Clinical trial NCT02375204: Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ Cell Tumors
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 type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Germ Cell Tumor
Teratoma
Choriocarcinoma
Germinoma
Mixed Germ Cell Tumor
Yolk Sac Tumor
Childhood Teratoma
Malignant Germ Cell Neoplasm
Extragonadal Seminoma
Non-seminomatous Germ Cell Tumor
Seminoma
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: European Organisation for Research and Treatment of Cancer - EORTC
name: Movember Foundation
name: Institute of Cancer Research (ICR), United Kingdom
name: Cancer Research UK
name: UNICANCER
name: Irish Group CTI
First posted: 2015-03-02
Enrollment: 420
Sex: MALE
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)
2. 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.
3. 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)
4. Age ≥ 14 years (≥ 18 years in Germany)
5. ECOG Performance Status 0 to 2
6. Male gender
7. 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)
8. 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.
9. 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
10. 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.
11. 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.
12. No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression.

Primary outcomes:
measure: overall survival
timeFrame: Up to 36 months post-treatment
Secondary outcomes:
measure: progression free survival
timeFrame: Up to 36 months post-treatment
measure: proportion of patients achieving either a complete response (CR) or partial response
timeFrame: Up to 3 months post-registration
measure: treatment related mortality
timeFrame: Up to 30 days post-treatment
measure: number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: Up to 3 months post-registration
measure: Validation of International Prognostic Factor Study Group stratification system (eg, primary site, prior response, progression free interval)
timeFrame: Up to 3 years post-registration
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Oakland
country: United States
facility: Kaiser Permanente-Oakland
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute Palo Alto
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Miami
country: United States
facility: Miami Cancer Institute
state: Florida
city: Orlando
country: United States
facility: Arnold Palmer Hospital for Children
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Saint Joseph's Hospital/Children's Hospital-Tampa
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Wichita
country: United States
facility: Ascension Via Christi Hospitals Wichita
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas - Wichita
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Medical Center Jefferson
state: Louisiana
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Wyoming
country: United States
facility: University of Michigan Health - West
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Las Vegas
country: United States
facility: Summerlin Hospital Medical Center
state: Nevada
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Paterson
country: United States
facility: Saint Joseph's Regional Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau
state: New York
city: West Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Boiling Springs
country: United States
facility: Prisma Health Cancer Institute - Spartanburg
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Easley
country: United States
facility: Prisma Health Cancer Institute - Easley
state: South Carolina
city: Greenville
country: United States
facility: Saint Francis Hospital
state: South Carolina
city: Greenville
country: United States
facility: BI-LO Charities Children's Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Butternut
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Faris
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Greenville Memorial Hospital
state: South Carolina
city: Greenville
country: United States
facility: Saint Francis Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Eastside
state: South Carolina
city: Greer
country: United States
facility: Prisma Health Cancer Institute - Greer
state: South Carolina
city: Seneca
country: United States
facility: Prisma Health Cancer Institute - Seneca
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Center
state: South Carolina
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: The Children's Hospital at TriStar Centennial
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: El Paso
country: United States
facility: El Paso Children's Hospital
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Eau Claire
country: United States
facility: Marshfield Medical Center-EC Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center-Marshfield
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Minocqua
country: United States
facility: Marshfield Clinic-Minocqua Center
state: Wisconsin
city: Rice Lake
country: United States
facility: Marshfield Medical Center-Rice Lake
state: Wisconsin
city: Stevens Point
country: United States
facility: Marshfield Medical Center-River Region at Stevens Point
state: Wisconsin
city: Weston
country: United States
facility: Marshfield Medical Center - Weston
state: Wisconsin
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: University Hospital Saint Luc
city: Copenhagen
country: Denmark
facility: Rigshospitalet University Hospital
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hopital Tenon/Assistance Publique - Hopitaux de Paris
city: Strasbourg
country: France
facility: CHRU Strasbourg - Hospital Civil
city: Toulouse
country: France
facility: Center Claudius Regaud
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Gustave Roussy
city: Dresden
country: Germany
facility: Technical University Dresden
state: Saxony
city: Berlin
country: Germany
facility: University of Berlin Charite Campus Benjamin Franklin
city: Dusseldorf
country: Germany
facility: University of Dusseldorf
city: Essen
country: Germany
facility: University of Essen
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: UniversitaetsKlinikum Heidelberg
city: Koblenz
country: Germany
facility: GK-Mittelrhein Saint Martin's
city: Marburg
country: Germany
facility: Philipps University Marburg
city: Munich
country: Germany
facility: Rotkreuzklinikum Munchen
city: Nurnberg
country: Germany
facility: Klinikum Nurnberg Nord
city: Ulm
country: Germany
facility: University Hospital Ulm
city: Dublin
country: Ireland
facility: Saint James Hospital
city: Busto Arsizio
country: Italy
facility: Ospedale di Circolo di Busto Arsizio
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo
city: Milano
country: Italy
facility: Istituto Nazionale Tumori
city: Pavia
country: Italy
facility: San Matteo Hospital
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
city: Barcelona
country: Spain
facility: Hospital De La Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Duran i Reynals Hospital-Catalan Institute of Oncology
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Bern
country: Switzerland
facility: Inselspital
city: Geneva
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: Zurich
country: Switzerland
facility: University Hospital Zurich
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: Manchester
country: United Kingdom
facility: Christie Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: West Yorkshire
country: United Kingdom
facility: Saint James's University Hospital
state: England
city: Glasgow
country: United Kingdom
facility: Beatson Oncology Center
state: Scotland
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Surrey
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust - Sutton
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Darren Feldman, MD
role: STUDY_CHAIR
References:
citation: Tan YY, Al-Bubseeree B, Irvine D, MacDonald G, McQuaker G, Parker A, Waterston A, White J. High-Dose Chemotherapy in Relapsed or Refractory Metastatic Germ-Cell Cancer: The Scotland Experience. Clin Genitourin Cancer. 2019 Apr;17(2):125-131. doi: 10.1016/j.clgc.2018.11.013. Epub 2018 Nov 17.