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A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants With Urothelial Cancer (RANGE)

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ClinicalTrials.gov Identifier: NCT02426125
Recruitment Status : Active, not recruiting
First Posted : April 24, 2015
Results First Posted : March 8, 2019
Last Update Posted : March 8, 2019
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Brief Summary:
The main purpose of this study is to evaluate the safety and efficacy of the study drug ramucirumab in combination with docetaxel in participants with urothelial cancer who failed prior platinum-based therapy.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Drug: Ramucirumab Drug: Docetaxel Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 530 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Ramucirumab Plus Docetaxel Versus Placebo Plus Docetaxel in Patients With Locally Advanced or Unresectable or Metastatic Urothelial Carcinoma Who Progressed on or After Platinum-Based Therapy
Actual Study Start Date : July 13, 2015
Actual Primary Completion Date : April 21, 2017
Estimated Study Completion Date : June 20, 2019


Arm Intervention/treatment
Experimental: Ramucirumab + Docetaxel
Ramucirumab (10 milligram/kilogram [mg/kg]) intravenously (IV) plus docetaxel (75 milligram/square meter [mg/m²]) IV in 21 day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
Drug: Ramucirumab
Administered IV
Other Name: LY3009806

Drug: Docetaxel
Administered IV

Placebo Comparator: Placebo + Docetaxel
Placebo IV plus docetaxel (75 mg/m²) IV in 21 day cycles. Participants may continue to receive treatment until discontinuation criteria are met.
Drug: Docetaxel
Administered IV

Drug: Placebo
Administered IV




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Randomization to Radiological Disease Progression or Death from Any Cause (Up to 18 Months) ]
    PFS defined as time from first day of therapy to first evidence of disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause. Progressive Disease (PD) is at least 20% increase in sum of diameters of target lesions, with reference being the smallest sum on study and plus absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If participant does not have complete baseline disease assessment, then PFS time was censored at date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for participant. If participant is not known to have died or have objective progression as of data inclusion cutoff date for analysis, PFS time was censored at last adequate tumor assessment date.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Randomization to Date of Death from Any Cause (Up to 21 Months) ]
    OS is the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data inclusion cutoff date for a particular analysis, OS was censored for that analysis at the last known alive date prior to the data inclusion cutoff date.

  2. Percentage of Participants With an Objective Response Rate (ORR) [ Time Frame: Randomization to Disease Progression (Up to 18 Months) ]
    Objective response rate is defined as the percentage of participants who achieve a best overall response of complete response (CR) + partial response (PR). ORR = CR + PR. CR is the disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.

  3. Percentage of Participants With Disease Control Rate (DCR) [ Time Frame: Randomization to Disease Progression (Up to 18 Months) ]
    DCR is the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1. Target lesions - CR: Disappearance of all lesions; any pathological lymph nodes must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum. Progressive Disease (PD): At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study (the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Non target lesions - CR: Disappearance of all lesions and normalization of tumor marker levels; all lymph nodes must be non-pathological in size. Non-CR/Non-PD: Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels. PD: Unequivocal progression of existing lesions or the appearance of new lesion(s).

  4. Duration of Response (DoR) [ Time Frame: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 18 Months) ]
    Objective response was achieved if they had a best overall response of CR or PR. Target lesions- CR: Disappearance of all lesions; any pathological lymph nodes have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of lesions vs the baseline sum. PD: At least a 20% increase in the sum of diameters of lesions vs the smallest sum on study(the sum must also demonstrate an absolute increase of at least 5 mm); or the appearance of new lesion(s). Non target lesions - CR: Disappearance of all lesions and normalization of tumour marker levels; all lymph nodes must be non-pathological in size. Non-CR/Non-PD: Persistence of lesion(s) and/or maintenance of abnormal tumor marker levels. PD: Unequivocal progression of existing lesions or the appearance of new lesion(s). If a participant was not known to have died or have radiographically documented PD as of the data inclusion cutoff date, DOR was censored at the date of the last adequate tumor assessment.

  5. Time to Deterioration in Quality of Life (QoL) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Global Health Status/ QoL Scale [ Time Frame: Randomization, 30 Days After Treatment Discontinuation (Up to 18 Months) ]
    Time to sustained deterioration was defined as time from randomization to first worsening in QoL with no subsequent non-worsened assessment. Worsening in global health status/QoL was defined as a decrease of ≥10 points on a 100-point scale. If a participant did not report worsening, time to sustained deterioration was censored at date of last non-worsened assessment. Scores for global health status/QoL range from 0 to 100 with; higher scores representing better QoL.

  6. Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Randomization, 30 Days After Treatment Discontinuation (Up to 18 Months) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. A unique EQ-5D health state is defined by combining 1 level from each of the 5 dimensions. Scores range from 0 (death) to 1 (perfect health), but scores <0 are possible based on the algorithm.

