Phase 3 Accelerated BEP: A Randomised Phase 3 Trial of Accelerated Versus Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 500
- 试验地点
- 79
- 主要终点
- Progression-free survival (disease progression or death)
研究概览
简要总结
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.
详细描述
Bleomycin, Etoposide, Cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line chemotherapy for intermediate- and poor-risk metastatic germ cell tumours (GCTs). Cure rates are over 90% for good-risk disease, 85% with intermediate-risk, and about 70% for poor-risk disease. Previous strategies to improve first-line chemotherapy have failed to improve cure rates and were more toxic than BEP. New strategies are needed for patients with intermediate and poor-risk disease. BEP is accelerated by cycling Cisplatin and etoposide 2-weekly instead of 3-weekly. The Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) is conducting a trial comparing accelerated BEP with standard BEP. The aim of this study is to determine if accelerated BEP is superior to standard BEP as first-line chemotherapy for intermediate and poor risk metastatic GCTs.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 11 Years 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 11 years and ≤ 50 years on the date of randomisation
- •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
- •Primary arising in testis, ovary, retro-peritoneum, or mediastinum
- •Metastatic disease or non-testicular primary
- •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).
- •Adequate bone marrow function with ANC ≥1.0 x 10^9/L, Platelet count ≥100 x 10^9/L
- •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
- •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
- •ECOG Performance Status of 0, 1, 2, or 3
- •Study treatment both planned and able to start within 14 days of randomisation.
- •Willing and able to comply with all study requirements, including treatment, timing and nature of required assessments
- •Able to provide signed, written informed consent
排除标准
- •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)
- •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 hasb. non-seminoma by IGCCC criteria or stage IV malignant ovarian germ cell tumour 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). Acceptable regimens include cisplatin 20 mg/m2 days 1-2 and etoposide 100 mg/m2 days 1-2; carboplatin AUC 3 days 1-2 and etoposide 100 mg/m2 days 1-2; or baby-BOP.43 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.
- •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
- •Inadequate contraception. Men must use 2 effective methods of contraception, including use of a condom, during chemotherapy and for a year after completing chemotherapy.
- •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
- •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.
研究组 & 干预措施
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.
干预措施: Cisplatin (Drug)
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.
干预措施: Filgrastim (Drug)
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.
干预措施: Pegylated G-CSF (Pegfilgrastim) (Drug)
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.
干预措施: Etoposide (Drug)
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.
干预措施: Cisplatin (Drug)
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.
干预措施: Pegylated G-CSF (Pegfilgrastim) (Drug)
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.
干预措施: Filgrastim (Drug)
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.
干预措施: Bleomycin (active name: Bleomycin Sulfate) (Drug)
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.
干预措施: Bleomycin (active name: Bleomycin Sulfate) (Drug)
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.
干预措施: Etoposide (Drug)
结局指标
主要结局
Progression-free survival (disease progression or death)
时间窗: From randomisation up to disease progression or date of death whichever come first, assessed up to 5 years
PFS is measured from the date of randomisation until the criteria for disease progression are met (as defined in the protocol) or death. Participants who are not observed to progress nor die will be censored at the date of last follow-up
次要结局
- Adverse events (worst grade according to NCI CTCAE v4.03)(From start of chemotherapy until 30 days after last dose, an average of 4 months)
- Initial response assessment(At end of chemotherapy treatment, treatment planned for 12 weeks)
- Health-related quality of life(From date of randomisation until date of 18 month follow-up)
- Health-related quality of life for testicular cancer(From date of randomisation until date of 18 month follow-up)
- Treatment preference(From date of randomisation until date of 18 month follow-up)
- Delivered dose-intensity of chemotherapy (relative to standard BEP)(From start date of chemotherapy treatment until date of end of chemotherapy, an average of 12 weeks)
- Overall survival(From randomisation up to disease progression or date of death whichever come first, assessed up to 5 years)
- Final response assessment(At 6 months)