Locally advanced or unresectable or metastatic urothelial carcinoma who have had disease progression on or after one prior first-line platinum-based chemotherapy. MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 100000004864
Conditions
Sponsors
Eli Lilly and Company
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Histologically or cytologically confirmed, locally advanced or unresectable or metastatic urothelial (transitional cell) carcinoma of the bladder, urethra, ureter, or renal pelvis. Patients with mixed pathology are eligible only if they have predominantly transitional cell tumor based on local pathology review. 2) Demonstrated disease progression while on a platinum-containing regimen in the first-line setting or within 14 months after completing the first-line platinum regimen. Patients who received treatment with one immune checkpoint inhibitor (for example PD-1, PDL1, CTLA4) regimen may have a longer interval since prior platinum-containing therapy (=24 months), as noted in Inclusion Criterion [4]. 3) A life expectancy of =3 months, in the judgment of the investigator. 4) The patient has received no more than one prior systemic chemotherapy regimen in the relapsed or metastatic setting. Prior cytotoxic therapy in an adjuvant or neoadjuvant setting is not considered as a prior line of systemic chemotherapy in the relapsed or metastatic setting. Prior treatment with intravesicular chemotherapy, bacillus Calmette-Guérin (BCG), or platinum given as a radiation-sensitizing agent will not be considered as a systemic line of treatment. Prior treatment with no more than one prior immune checkpoint inhibitor is permitted and will not be considered as a line of systemic chemotherapy. Patients enrolling after immune checkpoint inhibitor therapy must have demonstrated disease progression while on that therapy or within 24 months after the last dose of that therapy. 5) Measurable disease or nonmeasurable but evaluable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 6) Resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy to Grade =1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 7) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8) The patient has adequate hematologic function and has not received blood or blood components transfusion within 2 weeks prior to the laboratory test. 9) Adequate coagulation function as defined by international normalized ratio (INR) =1.5 and a partial thromboplastin time (PTT) =1.5 × upper limit of normal (ULN) if not receiving anticoagulation therapy. Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin. If on warfarin, the patient must have an INR =3 and have no active bleeding (defined as within 14 days prior to randomization, excluding trace hematuria) or pathological condition that carries a high risk of bleeding. 10) Adequate hepatic function as defined by bilirubin within normal limits (WNL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =3.0 × ULN, and alkaline phosphatase (AP) =2.5 × ULN. 11) The patient does not have: • cirrhosis at a level of Child-Pugh B (or worse), or • cirrhosis and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing tre
Exclusion criteria
Exclusion criteria: 18) The patient has received more than one prior systemic chemotherapy regimen for metastatic disease (except as noted in Inclusion Criterion [4]). A treatment regimen must consist of a minimum of 2 cycles to be considered as a prior regimen. 19) The patient has received prior systemic taxane therapy for TCC of the bladder, urethra, ureter, or renal pelvis in any setting (neoadjuvant, adjuvant, metastatic). Prior intravesical taxane therapy is allowed and will not be considered as a prior line of systemic therapy. 20) The patient has received more than one prior antiangiogenic agent (that is, bevacizumab, sorafenib, sunitinib) for TCC of the urothelium. 21) The patient has received radiation therapy (including full-dose pelvic radiotherapy) within 4 weeks prior to randomization or has not recovered from toxic effects of the treatment that was given >4 weeks prior to randomization. Single fraction radiotherapy for palliative bone stabilization within 4 weeks prior to randomization is allowed. If any tumor lesion is administered radiotherapy, then it cannot be considered for response assessment. 22) The patient has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders. 23) The patient has experienced a Grade =3 bleeding event (for example, via gastric ulcers, gastric varices, rectal bleeding, or gross hematuria) within 3 months prior to randomization. Patients must have complete resolution of any prior bleeding event prior to randomization. 24) The patient has uncontrolled intercurrent illness, including, but not limited to symptomatic anemia, uncontrolled hypertension (>160 mm Hg systolic and/or >100 mm Hg diastolic, despite antihypertensive medication), symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness, or any other serious uncontrolled medical disorders in the opinion of the investigator. 25) The patient has experienced any arterial or venothrombotic or thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 6 months prior to randomization. 26) The patient has known untreated brain metastases, uncontrolled spinal cord compression, or leptomeningeal disease. (Note: A brain scan via computed tomography [CT] with contrast or magnetic resonance imaging [MRI] is to be performed only after study eligibility is confirmed, to detect the presence of intracranial metastasis.) 27) The patient has an ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy. 28) The patient has known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome-related illness. 29) The patient has received a prior autologous or allogeneic organ or tissue transplantation. 30) The patient: • received chemotherapy within 21 days prior to randomization; and/or • is currently enrolled in, or discontinued within 21 days prior to randomization from, a clinical trial involving an investigational product (IP) or non-approved use of a drug or device, or is concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with th
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): To test PFS superiority with this assumption: The PFS hazard ratio for treatment group (ramucirumab plus docetaxel) vs control group (placebo plus docetaxel) is 0.70.;Timepoint(s) of evaluation of this end point: The primary analysis of PFS will be performed when a minimum of 331 PFS events have been observed from the first 437 randomized patients with 0.05 Alpha (two sided).;Main Objective: The primary objective of this study is to compare the progression-free survival (PFS) of ramucirumab in combination with docetaxel with the PFS of placebo in combination with docetaxel, in patients with locally advanced or unresectable or metastatic urothelial carcinoma who have had disease progression on or after one prior first-line platinum-based chemotherapy; Secondary Objective: The secondary objectives of this study are to compare each of the following variables between the treatment arms: • overall survival (OS) time • objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (DCR) • duration of response (DOR) • safety profile • patient-reported outcome (PRO) measures (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 [EORTC QLQ-C30] and EQ 5D-5L questionnaires) Secondary objectives also include the evaluation of: • the pharmacokinetic profile of ramucirumab • the immunogenicity of ramucirumab (anti-ramucirumab antibodies) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • overall survival (OS) time • objective response rate (ORR; complete response [CR] + partial response [PR]) and disease control rate (DCR) • duration of response (DOR) • safety profile • patient-reported outcome (PRO) measures (EORTC QLQ-C30 and EQ-5D-5L questionnaires). Secondary objectives also include the evaluation of: • the pharmacokinetic profile of ramucirumab - the immunogenicity of ramucirumab (anti-ramucirumab antibodies) ; Timepoint(s) of evaluation of this end point: A gatekeeping design will be used to assess PFS, OS, and ORR. The OS superiority is tested only if PFS superiority test is significant. Similarly, the ORR superiority is tested only if OS superiority test is significant. An interim OS analysis will be performed at PFS final analysis with Bonferroni alpha splitting of 0.001(two sided); all patients who have been randomized at that point will be used to compare OS between the 2 arms. The final OS analysis will be performed when observed 382 OS events with alpha of 0.049 (two sided). At the final analysis, all randomized patients will be used to compare OS between the 2 arms. ORR will be tested with 0.05 alpha. | — |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Democratic People's Republic of, Mexico, Netherlands, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactClinical Trial Registry Office
Eli Lilly
Outcome results
None listed