High-dose Chemotherapy for Poor-Prognosis Relapsed Germ-Cell Tumors

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if 2 cycles of high-dose chemotherapy can help to control germ-cell tumors. The first cycle of chemotherapy will include the drugs gemcitabine, docetaxel, melphalan, and carboplatin. The second cycle of chemotherapy will include the drugs ifosfamide, carboplatin, and etoposide. The safety of these drug combinations will also be studied. This is an investigational study. Gemcitabine, docetaxel, melphalan, ifosfamide, carboplatin, and etoposide are all FDA-approved and commercially available for the treatment of germ-cell tumors. Up to 67 patients will be enrolled in this study.

Detailed Description
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The Study Drugs: Carboplatin, melphalan, and ifosfamide are designed to damage the DNA (the genetic material) of cancer cells, which may cause the cancer cells to die. Docetaxel and etoposide are designed to stop the growth of cancer cells, which may cause the cancer cells to die. Gemcitabine is designed to disrupt the growth of cancer cells, which may cause cancer cells to die. It may also help docetaxel, carboplatin, and melphalan to be more effective by stopping tumor cells from repairing damage caused by these drugs. Study Drug Administration: You will receive 2 cycles of high-dose chemotherapy with stem-cell support, 1-2 months apart. Starting on the first day of your hospital stay, you will begin gargling and swishing Caphosol and Glutamine in your mouth 4 times a day. This is done to help prevent mouth and throat sores. On Day 2 of your stay in the hospital, through the CVC, you will receive gemcitabine over 4 hours and docetaxel over 2 hours. On Days 3-5, through the CVC, you will receive gemcitabine over 4 hours, melphalan over 15 minutes, and carboplatin over 2 hours. On Day 6, you will not receive any study drugs. On Day 7, you will receive the stem cells through the CVC over about 30-60 minutes. As part of standard care, you will receive G-CSF (filgrastim) as an injection under your skin daily, starting 5 days after the transplant, until your blood cell levels return to normal. As part of standard mouth care you will be asked to do mouthwashes 4 times a day with caphosol (artificial saliva) and glutamine. Two (2) to 4 weeks after you leave the hospital after Cycle 1, you will receive your second cycle of high-dose chemotherapy. On Days 2-4 of your stay in the hospital, through the CVC, you will receive ifosfamide over 6 hours, etoposide over 2 hours, and carboplatin over 2 hours. On Days 5-6, you will not receive any study drugs. On Day 7, you will receive the stem cells through the CVC over about 30-60 minutes. Study Visits: About 1 month, 100 days, 6 months and 1 year after your second stem cell transplant, the following tests and procedures will be performed: To check the status of the disease, you will have CT scans of your chest, abdomen, and pelvis. Blood (about 3 tablespoons) will be drawn for routine tests. Length of Study: You will be off study after about 1 year from your second transplant. You will be taken off study early if the disease gets worse or if you experience any intolerable side effects. Long-Term Follow-up: If your doctor thinks it is needed, you may have follow-up visits.

Official Title
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High-dose Chemotherapy for Poor-Prognosis Relapsed Germ-Cell Tumors

Conditions
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Testicular Cancer

