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

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Status: Active

Description

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.

Eligibility Criteria

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 * 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)
  • 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
  • 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; 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) * 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
  • 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 16 days prior to enrollment except for bleomycin which cannot have been given within 5 days prior to enrollment
  • Must have adequate recovery from prior surgery (e.g., healed scar, resumption of diet, etc.)
  • Age >= 14 years (>= 18 years in Germany)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • 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
  • Bilirubin =< 2.0 x upper limits of normal (ULN)
  • 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
  • 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
  • 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
  • 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
  • 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
  • No secondary somatic malignancy arising from teratoma (e.g., teratoma with malignant transformation) when it is actively part of the disease recurrence or progression

Locations & Contacts

California

Loma Linda
Loma Linda University Medical Center
Status: Active
Contact: Albert Kheradpour
Phone: 909-558-3375
Los Angeles
USC / Norris Comprehensive Cancer Center
Status: Active
Contact: James Shun Dah Hu
Phone: 323-865-0451
Palo Alto
Stanford Cancer Institute Palo Alto
Status: Active
Contact: Sandy Srinivas
Phone: 800-455-0057
San Francisco
UCSF Medical Center-Mission Bay
Status: Active
Contact: Terence Ware Friedlander
Phone: 877-827-3222

Florida

Gainesville
University of Florida Health Science Center �� Gainesville
Status: Active
Contact: William Birdsall Slayton
Phone: 352-273-8675 Email: trials@cancer.ufl.edu
Miami
Nicklaus Children's Hospital
Status: Active
Contact: Enrique Alberto Escalon
Phone: 888-823-5923 Email: ctsucontact@westat.com
Saint Petersburg
Johns Hopkins All Children's Hospital
Status: Active
Contact: Jennifer Lynne Root Mayer
Phone: 212-639-7202

Georgia

Atlanta
Emory University / Winship Cancer Institute
Status: Active
Contact: Bradley Curtis Carthon
Phone: 404-778-1868

Illinois

Chicago
Northwestern University
Status: Temporarily closed to accrual
Contact: Benedito Arruda Filho Carneiro
Phone: 312-695-1301 Email: cancer@northwestern.edu
Rush University Medical Center
Status: Active
Contact: Nicklas Robert Pfanzelter
Phone: 312-942-5498 Email: clinical_trials@rush.edu
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Walter M. Stadler
Phone: 773-834-7424

Kansas

Wichita
Cancer Center of Kansas - Wichita
Status: Active
Contact: Shaker R. Dakhil
Phone: 316-268-5374
Via Christi Regional Medical Center
Status: Active
Contact: Shaker R. Dakhil
Phone: 316-268-5374

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: Active
Contact: A. Lindsay Frazier
Phone: 877-442-3324

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Active
Contact: David C. Smith
Phone: 800-865-1125

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: Active
Contact: Michael Kerr Richards
Phone: 888-823-5923 Email: ctsucontact@westat.com
Rochester
Mayo Clinic
Status: Active
Contact: Brian A. Costello
Phone: 855-776-0015

Missouri

Saint Louis
Washington University School of Medicine
Status: Active
Contact: Joel Picus
Phone: 800-600-3606 Email: info@siteman.wustl.edu

Nebraska

Omaha
Nebraska Methodist Hospital
Status: Active
Contact: Ralph J. Hauke
Phone: 402-354-5144

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Darren Richard Feldman
Phone: 212-639-7202
Middletown
Memorial Sloan Kettering Monmouth Monmouth
Status: Temporarily closed to accrual
Contact: Darren Richard Feldman
Phone: 212-639-7202

New York

Buffalo
Roswell Park Cancer Institute
Status: Active
Contact: Ellis G. Levine
Phone: 877-275-7724
Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Darren Richard Feldman
Phone: 212-639-7202
New York
Memorial Sloan-Kettering Cancer Center
Status: Active
Contact: Darren Richard Feldman
Phone: 212-639-7202
Rockville Centre
Memorial Sloan Kettering Rockville Centre
Status: Active
Contact: Darren Richard Feldman
Phone: 212-639-7202
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Darren Richard Feldman
Phone: 212-639-7202

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: Active
Contact: Matthew Ivan Milowsky
Phone: 877-668-0683 Email: cancerclinicaltrials@med.unc.edu
Charlotte
Carolinas Medical Center / Levine Cancer Institute
Status: Active
Contact: Joel A. Kaplan
Phone: 704-355-2884

