Arsenic Trioxide, Temozolomide, and Radiation Therapy in Treating Patients With Malignant Glioma That Has Been Removed By Surgery

A Phase I/II Trial of Arsenic Trioxide and Temozolomide in Combination With Radiation Therapy for Patients With Malignant Gliomas

RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide and 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 arsenic trioxide and temozolomide together with radiation therapy after surgery may kill any remaining tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of arsenic trioxide and temozolomide when given together with radiation therapy and to see how well they work in treating patients with malignant glioma that has been removed by surgery.

Study Overview

• Status: Unknown
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: arsenic trioxide; Drug: temozolomide; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of arsenic trioxide and temozolomide when combined with radiotherapy in patients with resected supratentorial malignant glioma. (Phase I)
• Determine the toxicity of this regimen in these patients. (Phase I)

Secondary

• Determine the 6- and 12-month progression-free survival of patients treated with this regimen once an MTD is reached. (Phase II)
• Determine the radiographic response for patients treated with the above regimen. (Phase II)
• Determine the safety of this regimen in these patients. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of arsenic trioxide and temozolomide followed by a phase II study.

• Phase I: Patients undergo radiotherapy once daily 5 days a week and receive oral temozolomide once daily for approximately 6½ weeks. Patients also receive arsenic trioxide IV over 1-4 hours once daily, 5 days a week in week 1 and then twice a week in weeks 2-7. Beginning within 3-5 weeks after completion of radiotherapy, patients receive oral temozolomide once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 1 year in the absence of disease progression and unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of arsenic trioxide and temozolomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients undergo radiotherapy and receive arsenic trioxide and temozolomide as in phase I at the MTD. Patients then receive temozolomide as in phase I for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 1 year.

PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for the phase I portion of this study. A total of 25 patients will be accrued for the phase II portion of this study.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60611-2998
      • Hematology-Oncology Associates of Illinois
    • Naperville, Illinois, United States, 60540
      • Edward Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed supratentorial malignant glioma of 1 of the following types:

  • Glioblastoma multiforme
  • Gliosarcoma
  • Anaplastic astrocytoma
  • Anaplastic oligodendroglioma
  • Anaplastic mixed gliomas
  • Anaplastic gliomas not otherwise specified

• Has undergone surgical resection of tumor

  • Patients with biopsy only are eligible
  • Evaluable or measurable disease following resection of recurrent tumor is not mandated for entry into the study
• No brain metastases

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Life expectancy > 3 months
• WBC > 3,000/mm^3
• Absolute neutrophil count > 2,000/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 10 g/dL (eligibility level for hemoglobin may be reached by transfusion)
• Creatinine ≤ 1.5 mg/dL
• Bilirubin ≤ 2 mg/dL
• Transaminases ≤ 2 times the upper limit of normal
• Serum potassium* > 4.0 mEq/dL
• Serum magnesium* > 1.8 mg/dL NOTE: *If these serum electrolytes are below the specified limits on the baseline laboratory tests, supplemental electrolytes should be administered to bring the serum concentrations to these levels before administering arsenic trioxide
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• No second-degree heart block
• QT interval ≤ 460 msec
• No other malignancy within the past 3 years except curatively treated carcinoma in situ or basal cell carcinoma of the skin
• Patients who cannot undergo MRI are not eligible for this study
• No other serious concurrent infection or other medical illness that would jeopardize the ability of the patient to receive the therapy in this protocol with reasonable safety

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Patients must have recovered from the effects of surgery prior to the start of treatment (10-14 days minimum) and be maintained on a stable corticosteroid regimen for 5 days
• Concurrent glucocorticoid therapy allowed at the smallest effective dose
• Patients must be on non-enzyme-inducing anti-convulsants to minimize any drug reaction
• No prior radiation therapy, chemotherapy, immunotherapy, therapy with biologic agents (including immunotoxins, immunoconjugates, antisense agents, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cells, or gene therapy), or hormonal therapy for their brain tumor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Radiation + temozolomide and arsenic trioxide; Radiation therapy followed by the combination of temozolomide and arsenic trioxide at the maximum tolerated dose determined in phase 1

Drug: arsenic trioxide; Arsenic trioxide administered intravenously at a dose of 0.20mg/kg Daily x 5 week then twice per week; Other Names: ATO; TRISENOX; Drug: temozolomide; Temozolomide administered orally once per day 1 hour prior to radiation therapy at a dose of 75 mg/m2 x 42 days; at a dose of 200mg/m2 for 5 days every cycle (1 cycle = 28 days) after radiation therapy; Other Names: Temodar; TMZ; Radiation: radiation therapy; All patients will receive 5940-6120 cGy of radiation therapy as 28-33 treatments/fractions (180-200 cGy/treatment) depending on whether they receive standard 3-D conformal radiation therapy or intensity modulated radiation therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of arsenic trioxide and temozolomide in combination with radiotherapy	Escalating doses of study drug until dose limiting toxicities are observed.	Toxicity evaluated prior to each treatment cycle
Collect data on the toxicity of arsenic and temozolomide during radiation therapy	Toxicity of this drug combination during radiation therapy will be assessed.	Toxicity evaluated prior to each treatment cycle
Assess serum biomarkers and correlate with tumor tissue	Blood will be drawn at baseline, during radiation therapy, and prior to each cycle of chemotherapy to assess serum biomarkers and correlate with tumor tissue.	At baseline, during radiation therapy, and prior to each cycle of chemotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine progression free survival at 6 and 12 months	Patients will undergo an MRI and neurological evaluation every 6 months while on chemotherapy.	At 6 and 12 months after beginning chemotherapy
Determine time to disease progression	Disease status will be assessed by MRI and neurological examination every 6 months until disease progression.	At 6 and 12 months after beginning chemotherapy
To determine overall survival	Survival status will be evaluated every 6 months while on treatment.	Every 6 months while on treatment
To determine radiographic response to study regimen	Radiographic response will be assessed by MRI every 6 months while on treatment	Every 6 months while on treatment
To collect safety data during the radiation therapy phase	EKG's will be done once per week and labs twice per week during radiation therapy phase to evaluate safety data.	Weekly during radiation therapy
To evaluate a potential surrogate marker for outcomes	Blood will be drawn to analyze methylation patterns as a surrogate marker for outcomes at baseline, before and after radiation therapy, and every 2 cycles during chemotherapy.	At baseline, before and after radiation therapy, and every 2 cycles during chemotherapy

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: CTI BioPharma; Cephalon

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Anticipated): May 1, 2021
• Study Completion (Anticipated): May 1, 2021

Study Registration Dates

• First Submitted: January 10, 2006
• First Submitted That Met QC Criteria: January 10, 2006
• First Posted (Estimate): January 11, 2006

Study Record Updates

• Last Update Posted (Actual): February 25, 2020
• Last Update Submitted That Met QC Criteria: February 24, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor; adult anaplastic astrocytoma; adult anaplastic oligodendroglioma; adult mixed glioma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Arsenic Trioxide
• Other Study ID Numbers: NU 04C1 (Other Identifier: Northwestern University); CDR0000456504 (Registry Identifier: PDQ); STU00007792 (Other Identifier: Northwestern University IRB)