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: Melphalan
* Drug: Carboplatin
* Drug: Mesna
* Drug: Ifosfamide
* Drug: Etoposide
* Procedure: Stem Cell Transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, age 12 to 65 years. Patients with seminomatous or nonseminomatous germ-cell tumors (GCT) in one of the following groups: A) First relapse or progression or second response with an intermediate or high risk according to the Beyer model. B) Second relapse or beyond. Adequate renal glomerular and tubular function, as defined by estimated serum creatinine clearance >/=50 ml/min and/or serum creatinine </= 1.8 mg/dL, and urinary protein excretion </=500 mg/day. Adequate hepatic function, as defined by ALT and AST </=3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase </=2 x ULN or considered not clinically significant. Adequate pulmonary function with FEV1 (Forced expiratory volume in the first second), FVC (Forced vital capacity) and DLCO (diffusing capacity of the lung for carbon monoxide) >/=50% of predicted, corrected for volume and hemoglobin. Adequate cardiac function with LVEF (left ventricular ejection fraction) >/=40%. No uncontrolled arrhythmias or symptomatic cardiac disease. Zubrod performance status 0-2. A minimum apheresis collection of 5 million CD34+ cells/kg of autologous hematopoietic progenitor cells (AHPC). Written informed consent by patients and/ or their parents or legal guardians. Assent for those patients inclusive of ages 12 to 17. Exclusion Criteria: Growing teratoma syndrome, defined as enlarging tumor masses with normal serum markers during chemotherapy for nonseminomatous GCT. Major surgery within 30 days before the initiation of study treatment Radiotherapy within 21 days prior to initiation of study treatment Prior whole brain irradiation. Patients with active central nervous system (CNS) disease, defined as brain or meningeal metastases that are not in complete remission. Patients with active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/=10,000 copies/mL, or >/= 2,000 IU/mL). Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients who either show chronic hepatitis C or positive hepatitis C serology. Active infection requiring parenteral antibiotics. HIV infection, unless the patient is receiving effective antiretroviral therapy with undetectable viral load and normal CD4 counts Patients who have had a previous autologous or allogeneic stem cell transplant in the previous 12 months. Positive pregnancy test in a female patient of childbearing potential defined as not post menopausal for twelve months or no previous surgical sterilization.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 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: Cycle # 1<br>First Cycle High-dose (HD) chemotherapy followed by stem-cell infusion (PBPC) HD Cycle #1: Gemcitabine/Docetaxel/Melphalan/Carboplatin + PBPC | Drug: Gemcitabine<br>* 1800 mg/m^2 IV over 3 hours on Days -5 to Day -2.<br>* Other names: Gemzar;Drug: Docetaxel<br>* Docetaxel 300 mg/m^2 IV over 2 hours on Day -5.<br>* Other names: Taxotere;Drug: Melphalan<br>* 50 mg/m^2 IV over 15 minutes on Days -4 to Day -2.<br>* Other names: Alkeran;Drug: Carboplatin<br>* Cycle 1: 333 mg/m^2 IV over 2 hours on Days -4 to -2. Cycle #2: 300 mg/m^2 IV over 2 hours on Days -6 to -3.<br>* Other names: Paraplatin;Procedure: Stem Cell Transplant<br>* Stem cell infusion on Day 0.<br>* Other names: PBPC;|
| Experimental: Cycle #2<br>Second Cycle High-dose (HD) chemotherapy followed by stem-cell infusion (PBPC) HD Cycle #2: Ifosfamide/Carboplatin/Etoposide + PBPC | Drug: Carboplatin<br>* Cycle 1: 333 mg/m^2 IV over 2 hours on Days -4 to -2. Cycle #2: 300 mg/m^2 IV over 2 hours on Days -6 to -3.<br>* Other names: Paraplatin;Drug: Mesna<br>* 3,000 mg/m^2 per day in 96-hour continuous infusion, starting 30 minutes prior to the first dose of ifosfamide, on Days -6 to -4.<br>* Other names: Mesnex;Drug: Ifosfamide<br>* 3,000 mg/m^2 IV over 6 hours on Days -6 to -3<br>* Other names: Ifex;Drug: Etoposide<br>* 200 mg/m^2 IV over 3 hours, every 12 hours on Days -6 to -4.<br>* Other names: VePesid;Procedure: Stem Cell Transplant<br>* Stem cell infusion on Day 0.<br>* Other names: PBPC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Event-Free Survival (EFS) | Event-free survival estimated from the first day of High-Dose Course Cycle #1 (Day -6) until tumor progression, relapse, or death from any cause. | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Avastin, Testis, Relapsed Testicular Cancer, Bevacizumab, Anti-VEGF monoclonal antibody, rhuMAb-VEGF, Carboplatin, Paraplatin, Docetaxel, Taxotere, Etoposide, VePesid, Gemcitabine, Gemcitabine Hydrochloride, Gemzar, Ifosfamide, Ifex, Melphalan, Alkeran