Accelerated or Standard BEP Chemotherapy in Treating Patients with Intermediate or Poor-Risk Metastatic Germ Cell Tumors

This randomized phase III trial studies how well an accelerated schedule of bleomycin sulfate, etoposide phosphate, and cisplatin (BEP) chemotherapy works compared to the standard schedule of BEP chemotherapy in treating patients with intermediate or poor-risk germ cell tumors that have spread to other places in the body (metastatic). Drugs used in chemotherapy, such as bleomycin sulfate, etoposide phosphate, and cisplatin, 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 BEP chemotherapy on a faster, or “accelerated” schedule may work better with fewer side effects in treating patients with intermediate or poor-risk metastatic germ cell tumors compared to the standard schedule.

Inclusion Criteria

• Histologically or cytologically confirmed germ cell tumor (non-seminoma or seminoma); or exceptionally raised tumor markers (alpha-fetoprotein [AFP] >= 1000ng/mL and/or human chorionic gonadotropin [HCG] >= 5000 IU/L) without histologic or cytologic confirmation in the rare case where pattern of metastases consistent with germ cell tumor (GCT), high tumor burden, and a need to start therapy urgently
• Primary arising in testis, ovary, retro-peritoneum, or mediastinum
• Metastatic disease or non-testicular primary
• Intermediate or poor prognosis as defined by International Germ Cell Cancer Consensus Classification (IGCCC) classification (modified with different lactate dehydrogenase [LDH] criteria for intermediate risk non-seminoma, and inclusion of ovarian primaries); see below * Primary site: Testis or retro-peritoneum or mediastinum ** Histology: Non-seminoma *** Prognostic category: Intermediate **** Clinical Factors: Testes/retroperitoneal primary and no liver, bone, brain or other non-pulmonary visceral metastases and intermediate markers – any of: ***** AFP >= 1000 ng/mL and =< 10 000 ng/mL ***** HCG >= 5000 IU/L and =< 50 000 IU/L ***** LDH >= 3.0 x upper limit of normal (ULN) and =< 10 x ULN *** Prognostic category: Poor **** Clinical Factors: Mediastinal primary or liver, bone, brain or other non-pulmonary visceral metastases or poor markers – any of: ***** AFP > 10 000 ng/mL or ***** HCG > 50 000 IU/L or ***** LDH > 10 x ULN ** Histology: Seminoma *** Prognostic category: Intermediate **** Clinical factors: Any primary site and liver, bone, brain or other non-pulmonary visceral metastases and normal AFP, any HCG, any LDH * Primary site: Ovary ** Histology: Malignant germ cell tumour histology (any of yolk sac, choriocarcinoma, embryonal carcinoma, mixed malignant GCT) *** Prognostic category: Federation of Gynecology and Obstetrics (FIGO)/Children's Oncology Group (COG) stage IV **** Distant metastases involving liver/spleen parenchyma and/or extra-abdominal organs (including but not limited to inguinal lymph nodes and lymph nodes outside abdominal cavity, lungs, bone, brain) and/or pleural effusion with positive cytology
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Platelet count >= 100 x 10^9/L
• Bilirubin must be =< 1.5 x ULN, except participants with Gilbert’s syndrome where bilirubin must be =< 2.0 x ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be =< 2.5 x ULN, except if the elevations are due to hepatic metastases, in which case ALT and AST must be =< 5 x ULN
• Estimated creatinine clearance of >= 60 ml/min according to the Cockcroft-Gault formula, unless calculated to be < 60 ml/min or borderline in which case glomerular filtration rate (GFR) should be formally measured, e.g. with edetic acid (EDTA) scan
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3
• Study treatment both planned and able to start within 14 days of randomization
• Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments
• Able to provide signed, written informed consent

Exclusion Criteria

• Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the skin, germ cell tumor, or other malignancy treated at least 5 years previously with no evidence of recurrence)
• Previous chemotherapy or radiotherapy, except: * Pure seminoma relapsing after adjuvant radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent carboplatin * Non-seminoma and poor prognosis by IGCCC criteria in the rare case where low-dose induction chemotherapy is given prior to registration because patient is not fit enough to receive protocol chemotherapy (e.g. organ failure, vena cava obstruction, overwhelming burden of disease); acceptable regimens include cisplatin 20 mg/m^2 days 1-2 and etoposide 100 mg/m^2 days 1-2; carboplatin area under curve (AUC) 3 days 1-2 and etoposide 100 mg/m^2 days 1-2; or baby-BOP; patients must meet all other inclusion and exclusion criteria at the time of registration * Participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomization; such patients must be discussed with the coordinating center prior to registration, and must be registered within 10 days of commencing study chemotherapy
• Significant cardiac disease resulting in inability to tolerate IV fluid hydration for cisplatin
• Significant co-morbid respiratory disease that contraindicates the use of bleomycin
• Peripheral neuropathy >= grade 2 or clinically significant sensorineural hearing loss or tinnitus
• Concurrent illness, including severe infection that may jeopardize the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation; women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration
• Known allergy or hypersensitivity to any of the study drugs
• Presence of any psychological, familial, sociological or geographical condition that in the opinion of the investigator would hamper compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse

PRIMARY OBJECTIVES:

I. To compare the two treatment arms with respect to progression-free survival (disease progression or death).

SECONDARY OBJECTIVES:

I. To compare the two treatment arms with respect to:

Ia. Response following treatment completion (protocol-specific response criteria).

Ib. Adverse events (worst grade according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.03).

Ic. Health-related quality of life (summary scales from Quality of Life Questionnaire [QLQ]-C30 & -Testicular Cancer [TC]-26).

Id. Treatment preference (proportion preferring each treatment arm).

Ie. Delivered dose-intensity of chemotherapy (relative to standard BEP).

If. Overall survival (death from any cause).

CORRELATIVE OBJECTIVES:

I. Determine associations between biomarkers to be specified and their correlations with clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive bleomycin sulfate intravenously (IV) over 10 minutes on days 1, 8, and 15 or 2, 9, and 16, etoposide phosphate IV over 1-2 hours once daily (QD) on days 1-5, cisplatin IV over 1-3 hours QD on days 1-5, and pegfilgrastim subcutaneously (SC) or filgrastim on day 6. Cycles repeat every 21 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients receiving fewer than 8 doses of bleomycin sulfate due to pulmonary toxicity receive ifosfamide IV, mesna IV, etoposide phosphate IV, and cisplatin IV on days 1-5 and pegfilgrastim SC on day 6. Cycles repeat every 21 days for 12 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive bleomycin sulfate IV over 10 minutes on days 1 and 8 or 2 and 9, etoposide phosphate IV over 1-2 hours QD over 1-3 hours QD on days 1-5, cisplatin IV on days 1-5, and pegfilgrastim SC or filgrastim on day 6. Cycles repeat every 14 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients receiving fewer than 8 doses of bleomycin sulfate due to pulmonary toxicity receive ifosfamide IV, mesna IV, etoposide phosphate IV, and cisplatin IV on days 1-5 and pegfilgrastim SC on day 6. Cycles repeat every 21 days for 12 weeks in the absence of disease progression or unacceptable toxicity. After 12 weeks, patients then receive bleomycin sulfate IV over 60 minutes weekly for 4 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months, annually until disease progression, and then every 6 months after disease progression.

Lead Organization
Childrens Oncology Group

Principal Investigator
Farzana Pashankar