Clinical trial NCT00003288: Tirapazamine Plus Cyclophosphamide in Treating Children With Refractory Solid Tumors
Official title: A Trial of Tirapazamine and Cyclophosphamide in Children With Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: unspecified childhood solid tumor, protocol specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-09-13
Enrollment: 12
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Comprehensive Cancer Center
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: La Jolla
country: United States
facility: University of California San Diego Cancer Center
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford
state: California
city: Miami
country: United States
facility: Sylvester Cancer Center, University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital - Atlanta
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital, Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins Oncology Center
state: Maryland
city: Boston
country: United States
facility: Floating Hospital for Children
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Syracuse
country: United States
facility: State University of New York - Upstate Medical University
state: New York
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: Simmons Cancer Center - Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
Study officials:
affiliation: Simmons Cancer Center
name: Victor Aquino, MD
role: STUDY_CHAIR
References: