A Study of Chemotherapy and Ramucirumab Versus Chemotherapy Alone in Second Line Non-Small Cell Lung Cancer (NSCLC) Participants Who Received Prior First Line Platinum-based Chemotherapy

• ClinicalTrials.gov Identifier: NCT01168973
• Recruitment Status: Completed
• First Posted: July 23, 2010
• Results First Posted: December 29, 2014
• Last Update Posted: September 25, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: July 16, 2010
• First Posted Date: July 23, 2010
• Results First Submitted Date: December 17, 2014
• Results First Posted Date: December 29, 2014
• Last Update Posted Date: September 25, 2019
• Study Start Date: December 2010
• Actual Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 17, 2014)

Overall Survival [ Time Frame: Randomization to date of death from any cause (up to 34 months) ]

Overall survival was the time from randomization until the date of death from any cause. Participants who were alive at the end of the follow-up period (or lost to follow-up) were censored on the last date the participant was known to be alive.

• Original Primary Outcome Measures (submitted: July 22, 2010): Overall survival [ Time Frame: Baseline to date of death from any cause ]

Current Secondary Outcome Measures (submitted: July 12, 2017)

• Progression-Free Survival (PFS) Time [ Time Frame: Randomization to measured PD or date of death from any cause (up to 29 months) ]
  PFS time was the time from randomization until the date of objectively determined progressive disease (PD) or death due to any cause, whichever occurred first. According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), PD was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the 20% relative increase, the sum must have also demonstrated an absolute increase of at least 5 millimeters (mm). The appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions was also considered progression. Participants without objectively determined PD who were alive at the end of the follow-up period (or lost to follow-up) were censored on the date of the participant's last complete radiographic tumor assessment; if no baseline or post-baseline radiologic assessment was available, the participant was censored at the date of randomization.
• Percentage of Participants Achieving an Objective Response (Objective Response Rate) [ Time Frame: Baseline to measured PD (up to 29 months) ]
  Participants achieved an objective response if they had a best overall response of partial response (PR) or complete response (CR). According to RECIST v1.1, PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph node), taking as reference the baseline sum diameter; CR was the disappearance of all non-nodal target lesions, with the short axes of any target lymph node reduced to <10 mm, the disappearance of all nontarget lesions, and the normalization of tumor marker levels [if tumor markers were initially above the upper limit of normal (ULN)]. The percentage of participants who achieved an objective response=(number of participants with CR or PR)/(number of participants assessed)*100.
• Percentage of Participants Achieving Disease Control (Disease Control Rate) [ Time Frame: Baseline to measured PD (up to 29 months) ]
  Participants achieved disease control if they had a best overall response of PR, CR or stable disease (SD). According to RECIST v1.1, PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph node), taking as reference the baseline sum diameter; CR was the disappearance of all non-nodal target lesions, with the short axes of any target lymph node reduced to <10 mm, the disappearance of all nontarget lesions, and the normalization of tumor marker levels (if tumor markers were initially above the ULN). SD was neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as PD, taking as reference the smallest sum diameter since treatment started. The percentage of participants who achieved disease control=(number of participants with CR, PR, or SD)/(number of participants assessed)*100.
• Maximum Improvement on Lung Cancer Symptom Scale (LCSS) [ Time Frame: Baseline, Day 21 of each cycle, and 30 days following last infusion (up to Cycle 38, 21 days/cycle) ]
  The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 items were global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-mm lines. A higher score for any item represented a higher level of symptoms/problems. The Average Symptom Burden Index (ASBI) was the mean of the 6 symptom items of the LCSS, and the Total LCSS was the mean of all 9 LCSS items. ASBI and Total LCSS were not computed for a participant if he/she had 1 or more missing values for the 6 and 9 items, respectively. Maximum improvement in LCSS scores, ASBI, and Total LCSS score was the largest decrease from baseline for each variable, which was the smallest (most negative or smallest positive) non-missing value among all change from baseline values for each variable.
• Change From Baseline to 30-Day Follow-Up Visit on European Quality of Life Questionnaire-5 Dimension (EQ-5D) Health State Scores [ Time Frame: Baseline, 30 days following last infusion (up to Cycle 38, 21 days/cycle) ]
  The EQ-5D is a quality-of-life instrument that consists of 2 parts. The first part (Health State Index score) allowed participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a scale from 1 to 3 (no problem, some problems, and extreme problems, respectively). These combinations of attributes were converted into a weighted Health State Index score according to a United Kingdom population-based algorithm; the possible values for the Health State Index score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). The second part of the EQ-5D was a VAS that allowed participants to rate their present health condition. Possible EQ-5D VAS scores ranged from 0 (worst imaginable health state) to 100 (best imaginable health state).
• Maximum and Minimum Serum Concentrations (Cmax and Cmin) of Ramucirumab [ Time Frame: Prior to infusion and 1 hour following infusion for 4 and 8 (cycles 3 and 5 at 21 days/cycle) ]
• Number of Participants With Anti-Ramucirumab Antibodies [ Time Frame: Baseline, prior to infusion for week 4 and 8 (cycles 3 and 5), and 30 days following last infusion (up to Cycle 38, 21 days/cycle) ]
  The number of participants who had treatment-emergent or follow-up emergent anti-drug antibodies (ADA) is reported. Participants with treatment-emergent ADA were defined as participants who had any sample from baseline through Cycle 5 pre-infusion that was a 4-fold increase (2 dilution increase) in immunogenicity titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20). Participants with follow-up emergent ADA were defined as participants who had any sample during 30 days post last infusion that was a 4-fold increase (2 dilution increase) in immunogenicity titer over the baseline titer.

