E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced or unresectable or metastatic urothelial carcinoma who have had disease progression on or after one prior first-line platinum-based chemotherapy. |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the bladder and the urinary tract |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064467 |
E.1.2 | Term | Urothelial carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
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) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 treatment with diuretics and/or paracentesis. 12) Adequate renal function as defined by creatinine clearance >30 mL/min either as measured by 24-hour urine collection or as calculated. 13) The patient’s urinary protein is ≤1+ on dipstick or routine urinalysis; if urine protein ≥2+, a 24-hour urine collection must demonstrate <2 g of protein in 24 hours. 14) The patient, if female, is surgically sterile, postmenopausal, or agrees to use a highly effective method of contraception during and for 12 weeks after the treatment period. The patient, if male, is surgically sterile or agrees to use a reliable method of contraception and to not donate sperm during and for 12 weeks after the treatment period or country requirements, whichever is longer. 15) The patient is able to provide signed informed consent and is amenable to compliance with protocol schedules and testing. 16) The patient is ≥18 years of age or of an acceptable age to provide informed consent according to local regulations, whichever is older. 17) The patient is willing to provide blood, urine, and tissue samples for research purposes. Submission of blood and urine specimens is mandatory for participation in this study, unless restricted per local regulations. If prior archived tumor specimens are available, and unless restricted by local regulations, submission of archived tumor tissue is mandatory. If an archived specimen is not available, submission of a newly acquired biopsy is requested when biopsy is safe and feasible. |
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E.4 | Principal 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 this study; and/or • was treated with antiangiogenic therapy within 28 days prior to randomization. 31) The patient has undergone major surgery within 28 days prior to randomization or subcutaneous venous access device placement within 7 days prior to randomization. 32) The patient has had a serious nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization. 33) The patient has an elective or planned major surgery to be performed during the course of the trial. 34) The patient is pregnant or lactating. 35) The patient has a concurrent malignancy or had another malignancy within 5 years of study enrollment (with the exception of adequately treated non-melanomatous skin cancer, in-situ cervical cancer, other noninvasive carcinoma or in situ neoplasm, or localized prostate cancer with no evidence of biochemical or clinical recurrence over a minimum of 6 months [≥6 months]). 36) The patient has an acute/subacute bowel obstruction or history of chronic diarrhea requiring ongoing medical intervention. 37) The patient has a history of gastrointestinal perforation and/or fistula within 6 months prior to randomization. 38) The patient has active diverticulitis. 39) The patient has a known hypersensitivity to docetaxel or other drugs formulated with polysorbate 80. 40) The patient has a known hypersensitivity to agents of similar biologic composition as ramucirumab, or other agents that specifically target VEGF. |
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | 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). |
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E.5.2 | 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)
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient Reported Outcomes, Immunogenicity |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
Denmark |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Korea, Democratic People's Republic of |
Netherlands |
Poland |
Romania |
Russian Federation |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 21 |