Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors

Sponsor
Alliance for Clinical Trials in Oncology (Other)
Overall Status
Recruiting
CT.gov ID
NCT02375204
Collaborator
National Cancer Institute (NCI) (NIH), European Organisation for Research and Treatment of Cancer - EORTC (Other), Movember Foundation (Other), Institute of Cancer Research (ICR), United Kingdom (Other), Cancer Research UK (Other), UNICANCER (Other), Irish Group CTI (Other)
420
125
2
3.4

Study Details

Study Description

Brief 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 or did not respond to treatment. Drugs used in chemotherapy, 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. Giving 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.

Detailed Description

The study is an international collaboration with European sites. Collaborators on the study include the National Cancer Institute, the European Organization for Research and Treatment of Cancer and the Movember Foundation. Randomization will be stratified by region (North America and Europe) and by modified IPFSG (International Prognostic Factor Study Group) risk classification (low, intermediate and high). The primary and secondary objectives are described below.

Primary Objective:
  1. To compare the overall survival in patients treated with conventional-dose chemotherapy using the TIP regimen with high-dose chemotherapy (HDCT) plus autologous stem cell transplant (ASCT) using the TI-CE regimen as initial salvage treatment of patients with relapsed or refractory germ cell tumors (GCT)
Secondary Objectives:
  1. To compare the progression-free survival (PFS) of patients treated with initial salvage HDCT with TI-CE versus initial salvage CDCT with TIP

  2. To compare the favorable response rate (FRR) of patients treated with initial salvage HDCT with TI-CE versus initial salvage CDCT with TIP

  3. 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

  4. 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).

  5. To evaluate the association between tumor marker decline rates of Alpha-Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG) with OS and PFS.

Treatment is to continue until disease progression, unacceptable toxicity or completion of all protocol treatment.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
420 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Phase III Trial Comparing Conventional-Dose Chemotherapy Using Paclitaxel, Ifosfamide, and Cisplatin (TIP) With High-Dose Chemotherapy Using Mobilizing Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin and Etoposide (TI-CE) as First Salvage Treatment in Relapsed or Refractory Germ Cell Tumors
Study Start Date :
Mar 1, 2015
Anticipated Primary Completion Date :
Jun 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Other: Arm A: TIP

Patients will receive treatment for 4 cycles administered every 21 days. Cycles 1-4 (1 cycle = 21 days) paclitaxel 250 mg/m^2 IV over 24 hours on Day 1 including premedication as defined in the protocol (eg, dexamethasone, diphenhydramine and H2 blocker) ifosfamide 1500 mg/m^2 IV daily on Days 2-5 with mesna protection as defined in the protocol cisplatin 25 mg/m^2 IV daily on Days 2-5 pegylated G-CSF 6 mg subcutaneous on Day 6 or 7 or G-CSF as defined in the protocol on Days 6-18 Patients may commence with each Arm A cycle provided they meet the criteria as defined in the protocol.

Drug: paclitaxel
IV
Other Names:
  • Taxol
  • Drug: ifosfamide
    IV
    Other Names:
  • Ifex®, IFOS
  • Drug: cisplatin
    IV
    Other Names:
  • CDDP
  • Drug: pegylated G-CSF
    IV

    Drug: G-CSF
    IV

    Other: Arm B: TI-CE

    Patients will receive treatment for a total of 5 cycles. Cycles 1-2 (1 cycle = 14 days) paclitaxel 200 mg/m^2 IV over 3 hours on Day 1 including premedication as defined in the protocol (eg, dexamethasone, diphenhydramine and H2 blocker) ifosfamide 2000 mg/m^2 IV daily on Days 1-3 with mesna protection as defined in the protocol G-CSF 10 µg/kg subcutaneously on Days 3-15 (cycle 1) and Days 3-14 (cycle 2) or pegylated G-CSF 6 mg subcutaneous on Day 4 or 6 (cycle 1) and Day 4 or 5 (cycle 2) leukapheresis every 14 days, if there is an inadequate number of CD34+ cells/kg collected in cycle 1 Cycles 3-5 (1 cycle = 21 days) carboplatin daily on Days 1-3 etoposide 400 mg/m^2 daily on Days 1-3 stem cell reinfusion on day 5 pegylated G-CSF 6 mg subcutaneously or G-CSF at approximately 5 µg/kg daily on Days 5-15 Patients may commence with each Arm B cycle provided they meet the criteria as defined in the protocol.

