Dose Intensification Study in Refractory Germ Cell Tumors With Relapse and Bad Prognosis

Study Overview
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Brief Summary
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Not randomized, multicentric, national phase II trial estimating the efficacy of an intensification protocol in patients with refractory germ cell tumors with relapse and bad prognosis. Treatment consists in two Paclitaxel and Ifosfamide intensification cycles followed by three Carboplatine and Etoposide high dose cycles. The point is the individual Carboplatine adjustment to take into account inter-individual patients variability. This adaptation allow to control each patient plasmatic exposition to avoid both inacceptable toxicities (such as ear toxicity) and a low exposition losing then the benefit of this high dose protocol.

Official Title
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Dose Intensification Phase II Study in Refractory Germ Cell Tumors With Relapse and Bad Prognosis. TICE Protocol : Paclitaxel and Ifosfamide Followed by Carboplatine and Etoposide Intensification With Individual Carboplatine Dose Adjustment.

Conditions
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Germ Cell Tumors

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Ifosfamide
* Drug: Carboplatine
* Drug: Etoposide
* Procedure: cytapheresis + transfusion of autologous peripheral blood stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Germ cell tumors whatever histology (TGNS or séminoma : TGS ) whose origin is gonadic, extra-gonadic, retro-peritoneal or primitive mediastinal Age >= 18 years old Histologically confirmed germ cell tumor (TGS) or biomarkers rate allowing to diagnose germ cell tumor without histology (TGNS) Relapse or progression with bad prognosis in 1st treatment line : One of these criteria valid point 4 : progression after incomplete clinical response (Stable disease) to a Cisplatin basis chemotherapy; biomarker progression 4 weeks following the last chemotherapy cycle administration; progression during the first treatment line without obtention of at least stable disease; primitive mediastinal origin in first relapse. TGNS or TGS in relapse after 2 treatment lines Disease progression ( previous points 4 or 5) documented by : tumors biomarkers increase (AFP and/or HCG) if no, a biopsy is needed to confirm presence of tumors active cells ECOG Performance status 0-2 Biological Function : Neutrophils >= 1500/mm3, Platelets >= 150.000/mm3 ; normal creatinine (or clearance >= 50 ml/mn) ; SGOT, SGPT <= 2,5N (or 5N if hepatic metastases), Bilirubin < 1,5N Cardiac Functions (FEV >= 50%), Respiratory Functions , neurological Functions compatibles with high dose chemotherapy administration Absence of previous intensification Patient Information and Informed consent signature HIV and B and C hepatitis negative serologies Negative pregnancy test for women with reproductive potential and adequate contraception before study entry Patient affiliated to social security system Exclusion Criteria: Patients whose diagnosis of relapse was not confirmed by an anatomopathological examination or by an increase of tumors markers Primitive encephalic germ cell tumors Germ cell tumors in relapse with favorable factors of treatment response to conventional chemotherapy (RC sustainable after Cisplatin): prior cRC or incomplete clinical response but with normalization of markers and testicular origin Growing Teratoma lesions Patients with HIV infection, hepatitis B and C Patients with symptomatic brain metastases despite appropriate corticosteroid treatment Associated pathology may prevent the patient to receive treatment, creatinine clearance ≤ 50 mL / min (calculated by Cockcroft-Gault) FEV <50% History of cancer (except basal cell epithelioma skin cancer) in the 3 years preceding the entry into the trial Patient already included in another clinical trial involving an experimental molecule Pregnant or breast feeding women Persons without liberty or under guardianship, Geographical, social or psychological conditions that do not permit compliance with protocol

Ages Eligible for Study
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Minimum Age: 18 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

| Intervention/Treatment |
| --- |
|Drug: Paclitaxel|200mg/m2 for 3 hours at Cycle 1 day 1 and Cycle 2 day 1 with 14 days between cycles|
|Drug: Ifosfamide|2g/m²/day in 1 liter of G5 for 3 hours at Cycle 1 and Cycle 2 from day 2 to day 4 with 14 days between cycles|
|Drug: Carboplatine|From cycle 3 to cycle 5 : Carboplatine is administered with AUC = 24 mg/mL x min from Day 1 to Day 3. Day 3 Carboplatine dose is calculated taking into account real creatinine clearance defined at day 1 for each patient|
|Drug: Etoposide|From Cycle 3 to cycle 5, 400mg/m2/day from day 1 to day 3|
|Procedure: cytapheresis + transfusion of autologous peripheral blood stem cells|Cytapheresis occured between day 11 and day 13 of the 2 first cycle (Taxol® +Holoxan®). Cytapheresis total objective is 9X106 CD34+/kg of patient weight. At cycle 3, 4 and 5 at day 5 : Re-injection of stem cells (1/3 with minimum 2.106 CD34/kg) 48 hours after chemotherapy end|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate(by chemotherapy or chemotherapy + surgery), pathological complete response rate. |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | 8 years | 
| Time to progression |  | 8 years | 
| Toxicity |  | 6 months | 
| To find a predictive value for Cystatin C as a biomarker of renal function to avoid next to follow plasmatic concentrations to adapt Carboplatine dose in TICE protocol. |  | 4 years | 
| Etoposide pharmacokinetics (in particular inter-individual variability of Etoposide plasmatic concentrations AUC in such patients |  | 4 years | 
| Genetic polymorphisms involved in response and safety treatments |  | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory, germ cell tumors, relapse, bad prognosis, Refractory germ cell tumors with relapse and bad prognosis