  7. Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS) [ Time Frame: Randomization, 30 Days After Treatment Discontinuation (Up to 18 Months) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. A unique EQ-5D health state is defined by combining 1 level from each of the 5 dimensions. Participants indicated their current health status by marking on a visual analogue scale (VAS) ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).

  8. Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab [ Time Frame: Cycle 1 and Cycle 9, Day 1: Predose, Postdose ]
    Maximum concentration (Cmax) of Ramucirumab at the end of ramucirumab infusion

  9. PK: Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Day 1 of Cycle 2, 3, 5 and 9 (Predose and Postdose) ]
    Minimum concentration (Cmin) of Ramucirumab following administration every 3 weeks.

  10. Number of Participants With Anti-Ramucirumab Antibodies [ Time Frame: 18 Months ]
    Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have histologically or cytologically confirmed, locally advanced or unresectable or metastatic urothelial (transitional cell) carcinoma of the bladder, urethra, ureter, or renal pelvis.
  • Had disease progression while on a platinum containing regimen in the first-line setting or within 14 months after completing the first-line platinum regimen. Participants who received treatment with one immune checkpoint inhibitor regimen are eligible (for example Programmed death 1 (PD-1), Programmed death-ligand 1 (PDL1), or CTLA4) and may have a longer interval since prior platinum-containing therapy (≤24 months).
  • Have a life expectancy of ≥3 months.
  • Have received no more than one prior systemic chemotherapy regimen in the relapsed or metastatic setting. Prior treatment with no more than one prior immune checkpoint inhibitor is permitted and will not be considered as a line of systemic chemotherapy.
  • Have measurable disease or nonmeasurable but evaluable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).
  • Have an Eastern Cooperative Oncology Group (ECOG) of 0 or 1.
  • Have adequate hematologic function.
  • Have adequate coagulation function.
  • Have adequate hepatic function.
  • The participant does not have:

    • cirrhosis at a level of Child-Pugh B (or worse)
    • cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis
  • Have adequate renal function as defined by creatinine clearance >30 milliliters/minute.
  • Have urinary protein ≤1+ on dipstick or routine urinalysis.
  • The participant is willing to provide blood, urine, and tissue samples for research purposes.

Exclusion Criteria:

  • Have received more than one prior systemic chemotherapy regimen for metastatic disease.
  • Have received prior systemic taxane therapy for transitional cell carcinoma (TCC) of the bladder, urethra, ureter, or renal pelvis in any setting (neoadjuvant, adjuvant, metastatic).
  • Have received more than one prior antiangiogenic agent (that is, bevacizumab, sorafenib, sunitinib) for TCC of the urothelium.
  • Have received radiation therapy within 4 weeks (≤4 weeks) prior to randomization or has not recovered from toxic effects of the treatment that was given >4 weeks prior to randomization.
  • Have a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders.
  • Have experienced a Grade ≥3 bleeding event within 3 months (≤3 months) prior to randomization.
  • Have uncontrolled intercurrent illness, including, but not limited to symptomatic anemia, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness, or any other serious uncontrolled medical disorders.
  • Have experienced any arterial or venothrombotic or thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 6 months (≤6 months) prior to randomization.
  • Have known untreated brain metastases, uncontrolled spinal cord compression, or leptomeningeal disease.
  • Have human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome-related illness.
  • Have undergone major surgery within 28 days (≤28 days) prior to randomization or subcutaneous venous access device placement within 7 days (≤7 days) prior to randomization.
  • The participant is pregnant prior to randomization or lactating.
  • Have a concurrent malignancy or had another malignancy within 5 years (≤5 years) of study enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02426125


  Show 141 Study Locations
Sponsors and Collaborators
Eli Lilly and Company
Investigators
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Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol  [PDF] January 14, 2015
Statistical Analysis Plan  [PDF] January 27, 2016


Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02426125     History of Changes
Other Study ID Numbers: 15679
I4T-MC-JVDC ( Other Identifier: Eli Lilly and Company )
2014-003655-66 ( EudraCT Number )
First Posted: April 24, 2015    Key Record Dates
Results First Posted: March 8, 2019
Last Update Posted: March 8, 2019
Last Verified: December 1, 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
Access Criteria:

Access Criteria:

A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.

URL: https://www.clinicalstudydatarequest.com/

Keywords provided by Eli Lilly and Company:
carcinoma of the bladder
carcinoma of the urethra
carcinoma the of ureter
carcinoma of the renal pelvis
transitional cell carcinoma
transitional cell tumor
RANGE
bladder cancer

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Docetaxel
Ramucirumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action