Study of Durvalumab Given With Chemotherapy, Durvalumab in Combination With Tremelimumab Given With Chemotherapy, or Chemotherapy in Patients With Unresectable Urothelial Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of combining durvalumab ± tremelimumab with standard of care (SoC) chemotherapy (cisplatin + gemcitabine or carboplatin + gemcitabine doublet) followed by durvalumab monotherapy versus SoC alone as first-line chemotherapy in patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra).

Official Title
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A Phase III, Randomized, Open-Label, Controlled, Multi-Center, Global Study of First-Line Durvalumab in Combination With Standard of Care Chemotherapy and Durvalumab in Combination With Tremelimumab and Standard of Care Chemotherapy Versus Standard of Care Chemotherapy Alone in Patients With Unresectable Locally Advanced or Metastatic Urothelial Cancer.

Conditions
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Unresectable Locally Advanced Urothelial Cancer, Metastatic Urothelial Cancer

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Tremelimumab
* Drug: Cisplatin + Gemcitabine
* Drug: Carboplatin + Gemcitabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients with histologically or cytologically documented, unresectable, locally advanced or metastatic transitional cell carcinoma (transitional cell and mixed transitional/non-transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra) Patients who have not been previously treated with first-line chemotherapy. Patients who have received prior definitive chemoradiation, adjuvant or neoadjuvant treatment for locally advanced disease are eligible provided that progression to locally advanced or metastatic disease has occurred >12 months from the last therapy [for chemoradiation and adjuvant treatment] or >12 months from the last surgery [for neoadjuvant treatment]. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion at baseline. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrolment Adequate organ and marrow function as defined in the protocol Life expectancy ≥12 weeks in the opinion of the investigator Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Key Exclusion Criteria: Prior exposure to immune-mediated therapy (with exclusion of Bacillus Calmette Guerin), including but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD L1, or anti-PD-L2 antibodies, except therapeutic anticancer vaccines, which are permitted. Prior local intervesical chemotherapy or immunotherapy is allowed if completed at least 28 days prior to the initiation of study treatment. No severe concomitant condition that requires immunosuppression medication Untreated central nervous system (CNS) metastases and/or carcinomatous meningitis Patients who may be eligible for or are being considered for radical resection during the course of the study. Any medical contraindications to platinum (cisplatin or carboplatin) based doublet chemotherapy and/or known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab in Combination with SoC Chemotherapy<br>Durvalumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks. All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: cisplatin+ gemcitabine If the patient is cisplatin-ineligible, carboplatin + gemcitabine | Drug: Durvalumab<br>* Durvalumab IV (intravenous infusion)<br>* Other names: MEDI4736;Drug: Cisplatin + Gemcitabine<br>* Cisplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.<br>Drug: Carboplatin + Gemcitabine<br>* Carboplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.<br>|
| Experimental: Durvalumab in Combination with Tremelimumab+SoC Chemotherapy<br>Durvalumab and Tremelimumab every 3 weeks in concurrence with chemotherapy, followed by durvalumab monotherapy every 4 weeks Tremelimumab will be provided for 4 cycles. All patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: cisplatin+ gemcitabine If the patient is cisplatin-ineligible, carboplatin + gemcitabine | Drug: Durvalumab<br>* Durvalumab IV (intravenous infusion)<br>* Other names: MEDI4736;Drug: Tremelimumab<br>* Tremelimumab IV (intravenous infusion)<br>Drug: Cisplatin + Gemcitabine<br>* Cisplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.<br>Drug: Carboplatin + Gemcitabine<br>* Carboplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.<br>|
| Active Comparator: SoC Chemotherapy<br>Patients will receive one of the following standard of care chemotherapy regimens every 3 weeks for 6 cycles: cisplatin+ gemcitabine If the patient is cisplatin-ineligible, carboplatin + gemcitabine | Drug: Cisplatin + Gemcitabine<br>* Cisplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.<br>Drug: Carboplatin + Gemcitabine<br>* Carboplatin IV (intravenous)+ Gemcitabine IV(intravenous), as standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of randomization until death due to any cause | approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Additional analysis beyond the primary endpoint | approximately 5 years | 
| Overall Survival at 24 months (OS24) | The OS24 will be defined as the Kaplan-Meier estimate of OS at 24 months | 24 months | 
| Progression Free Survival (PFS) | PFS (per RECIST 1.1) will be defined as the time from the date of randomization until the date of first objective disease progression or death | approximately 5 years | 
| Alive and Progression Free Survival at 12 months (APF12) | The APF12 will be defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1) at 12 months | 12 months | 
| Objective Response Rate (ORR) | ORR (per RECIST 1.1) is defined as the number (%) of patients with at least 1 visit response of complete response or partial response and will be based on a subset of all randomized patients | approximately 5 years | 
| Duration of Response (DoR) | DoR (per RECIST 1.1) will be defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression | approximately 5 years | 
| Disease Control Rate (DCR) | DCR is defined as the proportion of subjects with the best overall response of complete response, partial response or stable disease per RECIST 1.1 | approximately 5 years | 
| Time from randomization to second (PFS2) | PFS2 will be defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the PFS endpoint or death | approximately 5 years | 
| To assess disease-related symptoms, physical functioning, and other Health-related quality of life | Collection of patient reported outcome questionnaires | approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal pelvis, ureters, urinary bladder, urethra, bladder cancer