    Drug: paclitaxel
    IV
    Other Names:
  • Taxol
  • Drug: ifosfamide
    IV
    Other Names:
  • Ifex®, IFOS
  • Drug: pegylated G-CSF
    IV

    Drug: G-CSF
    IV

    Drug: carboplatin
    IV
    Other Names:
  • Paraplatin®, CBDCA
  • Drug: etoposide phosphate
    IV
    Other Names:
  • VePesid®, Toposar®, VP16
  • Procedure: stem cell reinfusion
    surgical procedure

    Outcome Measures

    Primary Outcome Measures

    1. overall survival [Up to 36 months post-treatment]

    Secondary Outcome Measures

    1. progression free survival [Up to 36 months post-treatment]

    2. proportion of patients achieving either a complete response (CR) or partial response [Up to 3 months post-registration]

    3. treatment related mortality [Up to 30 days post-treatment]

    4. number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [Up to 3 months post-registration]

    5. Validation of International Prognostic Factor Study Group stratification system (eg, primary site, prior response, progression free interval) [Up to 3 years post-registration]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    14 Years and Older
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    1. Documentation of Disease
    • Histologic Documentation: 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)

    1. Evidence of Disease
    • 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.

    1. Prior Treatment
    • 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.

    • Note: For patients requiring immediate treatment, 1 cycle of conventional-dose salvage chemotherapy is allowed. 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.

    • No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy as defined in the protocol)

    • 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.

    • 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.

    • No prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue)

    • 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.

    • No concurrent treatment with other cytotoxic drugs or targeted therapies.

    • 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.

    • No previous chemotherapy within 17 days prior to enrollment. A minimum of three weeks after the last day of the start of the previous chemotherapy regimen before the first day of chemotherapy on study protocol.

    • Must have adequate recovery from prior surgery (eg, healed scar, resumption of diet)

    1. Age ≥ 14 years (≥ 18 years in Germany)

    2. ECOG Performance Status 0 to 2

    3. Male gender

    4. Required Initial Laboratory Values:

    • Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3

    • Platelet Count ≥ 100,000/mm^3

    • Calculated creatinine clearance ≥ 50 mL/min

    • Bilirubin ≤ 2.0 x upper limits of normal (ULN)

    • AST/ALT ≤ 2.5 x upper limits of normal (ULN)

    1. No 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.

    2. 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 US but optional in Canada and Europe)

    • Hepatitis B surface antigen

    • Hepatitis C antibody

    1. 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.

    2. 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.