Original Secondary Outcome Measures (submitted: July 22, 2010)

• Progression free survival time [ Time Frame: Baseline to measured progressive disease or date of death from any cause ]
• Proportion of patients achieving an objective response (objective response rate) [ Time Frame: Baseline to measured progressive disease ]
• Proportion of patients achieving disease control (Disease Control Rate) [ Time Frame: Baseline to measured progressive disease ]
• Maximum Improvement on Lung Cancer Sympton Scale [ Time Frame: Baseline through 30 day follow up visit ]
• Change from baseline up to 30 day follow up visit on EuroQol score [ Time Frame: Baseline, 30 day follow up visit ]
• Cmax and Cmin of Ramucirumab [ Time Frame: Baseline, prior to infusion of Cycle 3 and 5, and 30 days following last infusion ]
• Incidence of anti Ramucirumab antibodies [ Time Frame: Baseline, prior to infusion of Cycle 3 and 5, and 30 days following last infusion ]

Current Other Pre-specified Outcome Measures (submitted: December 17, 2014)

Number of Participants Who Had Treatment-Emergent Adverse Events (TEAEs) or Died [ Time Frame: First infusion up to 30 days following last infusion (up to Cycle 38, 21 days/cycle) ]

Data presented are the number of participants who experienced at least 1 TEAE, Grade 3, 4, or 5 TEAE, treatment-emergent serious adverse event (SAE), TEAE leading to discontinuation of study treatment (ramucirumab/placebo or docetaxel), and TEAE leading to death. Clinically significant events were defined as treatment-emergent SAEs and other non-serious adverse events (AEs) regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Chemotherapy and Ramucirumab Versus Chemotherapy Alone in Second Line Non-Small Cell Lung Cancer (NSCLC) Participants Who Received Prior First Line Platinum-based Chemotherapy
• Official Title: A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small Cell Lung Cancer Following Disease Progression After One Prior Platinum-Based Therapy
• Brief Summary: The purpose of the study is to compare the survival of participants who receive chemotherapy and ramucirumab versus chemotherapy alone as second line treatment for NSCLC after prior first line platinum-based chemotherapy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non-Small Cell Lung Cancer

