Surgery and Combination Chemotherapy in Treating Children With Extracranial Germ Cell Tumors

Study Overview
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Brief Summary
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This phase III trial is studying surgery followed by combination chemotherapy to see how well it works in treating children with germ cell tumors that are not located in the head. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug, and giving them after surgery, may kill any remaining tumor cells following surgery. It is not yet known whether combination chemotherapy is effective in decreasing the recurrence of childhood germ cell tumors.

Detailed Description
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OBJECTIVES: I. Determine whether children with newly diagnosed low- or intermediate-risk extracranial germ cell tumors (GCTs) can maintain a 3-year event-free survival of at least 92% (for intermediate-risk tumors only) and overall survival of at least 95% (both low-risk and intermediate-risk tumors) after treatment with surgery followed by compressed cisplatin, etoposide, and bleomycin (low-risk disease closed to accrual as of 01/20/10). II. Determine the percentage of patients with stage I ovarian or stage I testicular GCTs for whom chemotherapy can be eliminated. III. Determine the percentage of intermediate-risk patients who require only 3 courses of therapy. IV. Determine the acute toxic effects of compressed therapy in these patients. V. Determine the long-term sequelae in patients treated with this regimen. VI. Determine the number of hospital days and total drug doses required for patients treated with compressed therapy. VII. Compare the number of protocol-directed treatment days used in CCG-8882 vs the number of treatment days used in this study. VIII. Determine the cytogenetic and molecular genetic features in patients treated with this regimen. OUTLINE: Patients are stratified according to disease risk (low vs intermediate). SURGERY: Patients undergo surgical resection. Low-risk disease: Patients with gonadal primaries and no evidence of disease after surgery undergo monitoring for disease progression. Patients who remain disease free receive no further treatment. Patients who have disease progression after surgery receive compressed induction chemotherapy. (closed to accrual as of 01/20/2010) Intermediate-risk disease: After surgery, patients proceed to compressed induction chemotherapy. COMPRESSED INDUCTION CHEMOTHERAPY: Patients receive cisplatin IV over 90 minutes and etoposide IV over 90 minutes on days 1-3 and bleomycin IV over ≥ 10 minutes on day 1. Treatment repeats every 3 weeks for 3 courses (weeks 0, 3, and 6). After completion of compressed induction chemotherapy, patients who have no change in disease status or disease progression are removed from study. Patients with no evidence of disease receive no further therapy. Patients with a partial response or who have abnormal tumor markers proceed to second-look surgery and/or 3 more courses of compressed consolidation chemotherapy. SECOND-LOOK SURGERY: Patients undergo surgical resection of residual tumor. After surgery, patients who are in pathologic complete response and have normal tumor markers receive no further therapy. Patients who remain with a partial response after surgery receive compressed consolidation chemotherapy. COMPRESSED CONSOLIDATION CHEMOTHERAPY: Patients receive cisplatin, etoposide, and bleomycin as in induction chemotherapy in weeks 10, 13, and 16. Patients are followed up monthly for 6 months, every 3 months for 18 months, and then annually for up to 10 years.

Official Title
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A Phase III Study Of Reduced Therapy In The Treatment Of Children With Low And Intermediate Risk Extracranial Germ Cell Tumors

Conditions
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Childhood Embryonal Tumor, Childhood Extracranial Germ Cell Tumor, Childhood Extragonadal Germ Cell Tumor, Childhood Malignant Ovarian Germ Cell Tumor, Childhood Malignant Testicular Germ Cell Tumor, Childhood Teratoma, Ovarian Embryonal Carcinoma, Ovarian Yolk Sac Tumor, Stage II Malignant Testicular Germ Cell Tumor, Stage IIA Ovarian Germ Cell Tumor, Stage IIB Ovarian Germ Cell Tumor, Stage IIC Ovarian Germ Cell Tumor, Stage III Malignant Testicular Germ Cell Tumor, Stage IIIA Ovarian Germ Cell Tumor, Stage IIIB Ovarian Germ Cell Tumor, Stage IIIC Ovarian Germ Cell Tumor, Testicular Choriocarcinoma and Yolk Sac Tumor, Testicular Embryonal Carcinoma