    1. No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 UC San Diego Moores Cancer Center La Jolla California United States 92093
    3 Loma Linda University Medical Center Loma Linda California United States 92354
    4 USC / Norris Comprehensive Cancer Center Los Angeles California United States 90033
    5 Kaiser Permanente-Oakland Oakland California United States 94611
    6 Stanford Cancer Institute Palo Alto Palo Alto California United States 94304
    7 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    8 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    9 MedStar Georgetown University Hospital Washington District of Columbia United States 20007
    10 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    11 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    12 Nicklaus Children's Hospital Miami Florida United States 33155
    13 Miami Cancer Institute Miami Florida United States 33176
    14 Arnold Palmer Hospital for Children Orlando Florida United States 32806
    15 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    16 Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida United States 33607
    17 Emory University Hospital/Winship Cancer Institute Atlanta Georgia United States 30322
    18 Northwestern University Chicago Illinois United States 60611
    19 Rush University Medical Center Chicago Illinois United States 60612
    20 University of Illinois Chicago Illinois United States 60612
    21 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    22 Ascension Via Christi Hospitals Wichita Wichita Kansas United States 67214
    23 Cancer Center of Kansas - Wichita Wichita Kansas United States 67214
    24 Ochsner Medical Center Jefferson New Orleans Louisiana United States 70121
    25 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    26 University of Michigan Comprehensive Cancer Center Ann Arbor Michigan United States 48109
    27 Spectrum Health at Butterworth Campus Grand Rapids Michigan United States 49503
    28 Metro Health Hospital Wyoming Michigan United States 49519
    29 Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota United States 55404
    30 Mayo Clinic in Rochester Rochester Minnesota United States 55905
    31 Washington University School of Medicine Saint Louis Missouri United States 63110
    32 Nebraska Methodist Hospital Omaha Nebraska United States 68114
    33 Summerlin Hospital Medical Center Las Vegas Nevada United States 89144
    34 Memorial Sloan Kettering Basking Ridge Basking Ridge New Jersey United States 07920
    35 Hackensack University Medical Center Hackensack New Jersey United States 07601
    36 Memorial Sloan Kettering Monmouth Middletown New Jersey United States 07748
    37 Saint Joseph's Regional Medical Center Paterson New Jersey United States 07503
    38 Roswell Park Cancer Institute Buffalo New York United States 14263
    39 Memorial Sloan Kettering Commack Commack New York United States 11725
    40 Memorial Sloan Kettering Westchester Harrison New York United States 10604
    41 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    42 Memorial Sloan Kettering Nassau Uniondale New York United States 11553
    43 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    44 Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina United States 28203
    45 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    46 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    47 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    48 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    49 University of Pennsylvania/Abramson Cancer Center Philadelphia Pennsylvania United States 19104
    50 University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania United States 15232
    51 Rhode Island Hospital Providence Rhode Island United States 02903
    52 Prisma Health Cancer Institute - Spartanburg Boiling Springs South Carolina United States 29316
    53 Medical University of South Carolina Charleston South Carolina United States 29425
    54 Prisma Health Cancer Institute - Easley Easley South Carolina United States 29640
    55 Saint Francis Hospital Greenville South Carolina United States 29601
    56 BI-LO Charities Children's Cancer Center Greenville South Carolina United States 29605
    57 Prisma Health Cancer Institute - Butternut Greenville South Carolina United States 29605
    58 Prisma Health Cancer Institute - Faris Greenville South Carolina United States 29605
    59 Prisma Health Greenville Memorial Hospital Greenville South Carolina United States 29605
    60 Saint Francis Cancer Center Greenville South Carolina United States 29607
    61 Prisma Health Cancer Institute - Eastside Greenville South Carolina United States 29615
    62 Prisma Health Cancer Institute - Greer Greer South Carolina United States 29650
    63 Prisma Health Cancer Institute - Seneca Seneca South Carolina United States 29672
    64 Spartanburg Medical Center Spartanburg South Carolina United States 29303
