Purpose

The purpose of this study is to determine whether accelerated BEP chemotherapy is more effective than standard BEP chemotherapy in males with intermediate and poor-risk metastatic germ cell tumours.

Category

IRB Number
20180694HU
NCT Number
NCT02582697
Sponsor
University of Sydney -



Study Contact

Principal Investigator
Aaron Sugalski

Virginia Diaz
210-562-9149
diazvr@uthscsa.edu

Jaclyn Hung
210-450-5358
hungj@uthscsa.edu



Eligibility

Eligible Ages
Between 11 Years and 45 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

    1. Age = 11 years and = 45 years on the date of randomisation 2. Histologically or cytologically confirmed germ cell tumour (non-seminoma or seminoma); or Exceptionally raised tumour markers (AFP = 1000ng/mL and/or HCG = 5000 IU/L) without histologic or cytologic confirmation in the rare case where pattern of metastases consistent with GCT, high tumour burden, and a need to start therapy urgently 3. Primary arising in testis, ovary, retro-peritoneum, or mediastinum 4. Metastatic disease or non-testicular primary 5. Intermediate or poor prognosis as defined by IGCCC classification3 (modified with different LDH criteria for intermediate risk non-seminoma, and inclusion of ovarian primaries). (See protocol for more information). 6. Adequate bone marrow function with ANC =1.0 x 10^9/L, Platelet count =100 x 10^9/L 7. Adequate liver function where bilirubin must be =1.5 x ULN, except participants with Gilbert's Syndrome where bilirubin must be =2.0 x ULN; ALT and 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 8. Adequate renal function with 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 GFR should be formally measured, eg. with EDTA scan 9. ECOG Performance Status of 0, 1, 2, or 3 10. Study treatment both planned and able to start within 14 days of randomisation. 11. Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments 12. Able to provide signed, written informed consent

Exclusion Criteria

    1. Other primary malignancy (EXCEPT adequately treated non-melanomatous carcinoma of the skin, germ cell tumour, or other malignancy treated at least 5 years previously with no evidence of recurrence) 2. Previous chemotherapy or radiotherapy, except if patient has pure seminoma relapsing after adjuvant radiotherapy or adjuvant chemotherapy with 1-2 doses of single agent carboplatin or if patient has 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 (eg. organ failure, vena cava obstruction, overwhelming burden of disease). In these instances acceptable regimens include cisplatin 20 mg/m^2 days 1-2 and etoposide 100 mg/m^2 days 1-2; carboplatin 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. Additionally participants who need to start therapy urgently prior to completing study-specific baseline investigations may commence study chemotherapy prior to registration and randomisation. Such patients must be discussed with the coordinating centre prior to registration, and must be registered within 10 days of commencing study chemotherapy. 3. Significant cardiac disease resulting in inability to tolerate IV fluid hydration for cisplatin 4. Significant co-morbid respiratory disease that contraindicates the use of bleomycin 5. Peripheral neuropathy = grade 2 or clinically significant sensorineural hearing loss or tinnitus 6. Concurrent illness, including severe infection that may jeopardize the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety 7. Inadequate contraception. Men must use 2 effective methods of contraception, including use of a condom, during chemotherapy and for a year after completing chemotherapy. 8. Known allergy or hypersensitivity to any of the study drugs 9. 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 The above inclusion and exclusion criteria will apply to stage 1 (n=150) and stage 2 (n=500 including stage 1) of the study. All sites will participate in both stages of the study with the exception of the Children's Oncology Group who will be participate in stage 1 only.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Condition
  • Germ Cell Tumor

    • Arm Groups

    ArmDescriptionIntervention
    Active Comparator

    Standard Arm - Standard BEP

    		Participants 16 years or older will receive 4 cycles of Standard BEP as follows: Bleomycin 30,000 IU IV weekly for 3 doses Etoposide 100 mg/m2 IV on day 1 - 5 Cisplatin 20 mg/m2 IV on day 1 - 5 Pegylated G-CSF 6 mg SCI on day 6 Patients < 16 years old and weighs = 45 kg will receive: Bleomycin *15,000 - 30,000 IU IV weekly for 3 doses Etoposide 100 mg/m2 IV on day 1 - 5 Cisplatin 20 mg/m2 IV on day 1 - 5 Pegylated G-CSF 6 mg SCI on day 6 Patients <16 years old and weighs < 45 kg will receive: Bleomycin *15,000 - 30,000 IU IV weekly for 3 doses Etoposide 100 mg/m2 IV on day 1 - 5 Cisplatin 20 mg/m2 IV on day 1 - 5 Filgrastim 10mcg/kg/day on day 6, until post-nadir Absolute Neutrophil Count =1 x10^9/ L The dose of bleomycin is decided by the treating physician and based on the patient's Body Surface Area. Each cycle is 3 weeks (21 days). The planned total duration of treatment is 12 weeks.
  • Drug: Bleomycin (active name: Bleomycin Sulfate)

    Standard Arm: Bleomycin 30,000 international units IV weekly for 3 doses (eg. days 1, 8 and 15 or days 2, 9 and 16 of a 21-day cycle) for 4 cycles. Accelerated Arm: Bleomycin 30,000 international units IV weekly for 2 doses (eg. days 1 and 8 or days 2 and 9 of a 14-day cycle) for 4 cycles. Followed by Bleomycin 30,000 international units IV weekly for 4 doses.

    Other names:

    • Blenamax (Aspen)
    • DBL Bleomycin Sulphate (Willow Pharmaceuticals Pty Limited)
    • Bleo Powder for injection (Hospira)

  • Drug: Cisplatin

    Standard Arm: Cisplatin 20 mg/m2 IV on days 1, 2, 3, 4, 5 of a 21-day cycle for 4 cycles. Accelerated Arm: Cisplatin 20 mg/m2 IV on days 1, 2, 3, 4, 5 of a 14-day cycle for 4 cycles.