Intervention

• Biological: Ramucirumab
  10 milligrams per kilogram (mg/kg) administered intravenously (IV) on Day 1 of 21-day cycle until disease progression, unacceptable toxicity, or another withdrawal criterion is met
  Other Names:

  • IMC 1121B
  • LY3009806
• Drug: Placebo (for Ramucirumab)
  Administered IV on Day 1 of 21-day cycle until disease progression, unacceptable toxicity, or another withdrawal criterion is met
• Drug: Docetaxel
  75 milligrams per square meter (mg/m^2) (60 mg/m^2 for the countries of Korea and Taiwan only with protocol amendment dated 22 May 2012) administered IV on Day 1 of 21-day cycle until disease progression, unacceptable toxicity, or another withdrawal criterion is met

Study Arms

• Experimental: Ramucirumab + Docetaxel
  Interventions:

  • Biological: Ramucirumab
  • Drug: Docetaxel
• Placebo Comparator: Placebo + Docetaxel
  Interventions:

  • Drug: Placebo (for Ramucirumab)
  • Drug: Docetaxel

Publications *

• Rolfo C, Hess LM, Jen MH, Peterson P, Li X, Liu H, Lai Y, Sugihara T, Kiiskinen U, Vickers A, Summers Y. External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer. ESMO Open. 2022 Aug;7(4):100551. doi: 10.1016/j.esmoop.2022.100551. Epub 2022 Aug 2.
• Garon EB, Scagliotti GV, Gautschi O, Reck M, Thomas M, Iglesias Docampo L, Kalofonos H, Kim JH, Gans S, Brustugun OT, Orlov SV, Cuyun Carter G, Zimmermann AH, Oton AB, Alexandris E, Lee P, Wolff K, Stefaniak VJ, Socinski MA, Perol M. Exploratory analysis of front-line therapies in REVEL: a randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy. ESMO Open. 2020 Jan;5(1):e000567. doi: 10.1136/esmoopen-2019-000567.
• Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Perol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2.
• Garon EB, Cao D, Alexandris E, John WJ, Yurasov S, Perol M. A randomized, double-blind, phase III study of Docetaxel and Ramucirumab versus Docetaxel and placebo in the treatment of stage IV non-small-cell lung cancer after disease progression after 1 previous platinum-based therapy (REVEL): treatment rationale and study design. Clin Lung Cancer. 2012 Nov;13(6):505-9. doi: 10.1016/j.cllc.2012.06.007. Epub 2012 Jul 31.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 29, 2014): 1253
• Original Estimated Enrollment (submitted: July 22, 2010): 1156
• Actual Study Completion Date: August 2016
• Actual Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Disease progression during or after one prior first-line platinum-based chemotherapy with or without maintenance therapy
• Prior bevacizumab as first-line and/or maintenance therapy is allowed
• Signed informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Histologically or cytologically confirmed NSCLC
• Stage IV NSCLC disease
• Participants have measurable or nonmeasurable disease

• Adequate organ function, defined as:

