NCT02516241进行中（未招募）3 期
A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination With Tremelimumab Versus Standard of Care Chemotherapy in Patients With Unresectable Stage IV Urothelial Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 1,126
- 试验地点
- 222
- 主要终点
- To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set
研究概览
简要总结
A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line MEDI4736 (Durvalumab) Monotherapy and MEDI4736 (Durvalumab) in Combination with Tremelimumab Versus Standard of Care Chemotherapy in Patients with Stage IV Urothelial Cancer
详细描述
This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy and MEDI4736 (Durvalumab) in combination with tremelimumab versus SoC (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) first-line chemotherapy in treatment-naïve patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) and to allow sufficient flexibility for Investigators and patients to select the agents that reflect their normal clinical practice and national guidelines. The patients enrolled in the study will be randomized 1:1:1 to receive treatment with combination therapy, monotherapy, or SoC (cisplatin + gemcitabine or carboplatin + gemcitabine, based on cisplatin eligibility). Patients will be treated with MEDI4736 (Durvalumab) or MEDI4736 (Durvalumab) with tremelimumab, or treated with SoC until progressive disease (PD) is confirmed, unacceptable toxicity occurs, withdrawal of consent, or another discontinuation criterion is met. Patients will be followed for up to 2 years.
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
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with histologically or cytologically documented, unresectable, Stage IV transitional cell carcinoma of the urothelium who have not been previously treated with first-line chemotherapy.
- •Patients eligible or ineligible for cisplatin-based chemotherapy. Cisplatin ineligibility is defined as meeting 1 of the following criteria: • Creatinine clearance (calculated or measured) <60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection for determination • Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 audiometric hearing loss • CTCAE Grade ≥2 peripheral neuropathy • New York Heart Association ≥Class III heart failure.
- •Tumor PD-L1 status, with Immunohistochemical (IHC) assay confirmed by a reference laboratory, must be known prior to randomization.
排除标准
- •Prior exposure to immune-mediated therapy, including but not limited to, other anti cytotoxic T-lymphocyte-associated protein 4 (CTLA 4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment.
- •History of allogenic organ transplantation that requires use of immunosuppressive agents.
- •Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: • Patients with vitiligo or alopecia • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement • Any chronic skin condition that does not require systemic therapy • Patients without active disease in the last 3 years may be included but only after consultation with AstraZeneca • Patients with celiac disease controlled by diet alone may be included but only after consultation with AstraZeneca.
- •Brain metastases or spinal cord compression unless the patient's condition is stable and off steroids for at least 14 days prior to the start of study treatment. Patients with suspected or known brain metastases at screening should have an MRI (preferred)/CT, preferably with IV contrast to access baseline disease status.
- •Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
- •Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). The following are exceptions to this criterion: • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection) • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
- •Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.
研究组 & 干预措施
Combination Therapy
Experimental
MEDI4736 (Durvalumab) + Tremelimumab
干预措施: MEDI4736 (Durvalumab) (Drug)
Monotherapy
Experimental
MEDI4736 (Durvalumab)
干预措施: MEDI4736 (Durvalumab) (Drug)
Standard of Care
Active Comparator
Standard of Care Chemotherapy Treatment
干预措施: Carboplatin (Drug)
Combination Therapy
Experimental
MEDI4736 (Durvalumab) + Tremelimumab
干预措施: Tremelimumab (Drug)
Standard of Care
Active Comparator
Standard of Care Chemotherapy Treatment
干预措施: Gemcitabine (Drug)
Standard of Care
Active Comparator
Standard of Care Chemotherapy Treatment
干预措施: Cisplatin (Drug)
结局指标
主要结局
To Assess the Efficacy of Durvalumab + Tremelimumab Combination Therapy Versus SoC in Terms of OS in Full Analysis Set
时间窗: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
To Assess the Efficacy of Durvalumab Monotherapy Versus SoC in Terms of OS in PD-L1-High Analysis Set
时间窗: From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).