    Other names:

    • Cisplatin Ebewe (Sandoz)
    • Cisplatin injection (Pfizer)
    • DBL Cisplatin Injection (Hospira)

  • Drug: Filgrastim

    Standard Arm: 10 mcg/kg/day on day6, until post-nadir absolute neutrophil count = 1.0 x 10^9/L, of a 21-day cycle for 4 cycles. Accelerated Arm: 10 mcg/kg/day on day 6, until post-nadir absolute neutrophil count = 1.0 x 10^9/L, of a 14-day cycle for 4 cycles.

    Other names:

    • Neupogen (Amgen)
    • Nivestim (Hospira)
    • Tevagrastim (Teva Pharma Australia Pty Ltd)
    • Zarzio (Sandoz)

  • Drug: Etoposide

    Standard Arm: Etoposide 100 mg/m2 IV on days 1, 2, 3, 4, 5 of a 21-day cycle for 4 cycles. Accelerated Arm: 100 mg/m2 IV on days 1, 2, 3, 4, 5 of a 14-day cycle for 4 cycles.

    Other names:

    • DBL Etoposide Injection (Hospira)
    • Etopophos (Bristol-Myers Squibb)
    • Etoposide (Pfizer)
    • Etoposide Ebewe (Sandoz)

  • Drug: Pegylated G-CSF (Pegfilgrastim)

    Standard Arm: 6 mg SCI on day 6 of a 21-day cycle for 4 cycles. Accelerated Arm: 6 mg SCI on day 6 of a 14-day cycle for 4 cycles.

    Other names:

    • Neulasta Syringe with Automatic Needle Guard (Amgen)

    • Experimental

    Experimental Arm - Accelerated BEP

    		Participants 16years or older will receive 4 cycles of Accelerated BEP as follows: Bleomycin 30,000 IU IV wkly for 2 doses Etoposide 100 mg/m2 IV on day 1 - 5 Cisplatin 20 mg/m2 IV on day 1- 5 Pegylated G-CSF 6 mg SCI on day 6 Patients <16years and weighs =45 kg will receive: Bleomycin *15,000 - 30,000 IU IV wkly for 2 doses Etoposide 100 mg/m2 IV on day 1 - 5 Cisplatin 20 mg/m2 IV on day 1 - 5 Pegylated G-CSF 6 mg SCI on day 6 Patients <16years and weighs <45 kg will receive: Bleomycin *15,000 - 30,000 IU IV wkly for 2 doses Etoposide 100 mg/m2 IV on day 1 - 5 Cisplatin 20 mg/m2 IV on day 1 - 5 Filgrastim 10mcg/kg/day on day 6, until ANC =1 x10^9/ L Each cycle is 2 weeks (14days) Following 4xBEP cycles, patients will receive additional bleomycin as follows: - Bleomycin *15,000 - 30,000 IU IV wkly for 4 doses * The dose of bleomycin is decided by the treating physician and based on the patient's BSA. The planned total duration is 12 weeks.
  • Drug: Bleomycin (active name: Bleomycin Sulfate)

    Standard Arm: Bleomycin 30,000 international units IV weekly for 3 doses (eg. days 1, 8 and 15 or days 2, 9 and 16 of a 21-day cycle) for 4 cycles. Accelerated Arm: Bleomycin 30,000 international units IV weekly for 2 doses (eg. days 1 and 8 or days 2 and 9 of a 14-day cycle) for 4 cycles. Followed by Bleomycin 30,000 international units IV weekly for 4 doses.

    Other names:

    • Blenamax (Aspen)
    • DBL Bleomycin Sulphate (Willow Pharmaceuticals Pty Limited)
    • Bleo Powder for injection (Hospira)

  • Drug: Cisplatin

    Standard Arm: Cisplatin 20 mg/m2 IV on days 1, 2, 3, 4, 5 of a 21-day cycle for 4 cycles. Accelerated Arm: Cisplatin 20 mg/m2 IV on days 1, 2, 3, 4, 5 of a 14-day cycle for 4 cycles.

    Other names:

    • Cisplatin Ebewe (Sandoz)
    • Cisplatin injection (Pfizer)
    • DBL Cisplatin Injection (Hospira)

  • Drug: Filgrastim

    Standard Arm: 10 mcg/kg/day on day6, until post-nadir absolute neutrophil count = 1.0 x 10^9/L, of a 21-day cycle for 4 cycles. Accelerated Arm: 10 mcg/kg/day on day 6, until post-nadir absolute neutrophil count = 1.0 x 10^9/L, of a 14-day cycle for 4 cycles.

    Other names:

    • Neupogen (Amgen)
    • Nivestim (Hospira)
    • Tevagrastim (Teva Pharma Australia Pty Ltd)
    • Zarzio (Sandoz)

  • Drug: Etoposide

    Standard Arm: Etoposide 100 mg/m2 IV on days 1, 2, 3, 4, 5 of a 21-day cycle for 4 cycles. Accelerated Arm: 100 mg/m2 IV on days 1, 2, 3, 4, 5 of a 14-day cycle for 4 cycles.

    Other names:

    • DBL Etoposide Injection (Hospira)
    • Etopophos (Bristol-Myers Squibb)
    • Etoposide (Pfizer)
    • Etoposide Ebewe (Sandoz)

  • Drug: Pegylated G-CSF (Pegfilgrastim)

    Standard Arm: 6 mg SCI on day 6 of a 21-day cycle for 4 cycles. Accelerated Arm: 6 mg SCI on day 6 of a 14-day cycle for 4 cycles.

    Other names:

    • Neulasta Syringe with Automatic Needle Guard (Amgen)

    •