Summary

This phase III trial compares the effect of an accelerated schedule of bleomycin sulfate, etoposide phosphate, and cisplatin (BEP) chemotherapy to the standard schedule of BEP chemotherapy for the treatment of patients with intermediate or poor-risk germ cell tumors that have spread to other places in the body (metastatic). Chemotherapy drugs, 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.

Objectives

PRIMARY OBJECTIVE:
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) on day 6 or filgrastim for a minimum of 5 days until post-nadir absolute neutrophil count >= 1.0 x 10^9/L. 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. Additionally, patients undergo blood sample collection and chest X-ray on study and CT or MRI and bone scans throughout the study.


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 on days 1-5, cisplatin IV over 1-3 hours QD on days 1-5, and pegfilgrastim SC on day 6 or filgrastim for a minimum of 5 days until post-nadir absolute neutrophil count >= 1.0 x 10^9/L. 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. Additionally, patients undergo blood sample collection and chest X-ray on study and CT or MRI and bone scans throughout the study.

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.