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

Germ Cell Tumor Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02375204
• Other study ID #: A031102
• Secondary ID: U10CA180821NCI-2
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 5, 2015
• Est. completion date: June 2024

Study information

• Verified date: March 2023
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 420
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 14 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Childhood Teratoma
• Choriocarcinoma
• Extragonadal Seminoma
• Germ Cell Tumor
• Germinoma
• Malignant Germ Cell Neoplasm
• Mixed Germ Cell Tumor
• Neoplasms
• Neoplasms, Germ Cell and Embryonal
• Non-seminomatous Germ Cell Tumor
• Seminoma
• Teratoma
• Yolk Sac Tumor

Intervention

Drug:
• paclitaxel
IV
• ifosfamide
IV
• cisplatin
IV
• pegylated G-CSF
IV
• G-CSF
IV
• carboplatin
IV
• etoposide phosphate
IV

Procedure:
• stem cell reinfusion
surgical procedure

Locations

Country	Name	City	State
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Belgium	Institut Jules Bordet	Anderlecht
Belgium	University Hospital Saint Luc	Brussels
Denmark	Rigshospitalet University Hospital	Copenhagen
France	Centre Leon Berard	Lyon
France	Institut Paoli Calmettes	Marseille
France	Hopital Tenon/Assistance Publique - Hopitaux de Paris	Paris
France	CHRU Strasbourg - Hospital Civil	Strasbourg
France	Center Claudius Regaud	Toulouse
France	Centre Alexis Vautrin	Vandoeuvre-les-Nancy
France	Gustave Roussy	Villejuif
Germany	University of Berlin Charite Campus Benjamin Franklin	Berlin
Germany	Technical University Dresden	Dresden	Saxony
Germany	University of Dusseldorf	Dusseldorf
Germany	University of Essen	Essen
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	UniversitaetsKlinikum Heidelberg	Heidelberg
Germany	GK-Mittelrhein Saint Martin's	Koblenz
Germany	Philipps University Marburg	Marburg
Germany	Rotkreuzklinikum Munchen	Munich
Germany	Klinikum Nurnberg Nord	Nurnberg
Germany	University Hospital Ulm	Ulm
Ireland	Saint James Hospital	Dublin
Italy	Ospedale di Circolo di Busto Arsizio	Busto Arsizio
Italy	Istituto Scientifico Romagnolo	Meldola
Italy	Istituto Nazionale Tumori	Milano
Italy	San Matteo Hospital	Pavia
Netherlands	The Netherlands Cancer Institute	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen
Spain	Duran i Reynals Hospital-Catalan Institute of Oncology	Barcelona
Spain	Hospital De La Santa Creu I Sant Pau	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital General Universitario Morales Meseguer	Murcia
Switzerland	Inselspital	Bern
Switzerland	Hopitaux Universitaires de Geneve	Geneva
Switzerland	University Hospital Zurich	Zurich
United Kingdom	Beatson Oncology Center	Glasgow	Scotland
United Kingdom	Saint Bartholomew's Hospital	London	England
United Kingdom	Christie Hospital	Manchester	England
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Weston Park Hospital	Sheffield	England
United Kingdom	Southampton General Hospital	Southampton	England
United Kingdom	The Royal Marsden NHS Foundation Trust - Sutton	Surrey
United Kingdom	Saint James's University Hospital	West Yorkshire	England
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Prisma Health Cancer Institute - Easley	Easley	South Carolina
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	El Paso Children's Hospital	El Paso	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	M D Anderson Cancer Center	Houston	Texas
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Summerlin Hospital Medical Center	Las Vegas	Nevada
United States	Loma Linda University Medical Center	Loma Linda	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Miami Cancer Institute	Miami	Florida
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Arnold Palmer Hospital for Children	Orlando	Florida
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Ascension Via Christi Hospitals Wichita	Wichita	Kansas
United States	Cancer Center of Kansas - Wichita	Wichita	Kansas
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	University of Michigan Health - West	Wyoming	Michigan

Sponsors (8)

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

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Denmark,  France,  Germany,  Ireland,  Italy,  Netherlands,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	overall survival		Up to 36 months post-treatment
Secondary	progression free survival		Up to 36 months post-treatment
Secondary	proportion of patients achieving either a complete response (CR) or partial response		Up to 3 months post-registration
Secondary	treatment related mortality		Up to 30 days post-treatment
Secondary	number of participants with treatment-related adverse events as assessed by CTCAE v4.0		Up to 3 months post-registration
Secondary	Validation of International Prognostic Factor Study Group stratification system (eg, primary site, prior response, progression free interval)		Up to 3 years post-registration