 (Registry Identifier)

NABTC-9907

UCLA-0006095

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase I/II trial to study the effectiveness of temozolomide plus irinotecan in treating patients who have recurrent malignant glioma.

Full description

OBJECTIVES:

• Determine the maximum tolerated dose and dose-limiting toxicity of irinotecan when administered with temozolomide in patients with recurrent malignant glioma.
• Determine the safety profile of this regimen in this patient population.
• Determine the efficacy of this treatment regimen as measured by 6-month progression-free survival and objective tumor response in these patients.
• Characterize the pharmacokinetics of this treatment regimen in these patients.
• Determine the antitumor activity of this treatment regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of irinotecan. Patients are stratified according to concurrent enzyme-inducing anti-epileptic drugs (EIAEDs) (e.g., phenytoin, phenobarbital, carbamazepine, or primidone) (yes vs no).

In phase I of the study, patients receive oral temozolomide on days 1-5 and irinotecan IV over 90 minutes on days 1 and 14. Treatment continues every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Patients concurrently on EIAEDs undergo dose escalation of irinotecan. Cohorts of 3 to 6 patients receive escalating doses of irinotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6 patients experience dose-limiting toxicity.

In phase II of the study, patients receive the same treatment as in phase I at the MTD.

Patients are followed every 2 months for 1 year, every 3 months for 1 year, every 4 months for 1 year, every 6 months until progression, and then every 4 months for survival.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for phase I within 10 months and 48 patients will be accrued for phase II within 6-8 months.

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed supratentorial malignant primary glioma of one of the following subtypes:

  • Glioblastoma multiforme
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma
  • Mixed malignant glioma

• Original histology of low-grade glioma allowed if subsequent histological confirmation of malignant glioma

• Measurable recurrent or residual primary disease by MRI

  • Lesions with clearly defined margins

• Evidence of tumor recurrence or progression by MRI or CT scan

• Confirmation of true progressive disease by PET or thallium scan, magnetic resonance spectroscopy, or surgical documentation after prior interstitial brachytherapy or stereotactic radiosurgery

• No more than 3 relapses after prior chemotherapy/cytotoxic therapy (including polifeprosan 20 with carmustine implant) for phase I and no more than 2 relapses for phase II

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10 g/dL

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• SGOT no greater than 2 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL

Cardiovascular:

• No uncontrolled hypertension, unstable angina, or symptomatic congestive heart failure
• No myocardial infarction within the past 6 months
• No serious uncontrolled cardiac arrhythmia

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No mental incapacitation
• HIV negative
• No AIDS-related disease
• No significant ongoing alcoholism or substance abuse
• No severe nonmalignant systemic disease
• No active infection
• No other severe disease that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 1 week since prior interferon or thalidomide and recovered
• No concurrent anticancer immunotherapy
• No concurrent sargramostim (GM-CSF)
• No concurrent prophylactic filgrastim (G-CSF) during first course of study therapy

Chemotherapy:

• See Disease Characteristics
• Recovered from prior chemotherapy
• At least 2 weeks since prior vincristine
• At least 3 weeks since prior procarbazine
• At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosourea)
• Prior radiosensitizers allowed
• No prior temozolomide or irinotecan
• No other concurrent anticancer chemotherapy

Endocrine therapy:

• At least 1 week since prior tamoxifen and recovered

• No concurrent anticancer hormonal therapy

• Phase II:

  • Non-increasing dose of corticosteroids allowed

Radiotherapy:

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy and recovered
• No concurrent anticancer radiotherapy

Surgery:

• See Disease Characteristics
• At least 1-3 weeks since prior surgical resection and recovered

Other:

• At least 1 week since prior noncytotoxic agents (e.g., isotretinoin) and recovered
• Concurrent enzyme-inducing anti-epileptic drugs with or without steroids allowed
• No concurrent valproic acid as a single agent
• No concurrent medication that would preclude study (e.g., nonsteroidal immunosuppressive agents)
• No other concurrent investigational drugs
• No concurrent participation in other clinical study