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

Phase 1
21 Years
Not Enrolling
Unspecified Childhood Solid Tumor, Protocol Specific

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Trial Information

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


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

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.

Inclusion Criteria


- 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

- 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


- 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

- Not pregnant or nursing

- Negative pregnancy test required


- No concurrent anticancer therapy

- At least 6 months since bone marrow transplant and no evidence of graft versus host

- 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

- 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

- Recovered from prior radiotherapy

- Stratum 2: No prior central axis radiation

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Victor Aquino, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Simmons Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 1998

Completion Date:

Related Keywords:

  • Unspecified Childhood Solid Tumor, Protocol Specific
  • unspecified childhood solid tumor, protocol specific
  • Neoplasms



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Emory University Hospital - Atlanta Atlanta, Georgia  30322
Johns Hopkins Oncology Center Baltimore, Maryland  21287
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Simmons Cancer Center - Dallas Dallas, Texas  75235-9154
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Children's Hospital of Michigan Detroit, Michigan  48201
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State University of New York - Upstate Medical University Syracuse, New York  13210
Dana-Farber Cancer Institute Boston, Massachusetts  02115
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University of Kansas Medical Center Kansas City, Kansas  66160-7353
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