Combination Chemotherapy in Treating Children With Newly Diagnosed Malignant Germ Cell Tumors

Children's Oncology Group

Status: Completed

Conditions: Extragonadal Germ Cell Tumor; Childhood Germ Cell Tumor

Treatments: Biological: MESNA; Procedure: conventional surgery; Drug: cyclophosphamide; Drug: cisplatin; Drug: etoposide; Biological: bleomycin sulfate; Biological: filgrastim

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00066482

CDR0000316244 (Other Identifier)

AGCT01P1

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 trial to study the effect on the body of combining cyclophosphamide with cisplatin, etoposide, and bleomycin in treating children who have newly diagnosed malignant germ cell tumors that are not in the brain and gonads.

Full description

OBJECTIVES:

• Determine the maximum tolerated dose and toxicity profile of cyclophosphamide in combination with bleomycin, etoposide, and cisplatin in pediatric patients with newly diagnosed high-risk extracranial, extragonadal malignant germ cell tumors.
• Determine the response rate in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter, dose-escalation study of cyclophosphamide.

• Induction therapy: Patients receive bleomycin IV over 10-20 minutes on day 1, etoposide IV over 1 hour and cisplatin IV over 4 hours on days 1-5, and cyclophosphamide IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of cyclophosphamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Patients are evaluated after 4 courses of therapy. Patients with partial response or stable disease undergo second-look surgery, receive 2 more courses of induction therapy, and are then re-evaluated. Patients who do not achieve complete response (CR) after a total of 6 courses may undergo a third surgery. Patients who still have tumor that cannot be removed are removed from study therapy. Patients who achieve a CR at anytime are followed.

Patients are followed monthly for 1 year, every 6 months for 1 year, and then annually for 3 years.

PROJECTED ACCRUAL: A total of 6-18 patients will be accrued for this study within 1.3 years.

Enrollment: 19 patients

Sex: All

Ages: Under 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed extracranial germ cell tumors, including 1 of the following types:

  • Yolk sac carcinoma (endodermal sinus tumor)
  • Embryonal carcinoma
  • Choriocarcinoma
  • Teratoma with mixed malignant elements (malignant teratoma)

• High-risk disease, defined as stage III or IV extragonadal germ cell tumors

• Must be enrolled on study within 21 days of diagnostic surgical procedure

PATIENT CHARACTERISTICS:

Age

• 21 and under (at original diagnosis)

Performance status

• ECOG 0-2

  • Karnofsky 50-100% (in patients over 16 years of age)
  • Lansky 50-100% (in patients 16 years of age and under)

Life expectancy

• At least 2 months

Hematopoietic

• Absolute neutrophil count at least 1,000/mm^3
• Platelet count at least 100,000/mm^3 (transfusion independent)
• Hemoglobin at least 10.0 g/dL (transfusion allowed)

Hepatic

• Not specified

Renal

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min OR

• Creatinine based on age as follows:

  • No greater than 0.8 mg/dL (5 years and under)
  • No greater than 1.0 mg/dL (6-10 years)
  • No greater than 1.2 mg/dL (11-15 years)
  • No greater than 1.5 mg/dL (over 15 years)

Pulmonary

• FEV_1/FVC greater than 60% OR

• Children who are uncooperative must meet all of the following criteria:

  • No dyspnea at rest
  • No exercise intolerance
  • Pulse oximetry greater than 94%

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• See Disease Characteristics

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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19 participants in 1 patient group

combination chemotherapy

Experimental group

Description:

Induction therapy: bleomycin sulfate IV over 10-20 minutes on day 1, etoposide IV over 1 hour and cisplatin IV over 4 hours on days 1-5, and cyclophosphamide IV over 1 hour on day 1. MESNA \& Filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. 6 patients receive escalating doses of cyclophosphamide until the maximum tolerated dose (MTD) is determined. Evaluated after 4 courses of therapy. Partial response or stable disease undergo second-look conventional surgery \& receive 2 more courses of induction therapy then re-evaluated. Those who do not achieve complete response (CR) after a total of 6 courses may undergo a third conventional surgery. Tumor that cannot be removed are removed from study therapy. Achievement of a CR at anytime are followed monthly for 1 year, every 6 months for 1 year, and then annually for 3 years.

Treatment:

Biological: bleomycin sulfate

Drug: cyclophosphamide

Procedure: conventional surgery

Biological: filgrastim

Drug: cisplatin

Biological: MESNA

Drug: etoposide