The OS was defined as the time from the date of randomization until death due to any cause (ie, date of death or censoring - date of randomization + 1). Any participant not known to have died at the time of analysis were censored based on the last recorded date on which the participant was known to be alive. Median OS was calculated using the Kaplan-Meier technique.
次要结局
- Alive at 24 Months (OS24), PD-L1-High Analysis Set(From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).)
- OS, Full Analysis Set - Durvalumab Monotherapy vs SoC(From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- OS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC(From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- OS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy(From randomization date until death due to any cause, assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- PFS, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Alive and Progression-free at 12 Months (APF12), PD-L1-High Analysis Set(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).)
- Objective Response Rate (ORR), Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Disease Control Rate (DCR) at 6 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).)
- Alive and Progression-free at 12 Months (APF12), PD-L1-Low/Negative Analysis Set(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).)
- PFS2, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Objective Response Rate (ORR) Based on BICR Assessment According to RECIST 1.1 - Responses Are Confirmed - Durvalumab Cisplatin Ineligible Population(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (01NOV2017, a maximum of 3 years).)
- Alive at 24 Months (OS24), Full Analysis Set(From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).)
- Alive at 24 Months (OS24), PD-L1-Low/Negative Analysis Set(From randomization date until death due to any cause, assessed up to 24 months or the data cut-off date (27JAN2020).)
- PFS, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Objective Response Rate (ORR), PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- PFS, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Alive and Progression-free at 12 Months (APF12), Full Analysis Set(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).)
- PFS2, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- PFS2, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy(Tumour scans performed at baseline then every 8 weeks since randomization until first confirmed disease progression, disease then assessed per local practice until 2nd progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Objective Response Rate (ORR), PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Disease Control Rate (DCR) at 12 Months, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020))
- Disease Control Rate (DCR) at 12 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).)
- Disease Control Rate (DCR) at 6 Months, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Monotherapy vs SoC(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).)
- Disease Control Rate (DCR) at 6 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 6 months or the data cut-off date (27JAN2020).)
- Disease Control Rate (DCR) at 12 Months, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy Versus SoC and Durvalumab + Tremelimumab Combination Therapy Versus Durvalumab Monotherapy(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to 12 months or the data cut-off date (27JAN2020).)
- Duration of Response (DoR), PD-L1-Low/Negative Analysis Set(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Serum Concentrations of Durvalumab, Pharmacokinetic Analysis Set(Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.)
- Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Duration of Response (DoR), Full Analysis Set(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Duration of Response (DoR), PD-L1-High Analysis Set(Tumour scans performed at baseline then every 8 weeks since randomization until confirmed disease progression. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Serum Concentrations of Tremelimumab, Pharmacokinetic Analysis Set(Pre-dose and within 1 hour after end of infusion at Week 0, 12 and 24, pre-dose at week 4, and at follow-up Month 3.)
- Number of Participants With Anti-Drug Antibody (ADA) Response to Durvalumab, Safety Analysis Set - ADA Evaluable Patients(At week 0, 4, 12 and 24, and at follow-up Month 3.)
- Change From Baseline in FACT-BL (Derived NFBlSI-18 Score, FACT-BL TOI, and FACT-BL Total Score) by MMRM Analysis, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Number of Participants With Anti-Drug Antibody (ADA) Response to Tremelimumab, Safety Analysis Set - ADA Evaluable Patients(At week 0, 4, 12 and at follow-up Month 3.)
- Improvement in Fatigue and Deterioration in Pain Per FACT-BL, Full Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-High Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
- Improvement in Fatigue and Deterioration in Pain Per FACT-BL, PD-L1-Low/Negative Analysis Set -Durvalumab + Tremelimumab Combination Therapy vs SoC and Durvalumab Mono Therapy vs SoC(At baseline then every 8 weeks until second progression/death, whichever comes first. Assessed up to the data cut-off date (27JAN2020, a maximum of 5 years).)
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