Trial Information

Sequential High-Dose Chemotherapy Combining Two Mobilization and Cyto-Reductive Treatments Followed by Three High-Dose Chemotherapy Regimens Supported by Autologous Stem Cell Transplantation

The treatment is designed for relapsed poor prognosis patients with testicular or
extra-gonadal GCTs previously treated with cisplatin-containing regimens.

Poor prognosis patients are defined as either relapsed/refractory patients more than one
month after cisplatin administration, whether in the course of first-line CT or in that of
salvage treatment, or patients who showed evidence of progression after at least 2 lines of
cisplatin-containing CT (i.e., BEP and VeIP).

Eligibility requirements includes the following criteria: age >18 years and < 65,
performance status < 3, histologically or biologically documented GCTs, testicular,
abdominal or mediastinal tumors, measurable or evaluable disease, life expectancy > 3
months, normal cardiac, liver, and renal function tests, absence of infection, HIV negative
test, and signed informed consent. All patients had to have been previously treated with at
least one line of a cisplatin-containing regimen and were included if they were refractory
after one or two line(s) of cisplatin-based CT, or had relapsed after two lines of a
cisplatin-based CT.

Non-inclusion criteria are: patients with 'BEYER' score > 3, growing teratoma syndrome,
possibility of being treated with a conventional cisplatin-based CT, and previous HD-CT
regimen.

During the initial evaluation: each patient must have a clinical evaluation that includes
measurements of tumor marker levels, and an imaging work up. The tumor marker levels are
determined every week during all the sequence of treatment (normal level < 10 ng/ml for
alpha-foetoprotein and < 2 mU/mL for HCG). The tumor mass is measured after the first two
cycles of induction/mobilization therapy and at the end of the treatment.

Chemotherapy, patients are scheduled to receive 2 courses of front-line mobilization CT
followed by 3 HD-CT supported by PBSCT. The front-line treatment consists in a combination
of epirubicin, (100 mg/m² in a 30-minute infusion), and paclitaxel (Taxol, 250 mg/m² given
in a 3-hour infusion), administered both on days 1 and 14. These 2 cycles are supported by
filgrastim (Neupogen), 5 µg/kg, twice a day from days 2 and 15, respectively, until
apheresis performed on days 10-13 and 24-27. Apheresis is stopped when at least 9 x 106
CD34+ cells/Kg of BW are obtained for the 3 grafts. A third cycle is permitted if the number
of CD34+ cells is not achieved after the first 2 cycles, provided the patient was responsive
to CT, or for any reason decided upon by the investigator.

The first HD-CT regimen consists in an association of thiotepa, 720 mg/m² and taxol, 360
mg/m², both administered in a continuous infusion over 3 days (D34 to D36). The first pack
of CD34+ cells is infused on day 39. The second and the third courses (ICE) scheduled on
days 62-66 and 90-94 respectively, consist in a combination of etoposide (150 mg/m² twice a
day, in a 2-hour infusion, for 5 days), ifosfamide (2 400 mg/m²/d in a 3-hour infusion, for
5 days) supported by sodium mercaptoethanesulfonate (mesna, in a 30-minute infusion every 3
hours, during a 12-hour period, initiated at the same time as the ifosfamide infusion), and
carboplatin (AUC 4/d, in a 6-hour infusion, for 5 days). Infusion of PBSCs is planned on
days 71 and 99. During the 3 high-dose therapies, G-CSF is administered at a daily dose of
5µg/kg, from the day of PBSC infusion until PMN recovery (i.e., PMN > 1.5 x 109/L). Each of
these ICE regimens is delayed if the PMN level is less than 1.5 x 109/L and/or the platelet
level less than 100 x 109/L.

Toxicity and response to therapy are evaluated according to the ECOG and WHO criteria. The
duration of response is calculated from the date of documented response to the date of
progression. The duration of PFS and OS are calculated from the date of inclusion to the
date of progression, or death if no progression (PFS), and the date of death (OS), according
to Kaplan-Meier's method. Survival curves are established according to the classification
proposed by BEYER et al. Progression, death from treatment and withdrawal from protocol for
whatever reason are considered as treatment failures. Whenever possible, patients in
clinical partial response (PR) with normal tumor markers (PRm-) will be proposed for
surgery of residual masses at the end of the whole procedure. Sequential procedures are
proposed in the case of multiple metastatic sites. If surgery is complete and the
pathological examination does not show any viable tumor, patients will be considered as
complete responders. If surgery is complete and the pathological examination showed
persistent viable tumor, they will be considered as surgical complete response.