  • Total bilirubin less than or equal to Upper Limit of Normal (ULN),
  • Aspartate Aminotransferase (AST) and Alanine Aminotransaminase (ALT) less than or equal to 2.5 x ULN, or less than or equal to 5 x ULN if the transferase elevation is due to liver metastases,
  • Serum creatinine less than or equal to 1.5 x ULN or calculated creatinine clearance greater than or equal to 50 milliliters per minute (ml/min) (per the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection),
  • Absolute Neutrophil Count (ANC) greater than or equal to 1.5 x 10^3/microliters (µL), hemoglobin greater than or equal to 10.0 grams/deciliter (g/dL), and platelets greater than or equal to 100 x 10^3/µL,
  • Adequate coagulation function as defined by International Normalized Ratio (INR) less than or equal to 1.5, or prothrombin time and partial thromboplastin time less than or equal to 1.5 x ULN.
  • The participant does not have cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) 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.
• Urinary protein is less than or equal to 1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates proteinuria greater than or equal to 2+, a 24-hour urine must be collected and must demonstrate less than 1000 milligrams (mg) of protein.
• Participants of reproductive potential (both sexes) must agree to use reliable method of birth control (hormonal or barrier methods) during the study period and at least 12 weeks after the last dose of study therapy
• Life expectancy of greater than or equal to 3 months
• Prior radiation therapy is allowed if: In the case of chest radiotherapy at least 28 days have elapsed from the completion of radiation treatment prior to randomization; In the case of focal or palliative radiation treatment at least 7 days have elapsed from last radiation treatment prior to randomization (and provided that 25% or less of total bone marrow had been irradiated); In the case of Central Nervous System (CNS) radiation at least 14 days have elapsed from the completion of radiation treatment prior to randomization

Exclusion Criteria:

• Disease progression on more than 1 prior chemotherapy regimens
• Participants whose only prior treatment was a tyrosine kinase inhibitor
• The participant's tumor wholly or partially contains small cell lung cancer
• Major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months.
• Concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, or targeted therapy
• Last dose of bevacizumab must be at least 28 days from time of randomization
• Last dose of cytotoxic chemotherapy must be at least 14 days from time of randomization
• The participant has untreated CNS metastases. Participants with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. No evidence of Grade greater than or equal to 1 CNS hemorrhage based on pretreatment Magnetic Resonance Imaging (MRI) or IV contrast Computed Tomography (CT) scan.
• Radiologically documented evidence of major blood vessel invasion or encasement by cancer
• Radiographic evidence of intratumor cavitation
• History of uncontrolled hereditary or acquired thrombotic disorder
• Chronic therapy with nonsteroidal anti-inflammatory drug (NSAIDs) or other antiplatelet agents; Aspirin use at doses up to 325 milligrams per day (mg/day) is permitted
• History of gross hemoptysis (defined as bright red blood or greater than or equal to 1/2 teaspoon) within 2 months prior to randomization
• Clinically relevant congestive heart failure [New York Heart Association (NYHA II-IV)] or symptomatic or poorly controlled cardiac arrhythmia
• Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization
• Uncontrolled arterial hypertension greater than or equal to 150 / greater than or equal to 90 millimeters of mercury (mm Hg) despite standard medical management
• Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization
• Significant bleeding disorders, vasculitis, or Grade 3/4 gastrointestinal bleeding within 3 months prior to randomization
• Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to randomization
• Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection Crohn's disease, ulcerative colitis, or chronic diarrhea
• Peripheral neuropathy greater than or equal to Grade 2 [National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.02]
• Serious illness or medical condition(s) including, but not limited to: Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness; Active or uncontrolled clinically serious infection; Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration
• Known allergy or hypersensitivity reaction to any of the treatment components
• The participant is pregnant or breastfeeding
• Current or recent (within 28 days prior to randomization) treatment with an investigational drug or device that has not received regulatory approval for any indication at the time of randomization, or participation in another interventional clinical trial
• Prior therapy with docetaxel

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: Argentina, Austria, Brazil, Canada, France, Germany, Greece, Hungary, India, Israel, Italy, Korea, Republic of, Mexico, Netherlands, New Zealand, Norway, Poland, Puerto Rico, Romania, Russian Federation, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Japan

Administrative Information

• NCT Number: NCT01168973
• Other Study ID Numbers: 13852; I4T-MC-JVBA ( Other Identifier: Eli Lilly and Company ); 2010-021297-11 ( EudraCT Number ); CP12-1027 ( Other Identifier: ImClone Trial Number ); CTRI/2011/08/001942 ( Registry Identifier: Clinical Trials Registry India )
• 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: Chief Medical Officer, Eli Lilly
• 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 9AM - 5PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: September 2019