Combination Chemotherapy in Treating Young Patients With Recurrent or Resistant Malignant Germ Cell Tumors

Study Overview
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Brief Summary
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This phase II trial is studying how well giving combination chemotherapy works in treating young patients with recurrent or resistant malignant germ cell tumors. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the response rate in pediatric patients with recurrent or resistant malignant germ cell tumors (GCT) treated with paclitaxel, ifosfamide, and carboplatin. SECONDARY OBJECTIVES: I. Determine the toxicity of this regimen in these patients. II. To Collect tissue for the tumor bank that will aid in the identification of the biological characteristics of recurrent GCT. OUTLINE: This is a multicenter study. Patients receive paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1 and ifosfamide IV over 1 hour on days 1-5. Beginning on day 6, patients receive filgrastim (G-CSF) subcutaneously or IV once daily until blood count returns to normal. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 5 years.

Official Title
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Treatment of Recurrent or Resistant Pediatric Malignant Germ Cell Tumors With Paclitaxel, Ifosfamide and Carboplatin

Conditions
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Testicular Choriocarcinoma, Testicular Embryonal Carcinoma, Childhood Extracranial Germ Cell Tumor, Childhood Extragonadal Malignant Germ Cell Tumor, Childhood Malignant Ovarian Germ Cell Tumor, Childhood Malignant Testicular Germ Cell Tumor, Ovarian Choriocarcinoma, Ovarian Embryonal Carcinoma, Ovarian Yolk Sac Tumor, Recurrent Childhood Malignant Germ Cell Tumor, Recurrent Malignant Testicular Germ Cell Tumor, Recurrent Ovarian Germ Cell Tumor, Testicular Mixed Choriocarcinoma and Embryonal Carcinoma, Testicular Mixed Choriocarcinoma and Yolk Sac Tumor, Testicular Mixed Embryonal Carcinoma and Yolk Sac Tumor, Testicular Yolk Sac Tumor

Intervention / Treatment
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* Drug: Carboplatin
* Biological: Filgrastim
* Drug: Ifosfamide
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed (at original diagnosis) extracranial germ cell tumor (GCT) containing 1 of the following malignant elements: Yolk sac tumor (endodermal sinus tumor) Choriocarcinoma Embryonal carcinoma Meets 1 of the following disease criteria: Recurrent malignant disease Chemotherapy-resistant disease Relapsed disease Disease refractory to conventional therapy Measurable disease Must have received a prior first-line chemotherapy regimen that included cisplatin Patients with tumor marker (AFP and/or BHCG) elevation alone or bone scan findings alone are not eligible* Patients with immature teratoma (any grade), germinoma, sex-cord stromal tumors, or recurrent GCT previously treated with surgery alone are not eligible Karnofsky performance status (PS) 50-100% (age > 16 years) OR Lansky PS 50-100% (age ≤ 16 years) OR ECOG PS 0-2 Life expectancy ≥ 8 weeks Absolute neutrophil count ≥ 750/mm³ Platelet count ≥ 75,000/mm³ (transfusion independent) Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR creatinine normal based on age/gender, as defined by the following: ≤ 0.4 mg/dL (1 month to < 6 months of age) ≤ 0.5 mg/dL (6 months to < 1 year of age) ≤ 0.6 mg/dL (1 to < 2 years of age) ≤ 0.8 mg/dL (2 to < 6 years of age) ≤ 1.0 mg/dL (6 to < 10 years of age) ≤ 1.2 mg/dL (10 to < 13 years of age) ≤ 1.4 mg/dL (13 to ≥ 16 years of age) (female) ≤ 1.5 mg/dL (13 to < 16 years of age) (male) ≤ 1.7 mg/dL (≥ 16 years of age) (male) Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age ALT < 2.5 times ULN for age Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by gated radionuclide study No dyspnea at rest No exercise intolerance Pulse oximetry > 94% (if there is clinical indication for determination) Patients with seizure disorder are eligible provided they are on non-enzyme inducing anticonvulsants and seizures are well controlled No CNS toxicity > grade 2 No active graft-versus-host disease No allergy to Cremophor EL or castor oil Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other concurrent chemotherapy or immunomodulating agents Recovered from prior chemotherapy, immunotherapy, or radiotherapy At least 1 week since prior growth factors (2 weeks for pegfilgrastim) At least 1 week since prior biologic therapy At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosourea) At least 2 weeks since prior local palliative radiotherapy (i.e., small port) At least 6 months since prior craniospinal radiotherapy or radiotherapy to ≥ 50% of pelvis At least 6 weeks since other prior substantial bone marrow radiotherapy At least 6 months since prior allogeneic stem cell transplantation Concurrent radiotherapy to localized painful lesions allowed provided at least 1 measurable lesion is not irradiated

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, biological therapy)<br>Patients receive paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1 and ifosfamide IV over 1 hour on days 1-5. Beginning on day 6, patients receive filgrastim (G-CSF) subcutaneously or IV once daily until blood count returns to normal. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Biological: Filgrastim<br>* Given IV or subcutaneously<br>* Other names: Tevagrastim;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate as Measured by Response Evaluation Criteria in Solid Tumors (RECIST) Criteria | Patients who demonstrate a PR or CR, as defined below, will be considered as responders. RECIST criteria: CR (complete response) = disappearance of all target lesions, PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions, PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions and SD (stable disease) = small changes that do not meet above criteria. | At baseline (day 1) and after completion of protocol therapy (2 cycles or 42 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients Who Experience at Least One Grade 3 or Higher CTC Version 4 Toxicity. |  | Two cycles of chemotherapy; expected to be 42 days of treatment. |