Summary

This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement (relapsed) or did not respond to treatment (refractory). Chemotherapy drugs, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

Objectives

PRIMARY OBJECTIVE:
I. To compare the overall survival in patients treated with conventional-dose chemotherapy using the paclitaxel, ifosfamide, and cisplatin (TIP) regimen with high-dose chemotherapy (HDCT) plus autologous stem cell transplant (ASCT) using the high-dose carboplatin and etoposide (TI-CE) regimen as initial salvage treatment of patients with relapsed or refractory germ cell tumors (GCT).

SECONDARY OBJECTIVES:
I. To compare the progression-free survival (PFS) of patients treated with initial salvage HDCT with TI-CE versus (vs.) initial salvage conventional-dose chemotherapy (CDCT) with TIP.
II. To compare the favorable response rate (FRR) of patients treated with initial salvage HDCT with TI-CE vs. initial salvage CDCT with TIP.
III. To compare the 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.
IV. To prospectively evaluate the International Prognostic Factors Study Group (IPFSG) scoring system as a predictor of outcome to initial salvage therapy in patients with relapsed or refractory GCT.
V. To evaluate the association between tumor marker decline rates of alpha-fetoprotein (AFP) and human chronic gonadotropin (HCG) with overall survival (OS) and PFS.

CORRELATIVE SCIENCE OBJECTIVES:
I. To compare the quality of life among patients >= 18 years treated with TIP vs. those treated with TI-CE using the European Organization for Research and Treatment of Cancer (EORTC) quality of life instruments (EORTC Quality of Life-Core 30 [QOL-C30] and QLQ-Testicular Cancer 26 [TC26]). (Quality of Life Evaluation)
II. To evaluate the association between specific germline polymorphisms and patient outcome to treatment. (Pharmacogenomic)
III. To evaluate the frequency of aberrations in the RAS, PI3K, and p53 pathways among patients with refractory or relapsed GCT entering the study. (Tumor Biology)
IV. To correlate aberrations in the RAS, PI3K, and p53 pathways with patient outcome overall and within each treatment arm. (Tumor Biology)
V. 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. (Tumor Biology)
VI. To establish a GCT biospecimen bank for future analysis. (Tumor Biology)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A (TIP): Patients receive paclitaxel intravenously (IV) over 24 hours on day 1, ifosfamide IV over 30 minutes daily and cisplatin IV over 1-96 hours daily on days 2-5, and pegfilgrastim subcutaneously (SC) on day 6, 7, or 8. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM B (TI-CE): Patients receive paclitaxel IV over 3 hours on day 1, ifosfamide IV over 30 minutes daily on days 1-3, and filgrastim SC daily beginning on day 3 and continuing until adequate CD34+ cell collection or day 15, whichever occurs first. Treatment repeats every 14-21 days for 2 cycles in the absence of unacceptable toxicity. Patients then receive carboplatin IV daily and etoposide IV daily on days 1-3, undergo ASCT on day 5, and receive pegfilgrastim SC beginning on day 5 and continuing until absolute neutrophil count (ANC) recovery. Treatment repeats every 21-28 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 9, 12, 15, 18, 24, 36, 48, and 60 months.