    65 Saint Jude Children's Research Hospital Memphis Tennessee United States 38105
    66 The Children's Hospital at TriStar Centennial Nashville Tennessee United States 37203
    67 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    68 El Paso Children's Hospital El Paso Texas United States 79905
    69 M D Anderson Cancer Center Houston Texas United States 77030
    70 Seattle Children's Hospital Seattle Washington United States 98105
    71 Marshfield Medical Center-EC Cancer Center Eau Claire Wisconsin United States 54701
    72 Marshfield Medical Center-Marshfield Marshfield Wisconsin United States 54449
    73 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
    74 Marshfield Clinic-Minocqua Center Minocqua Wisconsin United States 54548
    75 Marshfield Medical Center-Rice Lake Rice Lake Wisconsin United States 54868
    76 Marshfield Medical Center-River Region at Stevens Point Stevens Point Wisconsin United States 54482
    77 Marshfield Medical Center - Weston Weston Wisconsin United States 54476
    78 Royal Prince Alfred Hospital Camperdown New South Wales Australia 2050
    79 Princess Alexandra Hospital Woolloongabba Queensland Australia 4102
    80 Box Hill Hospital Box Hill Victoria Australia 3128
    81 Peter MacCallum Cancer Centre Melbourne Victoria Australia 3000
    82 Institut Jules Bordet Anderlecht Belgium 1070
    83 University Hospital Saint Luc Brussels Belgium 1200
    84 Rigshospitalet University Hospital Copenhagen Denmark 2100
    85 Centre Leon Berard Lyon France 69373
    86 Institut Paoli Calmettes Marseille France 13273
    87 Hopital Tenon/Assistance Publique - Hopitaux de Paris Paris France 75970
    88 CHRU Strasbourg - Hospital Civil Strasbourg France 67091
    89 Center Claudius Regaud Toulouse France 31052
    90 Centre Alexis Vautrin Vandoeuvre-les-Nancy France 54511
    91 Gustave Roussy Villejuif France 94805
    92 Technical University Dresden Dresden Saxony Germany 01307
    93 University of Berlin Charite Campus Benjamin Franklin Berlin Germany 12203
    94 University of Dusseldorf Dusseldorf Germany 40225
    95 University of Essen Essen Germany 45122
    96 University Medical Center Hamburg-Eppendorf Hamburg Germany 20246
    97 UniversitaetsKlinikum Heidelberg Heidelberg Germany 69120
    98 GK-Mittelrhein Saint Martin's Koblenz Germany 56068
    99 Philipps University Marburg Marburg Germany 35033
    100 Rotkreuzklinikum Munchen Munich Germany 80634
    101 Klinikum Nurnberg Nord Nurnberg Germany 90419
    102 University Hospital Ulm Ulm Germany 89081
    103 Saint James Hospital Dublin Ireland 8
    104 Ospedale di Circolo di Busto Arsizio Busto Arsizio Italy 21052
    105 Istituto Scientifico Romagnolo Meldola Italy 47014
    106 Istituto Nazionale Tumori Milano Italy 20133
    107 San Matteo Hospital Pavia Italy 27100
    108 The Netherlands Cancer Institute Amsterdam Netherlands 1066 CX
    109 University Medical Center Groningen Groningen Netherlands 9700 GZ
    110 Radboud University Nijmegen Medical Centre Nijmegen Netherlands 6500 HB
    111 Hospital De La Santa Creu I Sant Pau Barcelona Spain 08025
    112 Duran i Reynals Hospital-Catalan Institute of Oncology Barcelona Spain 08908
    113 Hospital Universitario 12 de Octubre Madrid Spain 28041
    114 Hospital General Universitario Morales Meseguer Murcia Spain 30008
    115 Inselspital Bern Switzerland 3010
    116 Hopitaux Universitaires de Geneve Geneva Switzerland 1211
    117 University Hospital Zurich Zurich Switzerland 8091
    118 Saint Bartholomew's Hospital London England United Kingdom EC1A 7BE
    119 Christie Hospital Manchester England United Kingdom M20 4BX
    120 Weston Park Hospital Sheffield England United Kingdom S10 2SJ
    121 Southampton General Hospital Southampton England United Kingdom SO16 6YD
    122 Saint James's University Hospital West Yorkshire England United Kingdom LS9 7TF
    123 Beatson Oncology Center Glasgow Scotland United Kingdom G12 0YN
    124 Nottingham City Hospital Nottingham United Kingdom NG5 1PB
    125 The Royal Marsden NHS Foundation Trust - Sutton Surrey United Kingdom SM2 5PT

    Sponsors and Collaborators

    • Alliance for Clinical Trials in Oncology
    • National Cancer Institute (NCI)
    • European Organisation for Research and Treatment of Cancer - EORTC
    • Movember Foundation
    • Institute of Cancer Research (ICR), United Kingdom
    • Cancer Research UK
    • UNICANCER
    • Irish Group CTI

    Investigators

    • Study Chair: Darren Feldman, MD, Memorial Sloan Kettering Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Alliance for Clinical Trials in Oncology
    ClinicalTrials.gov Identifier:
    NCT02375204
    Other Study ID Numbers:
    • A031102
    • U10CA180821
    • NCI-2014-01696
    First Posted:
    Mar 2, 2015
    Last Update Posted:
    Aug 3, 2022
    Last Verified:
    Aug 1, 2022

    Study Results

    No Results Posted as of Aug 3, 2022