Ohio

Cincinnati
Cincinnati Children's Hospital Medical Center
Status: Active
Contact: James Ian Geller
Phone: 888-823-5923 Email: ctsucontact@westat.com
Columbus
Ohio State University Comprehensive Cancer Center
Status: Active
Contact: J. Paul Monk
Phone: 800-293-5066 Email: Jamesline@osumc.edu

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: Active
Contact: Sofia Ghani
Phone: 405-271-8777 Email: ou-clinical-trials@ouhsc.edu

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: Active
Contact: Frank M. Balis
Phone: 888-823-5923 Email: ctsucontact@westat.com
University of Pennsylvania / Abramson Cancer Center
Status: Active
Contact: David Joseph Vaughn
Phone: 800-474-9892
Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: Active
Contact: Leonard Joseph Appleman
Phone: 412-647-8073

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Alberto S. Pappo
Phone: 416-813-7654ext2027 Email: jason.mcguire@sickkids.ca
Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Contact: Scott C. Borinstein
Phone: 800-811-8480

Texas

Houston
M D Anderson Cancer Center
Status: Active
Contact: Yago L. Nieto
Phone: 713-792-3245

Wisconsin

Milwaukee
Froedtert and the Medical College of Wisconsin
Status: Active
Contact: Deepak Kilari
Phone: 888-469-6614

Belgium

Brussels
University Hospital Saint Luc
Status: Active
Contact: Jean-Pascal Machiels
Phone: 888-823-5923 Email: ctsucontact@westat.com

France

Lyon
Centre Leon Berard
Status: Active
Contact: Aude Flechon
Phone: 888-823-5923 Email: ctsucontact@westat.com

Ireland

Dublin
Saint James Hospital
Status: Active
Contact: Dearbhaile Mairi O'Donnell
Phone: 353 1 4162168

Italy

Milano
Istituto Nazionale Tumori
Status: Active
Contact: Andrea Necchi
Phone: 888-823-5923 Email: ctsucontact@westat.com
Pavia
San Matteo Hospital
Status: Active
Contact: Paolo Pedrazzoli
Phone: 888-823-5923 Email: ctsucontact@westat.com

Netherlands

Amsterdam
The Netherlands Cancer Institute
Status: Active
Contact: Jan Martijn Kerst
Phone: 888-823-5923 Email: ctsucontact@westat.com
Groningen
University Medical Center Groningen
Status: Active
Contact: Jourik A. Gietema
Phone: 888-823-5923 Email: ctsucontact@westat.com
Nijmegen
Radboud University Nijmegen Medical Centre
Status: Active
Contact: Sasja Francisca Mulder
Phone: 888-823-5923 Email: ctsucontact@westat.com

Spain

Barcelona
Hospital De La Santa Creu I Sant Pau
Status: Active
Contact: Jose Pablo Maroto Rey
Phone: 34 93 556 56 49
Murcia
Hospital General Universitario Morales Meseguer
Status: Active
Contact: Enrique Gonzalez-Billalabeitia
Phone: 888-823-5923 Email: ctsucontact@westat.com

Switzerland

Zurich
University Hospital Zurich
Status: Active
Contact: Joerg Beyer
Phone: 888-823-5923 Email: ctsucontact@westat.com

United Kingdom

Glasgow
Beatson Oncology Center
Status: Active
Contact: Jeffery David White
Phone: 888-823-5923 Email: ctsucontact@westat.com

Trial Objectives and Outline

PRIMARY OBJECTIVES:

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.

TERTIARY 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]).

II. To evaluate the association between specific germline polymorphisms and patient outcome to treatment.

III. To evaluate the frequency of aberrations in the RAS, PI3K, and p53 pathways among patients with refractory or relapsed GCT entering the study.

IV. To correlate aberrations in the RAS, PI3K, and p53 pathways with patient outcome overall and within each treatment arm.

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.

VI. To establish a GCT biospecimen bank for future analysis.

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 courses 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 courses 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 courses 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.

Trial Phase & Type

Trial Phase

Phase III

Trial Type

Treatment

Lead Organization

Lead Organization
Alliance for Clinical Trials in Oncology

Principal Investigator
Darren Richard Feldman

Trial IDs

Primary ID A031102
Secondary IDs NCI-2014-01696, 2014-003930-17, PA031102_A01PAMDREVW01, 1407-GUCG
Clinicaltrials.gov ID NCT02375204