Eligibility

1. Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment; tumor may have originated in any primary site * NOTE: in rare circumstances, patients will be allowed to enroll even if a pathologic diagnosis may not have been established; this would require a clinical situation consistent with the diagnosis of GCT (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor marker levels [HCG >= 500; AFP >= 500] and typical pattern of metastases)
2. 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 lactate dehydrogenase (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
3. Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy; prior cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide (POMBACE), carboplatin, bleomycin, vincristine, and cisplatin-bleomycin, etoposide, and cisplatin (CBOP-BEP), or methotrexate, actinomycin-D, etoposide, cisplatin, peg filgrastim (GAMEC) are allowed; Note: for patients requiring immediate treatment, 1 cycle of conventional-dose salvage chemotherapy is allowed (including TI or TIP); therefore, these patients may have received 7 prior cycles of chemotherapy; 6 cycles as part of first-line chemotherapy and 1 cycle of salvage conventional chemotherapy
4. No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy) * Definition of one line of chemotherapy: One line of therapy can in some cases consist of 2 different cisplatin-based treatment combinations, provided there is no disease progression between these two regimens; for example, a patient could have received 2 cycles of bleomycin, etoposide, and cisplatin (BEP) followed by 2 cycles of cisplatin, ifosfamide, and etoposide (VIP) if the switch from BEP to VIP was made due to pulmonary toxicity rather than disease progression; this would be considered 1 line of prior therapy; in addition, if a patient received 4 cycles of BEP and then underwent post-chemotherapy resection of residual tumor with findings of residual viable non-teratomatous GCT, and subsequently received 2 additional cycles of adjuvant chemotherapy (etoposide, cisplatin [EP] or an alternate regimen such as VIP) in the absence of disease progression, this would also be considered 1 regimen; however, if any change in therapy is prompted by tumor progression including rising tumor markers, this is considered to represent 2 lines of prior treatment * Prior treatment with carboplatin as adjuvant therapy is allowed, provided patients meet other eligibility criteria (e.g., the patient has also received 3-4 cycles of cisplatin-based chemotherapy) * Prior treatment with 1-2 cycles of BEP or EP as adjuvant chemotherapy for early stage GCT is allowed, provided the patient also received 3-4 cycles of BEP or EP again at relapse; patients treated with 3-4 cycles of VIP at relapse following 1-2 cycles of BEP/EP are not eligible as this would be considered more than 1 line of prior therapy
5. No prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue)
6. No 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
7. No concurrent treatment with other cytotoxic drugs or targeted therapies
8. No 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
9. No previous chemotherapy within 16 days prior to enrollment except for bleomycin which cannot have been given within 5 days prior to enrollment
10. Must have adequate recovery from prior surgery (e.g., healed scar, resumption of diet, etc.)
11. Age >= 14 years (>= 18 years in Germany)
12. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
13. Absolute neutrophil count (ANC) >= 1,500/mm^3
14. Platelet count >= 100,000/mm^3
15. Calculated (calc.) creatinine clearance >= 50 mL/min * Estimated creatinine clearance for patients >= 18 years old will be estimated by the Jelliffe equation modified for body surface area (BSA); patients with creatinine clearance estimated > 70ml/min by this formula are eligible; if the creatinine clearance estimated by the Jelliffe method is >= 50 mL/min but =< 70 mL/min, then a second method to confirm a creatinine clearance of >= 50 mL/min is required; methods of estimating glomerular filtration rate (GFR) that can be used for this confirmation consist of a 12 or 24-hour urine creatinine clearance or a nuclear creatinine clearance test; if the confirmatory creatinine clearance is < 50 mL/min, then the patient is not eligible; if the confirmatory creatinine clearance is >= 50 mL/min, the patient is eligible; if the cause of the patient’s renal dysfunction is tumor obstructing the ureters, then eligibility can be determined by the study chair even if it does not meet these minimal requirements; for patients < 18 years old, it is strongly suggested that a radioisotope estimation of GFR be obtained; if a radioisotope test is not possible, an estimated creatinine clearance using either a 12 or 24 hour urine creatinine clearance or the Schwartz formula can be used; patients will be considered eligible if the creatinine clearance is > 70 mL/min; if the creatinine clearance estimated by the Schwartz formula or urine creatinine clearance is >= 50 mL/min but =< 70 mL/min, then a second method to confirm a creatinine clearance of >= 50 mL/min is required; methods of estimating GFR that can be used for this confirmation consist of a 12- or 24-hour urine creatinine clearance if the Schwartz formula or radioisotope method was used as the primary method or a radioisotope estimation of GFR if the Schwartz formula or urine creatinine clearance method was used as the primary method; if the confirmatory creatinine clearance is < 50 mL/min, then the patient is not eligible; if the confirmatory creatinine clearance is >= 50 mL/min, the patient is eligible
16. Bilirubin =< 2.0 x upper limits of normal (ULN)
17. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 upper limits of normal (ULN) * Unless due to hepatic metastases in which case levels =< 5 x ULN are allowed
18. No concurrent malignancy other than non-melanoma skin cancer, superficial noninvasive (pTa or pT in situ [is]) transitional cell carcinoma (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
19. Negative serology (antibody test) for the following infectious diseases: * Human immunodeficiency virus (HIV) type 1 and 2 * Human T-cell leukemia virus (HTLV) type 1 and 2 (mandatory in United States [US] but optional in Canada and Europe) * Hepatitis B surface antigen * Hepatitis C antibody
20. No 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
21. No 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
22. No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression

Treatment Sites in Georgia