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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Basic Trial Information

PhaseTypeStatusAgeTrial IDs
Phase IIITreatmentActive14 and overA031102
NCI-2014-01696, 2014-003930-17, PA031102_A01PAMDREVW01, 1407-GUCG, NCT02375204

Trial Description

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 know 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.

Further Study Information

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.

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 [human chorionic gonadotropin (HCG) >= 500; alpha-fetoprotein (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

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

Alliance for Clinical Trials in Oncology

  • National Cancer Institute
Darren Richard Feldman, Principal Investigator

Trial Sites

U.S.A.

California
Loma Linda

Loma Linda University Medical Center

Albert Kheradpour
Ph: 909-558-3375

Albert Kheradpour
Principal Investigator

Los Angeles

USC / Norris Comprehensive Cancer Center

James Shun Dah Hu
Ph: 323-865-0451

James Shun Dah Hu
Principal Investigator

San Francisco

UCSF Medical Center-Mission Bay

Terence Ware Friedlander
Ph: 877-827-3222

Terence Ware Friedlander
Principal Investigator

Florida
Gainesville

University of Florida

William Birdsall Slayton
Ph: 352-273-8675
Email: trials@cancer.ufl.edu

William Birdsall Slayton
Principal Investigator

Miami

Nicklaus Children's Hospital

Enrique Alberto Escalon
Ph: 888-624-2778

Enrique Alberto Escalon
Principal Investigator

Georgia
Atlanta

Emory University/Winship Cancer Institute

Bradley Curtis Carthon
Ph: 404-778-1868

Bradley Curtis Carthon
Principal Investigator

Illinois
Chicago

Rush University Medical Center

Nicklas Robert Pfanzelter
Ph: 312-942-5498
Email: clinical_trials@rush.edu

Nicklas Robert Pfanzelter
Principal Investigator

University of Chicago Comprehensive Cancer Center

Walter M. Stadler
Ph: 773-834-7424

Walter M. Stadler
Principal Investigator

Kansas
Wichita

Cancer Center of Kansas - Wichita

Shaker R. Dakhil
Ph: 316-268-5374

Shaker R. Dakhil
Principal Investigator

Via Christi Regional Medical Center

Shaker R. Dakhil
Ph: 316-268-5374

Shaker R. Dakhil
Principal Investigator

Massachusetts
Boston

Dana-Farber Cancer Institute

A. Lindsay Frazier
Ph: 877-442-3324

A. Lindsay Frazier
Principal Investigator

Minnesota
Minneapolis

Children's Hospitals and Clinics of Minnesota - Minneapolis

Michael Kerr Richards
Ph: 612-813-5193

Michael Kerr Richards
Principal Investigator

Rochester

Mayo Clinic

Brian A. Costello
Ph: 855-776-0015

Brian A. Costello
Principal Investigator

Missouri
Saint Louis

Washington University School of Medicine

Joel Picus
Ph: 800-600-3606
Email: info@siteman.wustl.edu

Joel Picus
Principal Investigator

Nebraska
Omaha

Nebraska Methodist Hospital

Ralph J. Hauke
Ph: 402-393-3110

Ralph J. Hauke
Principal Investigator

New York
Buffalo

Roswell Park Cancer Institute

Ellis G. Levine
Ph: 877-275-7724

Ellis G. Levine
Principal Investigator

New York

Memorial Sloan-Kettering Cancer Center

Darren Richard Feldman
Ph: 212-639-7202

Darren Richard Feldman
Principal Investigator

North Carolina
Chapel Hill

UNC Lineberger Comprehensive Cancer Center

Matthew Ivan Milowsky
Ph: 877-668-0683
Email: cancerclinicaltrials@med.unc.edu

Matthew Ivan Milowsky
Principal Investigator

Charlotte

Carolinas Medical Center/Levine Cancer Institute

Joel A. Kaplan
Ph: 704-355-2884

Joel A. Kaplan
Principal Investigator

Ohio
Columbus

Ohio State University Comprehensive Cancer Center

J. Paul Monk
Ph: 800-293-5066
Email: Jamesline@osumc.edu

J. Paul Monk
Principal Investigator

Oklahoma
Oklahoma City

University of Oklahoma Health Sciences Center

Sofia Ghani
Ph: 405-271-8777
Email: ou-clinical-trials@ouhsc.edu

Sofia Ghani
Principal Investigator

Pennsylvania
Philadelphia

Children's Hospital of Philadelphia

Frank M. Balis
Ph: 215-590-2810

Frank M. Balis
Principal Investigator

University of Pennsylvania/Abramson Cancer Center

David Joseph Vaughn
Ph: 800-474-9892

David Joseph Vaughn
Principal Investigator

Pittsburgh

University of Pittsburgh Cancer Institute (UPCI)

Leonard Joseph Appleman
Ph: 412-647-8073

Leonard Joseph Appleman
Principal Investigator

Tennessee
Memphis

St. Jude Children's Research Hospital

Alberto S. Pappo
Ph: 866-278-5833
Email: info@stjude.org

Alberto S. Pappo
Principal Investigator

Nashville

Vanderbilt University/Ingram Cancer Center

Scott C. Borinstein
Ph: 800-811-8480

Scott C. Borinstein
Principal Investigator

Texas
Houston

M D Anderson Cancer Center

Yago L. Nieto
Ph: 713-792-3245

Yago L. Nieto
Principal Investigator

Wisconsin
Milwaukee

Froedtert and the Medical College of Wisconsin

Deepak Kilari
Ph: 414-805-4380

Deepak Kilari
Principal Investigator

Belgium

Brussels

University Hospital Saint Luc

Jean-Pascal Machiels
Ph: 888-823-5923
Email: ctsucontact@westat.com

Jean-Pascal Machiels
Principal Investigator

Ireland

Dublin

Saint James Hospital

Dearbhaile Mairi O'Donnell
Ph: 353 1 4162168

Dearbhaile Mairi O'Donnell
Principal Investigator

Italy

Milano

Istituto Nazionale Tumori

Andrea Necchi
Ph: 888-823-5923
Email: ctsucontact@westat.com

Andrea Necchi
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifier NCT02375204

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.