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

• ClinicalTrials.gov Identifier: NCT02426125
• Recruitment Status: Completed
• First Posted: April 24, 2015
• Results First Posted: March 8, 2019
• Last Update Posted: August 2, 2022
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: April 21, 2015
• First Posted Date: April 24, 2015
• Results First Submitted Date: January 25, 2019
• Results First Posted Date: March 8, 2019
• Last Update Posted Date: August 2, 2022
• Actual Study Start Date: July 13, 2015
• Actual Primary Completion Date: April 21, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 6, 2019)

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.

• Original Primary Outcome Measures (submitted: April 21, 2015): Progression Free Survival [ Time Frame: Randomization to Radiological Disease Progression or Death from Any Cause (Approximately 19 Months) ]

Current Secondary Outcome Measures (submitted: March 6, 2019)

• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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).
• 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
• 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.
• 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.

Original Secondary Outcome Measures (submitted: April 21, 2015)

• Overall Survival [ Time Frame: Randomization to Date of Death from Any Cause (Approximately 33 Months) ]
• Objective Response Rate (ORR) [ Time Frame: Randomization to Disease Progression (Approximately 33 Months) ]
• Disease Control Rate [ Time Frame: Randomization to Disease Progression (Approximately 33 Months) ]
• 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 (Approximately 33 Months) ]
• Change from Baseline on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [ Time Frame: Randomization, 30 Days After Treatment Discontinuation (Approximately 33 Months) ]
• Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) [ Time Frame: Randomization, 30 Days After Treatment Discontinuation (Approximately 33 Months) ]
• Pharmacokinetics (PK): Minimum Concentration (CMIN) of Ramucirumab [ Time Frame: Predose Cycle 1 through 30 Days After Treatment Discontinuation (Approximately 33 Months) ]
• Number of Participants with Anti-Ramucirumab Antibodies [ Time Frame: Predose Cycle 1 through 30 Days After Treatment Discontinuation (Approximately 33 Months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants With Urothelial Cancer
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Urothelial Carcinoma

Intervention

• Drug: Ramucirumab
  Administered IV
  Other Name: LY3009806
• Drug: Docetaxel
  Administered IV
• Drug: Placebo
  Administered IV

Study Arms

• 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.
  Interventions:

  • Drug: Ramucirumab
  • Drug: Docetaxel
• 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.
  Interventions:

  • Drug: Docetaxel
  • Drug: Placebo

Publications *

• van der Heijden MS, Powles T, Petrylak D, de Wit R, Necchi A, Sternberg CN, Matsubara N, Nishiyama H, Castellano D, Hussain SA, Bamias A, Gakis G, Lee JL, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Eigl BJ, Hozak RR, Rasmussen ER, Xia MS, Rhodes R, Wijayawardana S, Bell-McGuinn KM, Aggarwal A, Drakaki A. Predictive biomarkers for survival benefit with ramucirumab in urothelial cancer in the RANGE trial. Nat Commun. 2022 Apr 6;13(1):1878. doi: 10.1038/s41467-022-29441-y.
• Mitani S, Chen Y, Inoue K, Mori J, Gao L, Long A, Wakabayashi S. Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach. Gan To Kagaku Ryoho. 2021 Nov;48(11):1381-1387.
• Necchi A, Nishiyama H, Matsubara N, Lee JL, Petrylak DP, de Wit R, Drakaki A, Liepa AM, Mao H, Bell-McGuinn K, Powles T. Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE). BMC Urol. 2020 Nov 7;20(1):181. doi: 10.1186/s12894-020-00752-w.
• Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Flechon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Geczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):105-120. doi: 10.1016/S1470-2045(19)30668-0. Epub 2019 Nov 18.
• Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Flechon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Geczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial. Lancet. 2017 Nov 18;390(10109):2266-2277. doi: 10.1016/S0140-6736(17)32365-6. Epub 2017 Sep 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 6, 2019): 530
• Original Estimated Enrollment (submitted: April 21, 2015): 524
• Actual Study Completion Date: July 26, 2022
• Actual Primary Completion Date: April 21, 2017 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT02426125
• Other Study ID Numbers: 15679; I4T-MC-JVDC ( Other Identifier: Eli Lilly and Company ); 2014-003655-66 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: 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: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• 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

• PRS Account: Eli Lilly and Company
• Verification Date: July 2022