Intervention / Treatment
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* Procedure: conventional surgery
* Drug: cisplatin
* Drug: etoposide
* Biological: bleomycin sulfate
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Extracranial germ cell tumor that contains 1 of the following malignant histologies: NOTE: Mixed germ cell tumors that include mature/immature teratoma are eligible provided 1 of the 3 histologies listed above is also present in the tumor. Yolk sac tumor Embryonal carcinoma Choriocarcinoma Low-risk disease (closed to accrual as of 01/20/10) Stage I gonadal tumors (ovarian and testicular) Must have undergone complete surgical and radiologic staging to exclude the possibility of > stage I disease Intermediate-risk disease Stage II, III, or IV malignant testicular GCT Stage II or III malignant ovarian GCT Stage I or II malignant extragonadal GCT Previously stage I gonadal patients who have relapsed on the low-risk (observation) stratum of this study(closed to accrual as of 01/20/10) Patients with immature teratoma or mature teratoma who relapse with a malignant component No patients with any of the following diagnoses: Stage IV ovarian and stage III-IV extragonadal GCT Intracranial GCT Pure mature or immature teratoma, pure dysgerminoma, or seminoma Patients with a non-germ cell component in their GCT (e.g., primitive neuroectodermal tumors or rhabdomyosarcoma) Alpha-fetoprotein and beta human chorionic gonadotropin tumor markers known If > 5 days have elapsed from the time of obtaining original markers, tumor markers must be repeated before enrollment of low-risk patients and before initiating therapy in intermediate-risk patients (the results of the repeated tumor markers do not have to be known at the time of study enrollment) Must be enrolled within 6 weeks of original diagnostic surgery Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age/gender as follows: ≤ 0.4 mg/dL (for patients 1 to 5 months of age) ≤ 0.5 mg/dL (for patients 6 to 11 months of age) ≤ 0.6 mg/dL (for patients 1 year of age) ≤ 0.8 mg/dL (for patients 2 to 5 years of age) ≤ 1.0 mg/dL (for patients 6 to 9 years of age) ≤ 1.2 mg/dL (for patients 10 to 12 years of age) ≤ 1.4 mg/dL (for female patients ≥ 13 years of age) ≤ 1.5 mg/dL (for male patients 13 to 15 years of age) ≤ 1.7 mg/dL (for male patients ≥ 16 years of age) No prior chemotherapy No prior radiotherapy

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients enrolled with gonadal tumors of stage II or greater or extragonadal tumors of any stage receive cisplatin IV over 90 minutes & etoposide IV over 90 minutes days 1-3 and bleomycin sulfate IV over ≥ 10 minutes day 1. Treatment repeats every 3 weeks, 3 courses (weeks 0,3 & 6). After completion of compressed induction chemotherapy, patients with no change in disease status or disease progression are removed from study. Patients with no evidence of disease receive no further therapy. Patients with a partial response or abnormal tumor markers proceed to conventional surgery (second-look) and/or 3 more courses of compressed consolidation chemotherapy. After surgery, patients with pathologic complete response and have normal tumor markers receive no further therapy. Patients who remain with a partial response after surgery receive compressed consolidation chemotherapy. Patients receive cisplatin, etoposide, and bleomycin as induction chemotherapy in weeks 10,13, & 16. | Procedure: conventional surgery<br> <br> * Other names: surgery, conventional;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: bleomycin sulfate<br>* Given IV<br>* Other names: BLM;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| No Intervention: Arm 2<br>Patients who are enrolled with stage I gonadal tumors receive no further anticancer therapy until evidence of tumor recurrence or the diagnosis of a second malignant neoplasm. Observation only for recurrence or development of an SMN | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival (EFS) | Proportion of patients event free at 3 years following enrollment. Event-free survival is not a primary outcome measure for Arm 2 patients. | 3 Years after enrollment | 
| Overall Survival (OS) | Percentage probability of being alive at 3 years following enrollment. | 3 Years after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days Hospitalized for Patients Who Receive Chemotherapy | Calculated to quantify the treatment cost associated with this regimen. | Up to 126 days after the start of chemotherapy | 
| Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | The number of patients assigned to receive chemotherapy that experience CTC Version 4 grade 3 or higher at any time during protocol therapy | Up to 126 days after the start of chemotherapy |