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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed 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.

Official Title
-----------------
Pilot Study of Cisplatin, Etoposide, Bleomycin and Escalating Dose Cyclophosphamide Therapy for Children With High Risk Malignant Germ Cell Tumors

Conditions
-----------------
Childhood Germ Cell Tumor, Extragonadal Germ Cell Tumor

Intervention / Treatment
-----------------
* Biological: bleomycin sulfate
* Biological: filgrastim
* Drug: cisplatin
* Drug: cyclophosphamide
* Drug: etoposide
* Procedure: conventional surgery
* Biological: MESNA


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: combination chemotherapy<br>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. | Biological: bleomycin sulfate<br>* Given IV over 10 minutes. Children ≥ 12 months: 15 units/m2/dose Children < 12 months: 0.5 units/kg/dose Day 1 (Week 1, 4, 7, 10)<br>* Other names: NSC #125066;Biological: filgrastim<br>* Given SQ once daily 5 micrograms/kg/dose Starting on Day 6 (Week 1, 4, 7, 10) Daily until ANC > 5,000/uL<br>* Other names: NSC #614629;Drug: cisplatin<br>* Children ≥ 12 months: Given IV over one hour Dose: 20 mg/m2/dose Days 1-5 (Week 1,4,7,10) Children < 12 months: Given IV over 4 hours, 0.67 mg/kg/dose Days 1-5 (Week 1,4,7,10)<br>* Other names: NSC #119875;Drug: cyclophosphamide<br>* Given IV over 1 hour. Children ≥ 12 months: Level 1: 1.2 g/m2/dose Level 2: 1.8 g/m2/dose Level 3: 2.4 g/m2/dose Children < 12 months: Level 1: 40 mg/kg/dose Level 2: 60 mg/kg/dose Level 3: 80 mg/kg/dose Day 1 (Week 1, 4, 7, 10)<br>* Other names: NSC #026271;Drug: etoposide<br>* Given IV over 1 hour. Children ≥ 12 months: 100 mg/m2/dose Children < 12 months: 3.3 mg/kg/dose Day 1-5 (Week 1, 4, 7, 10)<br>* Other names: NSC #141540;Procedure: conventional surgery<br>* Stage III/IV extragonadal tumors: biopsy followed by a definitive surgical excision after maximal chemotherapy effect, likely after 4 cycles of therapy<br>Biological: MESNA<br>* Given IV or oral. The total daily MESNA dose is equal to at least 80% of the daily CPM dose. The oral dose of MESNA is 2x the IV dose. Day 1 (Week 1,4,7,10) To be given with CPM.<br>* Other names: NSC #113891;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of adding cyclophosphamide to a PEB backbone |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide combined with cisplatin, etoposide, bleomycin (C-PEB) in previously untreated children with high-risk malignant germ cell tumors (MGCT). | 21 days | 
| Estimate the response rate | To estimate the response rate in this group of patients to a regimen of cyclophosphamide combined with cisplatin, etoposide, bleomycin (C-PEB). | Length of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
childhood teratoma, childhood extragonadal germ cell tumor