| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| progressive or recurrent germ cell tumor (measurable or non-measurable) |
|
| E.1.1.1 | Medical condition in easily understood language |
| progressive or recurrent germ cell tumor (measurable or non-measurable) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10043338 |
| E.1.2 | Term | Testicular malignant germ cell tumor NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the overall survival in patients treated with conventional-dose chemotherapy using the TIP regimen with high-dose chemotherapy (HDCT) plus ASCT using the TI-CE regimen as initial salvage treatment of patients with relapsed or refractory GCT. |
|
| E.2.2 | Secondary objectives of the trial |
- To compare PFS of patients treated with initial salvage HDCT with TI-CE vs. initial salvage CDCT with TIP.
- To compare FRR of patients treated with initial salvage HDCT with TI-CE vs. initial salvage CDCT with TIP
- To compare toxicity, including treatment-related mortality, associated with high-dose chemotherapy and ASCT using TI-CE compared with conventional-dose chemotherapy using TIP as initial salvage treatment for patients with relapsed or refractory GCT
- To prospectively evaluate the IPFSG scoring system as a predictor of outcome to initial salvage therapy in patients with relapsed or refractory GCT. In this trial, randomization will be stratified by a modification of their IPFSG category and we will prospectively evaluate whether or not actual outcomes vary by risk group in the appropriate manner (low risk patients have higher OS than high-risk group).
- To evaluate the association between tumor marker decline rates of AFP and HCG with OS and PFS. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Quality of Life Evaluation Objective: to compare the quality of life among patients ≥ 18 years treated with TIP vs. those treated with TI-CE using the EORTC quality of life instruments (EORTC QLQ-C30 and QLQ-TC26).
- Pharmacogenomic Objective: to evaluate the association between specific germline polymorphisms and patient outcome to treatment.
- Tumor Biology Objectives:
A) To evaluate the frequency of aberrations in the RAS, PI3K, and p53 pathways among patients with refractory or relapsed GCT entering the study.
B) To correlate aberrations in the RAS, PI3K, and p53 pathways with patient outcome overall and within each treatment arm.
C) To characterize the range of other genetic aberrations (mutations and copy number gains and losses among 341 cancer-related genes) within relapsed and refractory GCT samples
D) To establish a GCT biospecimen bank for future analysis. |
|
| E.3 | Principal inclusion criteria |
- Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment. Tumor may have originated in any primary site.
- Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatin-based chemotherapy, defined as meeting at least one of the following criteria:
* Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT (enrollment on this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed). In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study.
* Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease.
* Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase.
- Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy. Prior POMBACE, CBOP-BEP, or GAMEC are allowed.
- No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy).
- Must have adequate recovery from prior surgery (e.g., healed scar, resumption of diet, etc.).
- Age ≥ 14 years (≥ 15 years in France, ≥ 16 years in Ireland, ≥ 18 years in Germany, Denmark, Switzerland, the Netherlands, Slovenia and Italy)
- ECOG Performance Status 0 to 2
- Male gender
- Required Initial Laboratory Values:
Absolute Neutrophil Count (ANC) ≥ 1,500/mm3
Platelet Count ≥ 100,000/mm3
Calc. Creatinine Clearance ≥ 50 mL/min
Bilirubin ≤ 2.0 x upper limits of normal (ULN)
AST/ALT ≤ 2.5 x upper limits of normal (ULN)
- Negative Serology (antibody test) for the following infectious diseases:
a. Human Immunodeficiency Virus (HIV) type 1 and 2
b. Human T-cell Leukemia Virus (HTLV) type 1 and 2 (mandatory in US but optional in Canada and Europe)
c. Hepatitis B surface antigen
d. Hepatitis C antibody
- Reproductive risk: patient must not father a baby while in this study. The treatment could affect sperm or semen. Therefore, patient and his partner must use an appropriate and effective contraceptive method during the study period and for approximately 6 months after taking the last dose of study drug. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently.
- Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
|
| E.4 | Principal exclusion criteria |
- Prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue).
- Prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed.
- Concurrent treatment with other cytotoxic drugs or targeted therapies.
- Radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy.
- Previous chemotherapy within 16 days prior to enrollment except for bleomycin which cannot have been given within 5 days prior to enrollment.
- Concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pTis) TCC of the bladder, contralateral GCT, or intratubular germ cell neoplasia. Patients with a prior malignancy, but at least 2 years since any evidence of disease are allowed.
- Late relapse with completely surgically resectable disease. Patients with late relapses (defined as relapse ≥ 2 years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable are not eligible. Patients with late relapses who have unresectable disease are eligible.
- Large (≥ 2 cm) hemorrhagic or symptomatic brain metastases until local treatment has been administered (radiation therapy or surgery). Treatment may begin ≥ 7 days after completion of local treatment. Patients with small (< 2 cm) and asymptomatic brain metastases are allowed and may be treated with radiation therapy and/or surgery concurrently with Arm A or cycles 1 and 2 of Arm B if deemed medically indicated. Radiation therapy should not be given concurrently with high-dose carboplatin or etoposide.
- Secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression.
- Contraindications to the use of paclitaxel, ifosfamide, cisplatine, carboplatine and etoposide as per summary of product characteristics (SPC). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall survival will be assessed at every visit during treatment and during the visits at months 9, 12, 15, 18, 24, 36, 48 and 60 from randomization. |
|
| E.5.2 | Secondary end point(s) |
- Progression Free Survival (PFS)
- Favorable Response Rate (FRR)
- Treatment-related mortality
- Toxicity
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS: will be assessed at each visit from the date of randomization to date of progression or death due to any cause, whichever occurs first
- FRR: will be assessed 4 weeks after end of treatment
- Treatment-related mortality: will be assessed at each visit during protocol chemotherapy until 30-days following end of treatment
- Toxicity: will be assessed at each visit
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 53 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Slovenia |
| United Kingdom |
| Netherlands |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis
There are no study specific procedures foreseen after the end of trial but patients may continue visits to their treating physician in the frame of standard of care. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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