High-dose Chemotherapy With Autologous Stem Cell Transplantation in Poor Prognosis Germ-cell Tumors: TAXIF II
Condition: Testicular Neoplasms
MeSH terms: Testicular Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      High-dose chemotherapy (HD-CT) is able to circumvent platinum-resistance of
      resistant/refractory germ-cell tumors (GCTs), but expectancy of cure remains low. New
      strategies are needed with new drugs and a sequential approach.

      Patients with relapsed (but not absolutely refractory to Cisplatinum-based chemotherapy)
      poor-prognosis GCTs are scheduled to receive 2 cycles combining epirubicin and paclitaxel
      followed by 3 consecutive HD-CT supported by stem cell transplantation. One course will
      combine Taxol, 360 mg/m² + thiotepa, 720 mg/m², followed by two ICE regimens (Ifosfamide, 12
      g/m², carboplatin, AUC 20, etoposide, 1500 mg/m²).

      This phase II study is designed as a Gehan method. The main objective of the study is the
      complete response rate. With this aim in view, it is planned to enroll in its first step 14
      patients to insure that if no complete response (CR) is noticed, study would be stopped for
      inefficacy (i.e., a CR rate lower than 20%). If one or more CR are noticed, protocol
      specified that up to 45 patients will be included in order to reduce the confidence interval
      (CI) of the CR rate. Secondary objectives are the overall response rate (RR), the overall
      survival (OS) and the progression-free survival (PFS) rates, toxicity and toxic death rate.
      The statistical analysis is done in terms of intent-to-treat.
    

Detailed description: 
      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.
    

Intervention name(s): epirubicin; high-dose and autologous stem cell transplantation; paclitaxel; etoposide; ifosfamide; carboplatin
Intervention type(s): Drug; Procedure; Drug; Drug; Drug; Drug
Intervention description(s): epirubicin; high-dose and autologous stem cell transplantation; paclitaxel; etoposide; ifosfamide; carboplatin
Intervention MeSH terms: Paclitaxel; Etoposide; Carboplatin; Epirubicin; Ifosfamide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: High-dose with autologous germ-cell tumors