Study of First Line MEDI4736 with or without Tremelimumab versus Standard of Care Chemotherapy in Advanced Unresectable Urothelial Bladder Cancer

Conditions: Adult patients (age > o = 18 years) with histologically or cytologically documented transitional cell carcinoma (transitional cell and mixed transitional/non transitional cell histologies) of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra), unresectable Stage IV (ie, ?T4bN0M0 for bladder), and who are chemotherapy-naïve.
MedDRA version: 18.1Level: LLTClassification code 10022880Term: Invasive bladder cancer stage IVSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2015-001633-24-ES

Lead Sponsor: AstraZeneca AB

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 525

Inclusion Criteria

1, 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.
2, 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 ? 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.
3, Tumor PD-L1 status, with IHC assay confirmed by a reference laboratory, must be known prior to randomization.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 300
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 225

Exclusion Criteria

1, Prior exposure to immune-mediated therapy, including but not limited to, other anti CTLA 4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines.
2, History of allogenic organ transplantation that requires use of immunosuppressive agents.
3, Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: ? Patients with vitiligo or alopecia ? Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement of psoriasis not requiring systemic treatment.
4, Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a CT/ MRI of the brain prior to study entry.
5, Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
6, Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 or tremelimumab. 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).
7, 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.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess PFS of MEDI4736 in combination with tremelimumab to standard of care (SoC) chemotherapy;Secondary Objective: 1, To assess PFS of MEDI4736+tremelimumab to SoC chemotherapy, and to monotherapy in patients with PD-L1-negative. 2, To assess OS of MEDI4736 + tremelimumab to SoC chemotherapy. 3, To assess PFS of MEDI4736 monotherapy to SoC chemotherapy. 4. To further assess ORR of MEDI4736 + tremelimumab to SoC chemotherapy. 5, To assess disease-related symptoms in terms of FACT-BL. 6, To assess the PK of MEDI4736 monotherapy and MEDI4736 + tremelimumab. 7, To investigate the immunogenicity of monotherapy and MEDI4736+tremelimumab. 8, To assess the safety and tolerability in terms of AEs.;Primary end point(s): Progression-free survival;Timepoint(s) of evaluation of this end point: Up to 3 years

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1, Overall survival. 2, OS24. 3, Proportion of patients alive and progression-free at 12 months. 4, Objective response rate. 5, Duration of response. 6, Disease control rate. 7, Best objective response.;Timepoint(s) of evaluation of this end point: Baseline to the end of treatment

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