Tirapazamine Plus Cyclophosphamide in Treating Children With Refractory Solid Tumors

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of tirapazamine plus cyclophosphamide in treating children who have refractory solid tumors. 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.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose and the dose limiting toxicity of tirapazamine when administered with cyclophosphamide as intravenous infusions to children with refractory solid tumors. II. Determine the incidence and severity of other toxicities of tirapazamine and cyclophosphamide in these patients. III. Determine a safe and tolerable dose of tirapazamine administered with cyclophosphamide for a phase II study for the same indications. IV. Determine the pharmacokinetics of tirapazamine in children and adolescents receiving the combination of tirapazamine and cyclophosphamide. V. Determine the preliminary evidence of antitumor activity of tirapazamine and cyclophosphamide. OUTLINE: This is a dose escalation study. Patients receive tirapazamine by 2 hour intravenous infusion (hours 0-2) followed 2 hours later by a 30 minute intravenous infusion of cyclophosphamide. This course is repeated every 3 weeks in patients with partial/complete response or stable disease for a maximum of 1 year. Cohorts of 3-6 patients each are treated at each dose level of tirapazamine. Dose escalation of tirapazamine occurs when 0 of 3 patients or 1 of 6 patients has experienced dose limiting toxicity (DLT). If DLT is experienced in 1 of 3 patients at a given dose level, up to 3 additional patients are treated at that same dose level. If none of the 3 additional patients at that dose level experiences DLT, the dose is escalated. If DLT is experienced in 1 or more of the additional 3 patients, the maximum tolerated dose (MTD) has been exceeded and 3 patients are treated at the next lower dose level (defined as the MTD). A total of six patients are treated at the MTD. If DLT is proved to be neutropenia, patients must then also meet the additional eligibility criteria listed for stratum 2. If neutropenia continues to be the DLT in stratum 2, then additional patients receive subcutaneous filgrastim (granulocyte colony-stimulating factor; G-CSF) beginning 24 hours after cyclophosphamide. A second MTD may be determined for chemotherapy with G-CSF. Patients are followed every 6 months for 4 years, and then annually thereafter.

Official Title
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A Trial of Tirapazamine and Cyclophosphamide in Children With Refractory Solid Tumors

Conditions
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Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: tirapazamine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed solid tumor that is refractory to conventional therapy or for which no effective therapy is known Brain tumors eligible Brainstem gliomas may waive histological verification requirement Neurologic deficits associated with CNS malignancies must be stable for a minimum of 4 weeks prior to study No leukemia Stratum 2 No marrow involvement PATIENT CHARACTERISTICS: Age: 21 and under Performance status: Karnofsky or Lansky 50-100% Life expectancy: At least 8 weeks Absolute neutrophil count at least 1,000/mm3 Platelet count at least 75,000/mm3 Hemoglobin at least 9 g/dL Bilirubin less than 1.5 mg/dL SGPT less than 5 times normal Creatinine normal for age OR creatinine clearance at least 70 mL/min Shortening fraction at least 27% of normal OR ejection fraction greater than 50% of normal Not pregnant or nursing Negative pregnancy test required PRIOR CONCURRENT THERAPY: No concurrent anticancer therapy At least 6 months since bone marrow transplant and no evidence of graft versus host disease At least 1 week since growth factors No concurrent granulocyte colony-stimulating factor Recovered from prior immunotherapy Stratum 2: No prior bone marrow transplantation (with or without total body irradiation) At least 6 weeks since prior nitrosourea At least 2 weeks since other prior myelosuppressive chemotherapy Dexamethasone must be a stable or decreasing dose for 2 weeks prior to study Recovered from prior chemotherapy Stratum 2: No more than 2 prior chemotherapy regimens At least 2 weeks since local palliative radiotherapy (small port) At least 6 months since prior substantial bone marrow radiation (e.g., cross- sectional radiotherapy [greater than 24 Gy], total body irradiation, hemi- pelvic radiotherapy) Recovered from prior radiotherapy Stratum 2: No prior central axis radiation

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>See arm description. | Biological: filgrastim<br> <br> Drug: cyclophosphamide<br> <br> Drug: tirapazamine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified childhood solid tumor, protocol specific