A Study in Second Line Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT01183780
• Recruitment Status: Completed
• First Posted: August 18, 2010
• Results First Posted: July 15, 2015
• 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: August 4, 2010
• First Posted Date: August 18, 2010
• Results First Submitted Date: June 19, 2015
• Results First Posted Date: July 15, 2015
• Last Update Posted Date: September 25, 2019
• Actual Study Start Date: December 2, 2010
• Actual Primary Completion Date: July 17, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 9, 2017)

Overall Survival (OS) [ Time Frame: Randomization to Date of Death from Any Cause Up to 39.36 Months ]

OS was defined as the time in months from the date of randomization to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last known date alive.

• Original Primary Outcome Measures (submitted: August 17, 2010): Overall Survival [ Time Frame: Baseline to date of death from any cause ]

Current Secondary Outcome Measures (submitted: June 9, 2017)

• Progression-free Survival (PFS) Time [ Time Frame: Randomization to Measured PD or Date of Death from Any Cause Up to 38.01 Months ]
  PFS was defined as the time from the date of randomization until the date of objectively determined progressive disease (PD) [according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v). 1.1] or death due to any cause, whichever was first. PD is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). Participants who died without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress or were lost to follow-up were censored at the day of their last radiographic tumor assessment.
• Percentage of Participants Achieving an Objective Response (Objective Response Rate) [ Time Frame: Randomization until Disease Progression Up to 38.01 Months ]
  The objective response rate is equal to the proportion of participants achieving a best overall response of partial response or complete response (PR + CR). Response was defined using RECIST, v. 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions taking as reference the baseline sum diameter.
• Change From Baseline in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 Global Health Status [ Time Frame: Baseline Up to 171 Weeks ]
  The EORTC QLQ-C30 (v. 3.0) is a self-administered, cancer-specific questionnaire with multidimensional scales assessing 15 domains (5 functional domains, 9 symptoms, and global health status). A linear transformation was applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For the functional domains and global health status scale, higher scores represent a better level of functioning. For symptom scales, higher scores represent a greater degree of symptoms. Maximum improvement is the best post-baseline change.
• Change From Baseline in EuroQol- 5D (EQ-5D) [ Time Frame: Baseline and 30-Day Follow-Up (FU) up to 171 Weeks ]
  The EQ-5D is a generic, multidimensional, health status instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale (no problem, some problems, and major problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). A negative change indicated a worsening of the participant's health status.
• Percentage of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies [ Time Frame: Cycles 1, 3, 5, and 30-Day FU ]
  Blood samples were tested to determine if a participant reacted to ramucirumab by producing anti-ramucirumab antibodies. Samples were identified as treatment emergent anti-drug antibody (TE ADA) if the post-treatment sample had an increase of at least 4 fold in titer from pre-treatment values. If the pre-treatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence. The percentage of participants with TE ADA was calculated as: (the number of participants with TE ADA / total number of participants with at least 1 post-treatment immunogenicity sample analyzed)*100.
• Observed Maximum Concentration (Cmax) and Observed Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Preinfusion and 1 hour postinfusion in Cycles 3, 5, 9, 13, and 17 ]

Original Secondary Outcome Measures (submitted: August 17, 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, every 6 weeks through week 36, then every 12 weeks thereafter until disease progression ]
• Change in European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 [ Time Frame: Every 2 cycles through cycle 14, then every 4 cycles ]
• Incidence of anti-ramucirumab antibodies [ Time Frame: Baseline, 30-day follow-up ]
• Cmax and Cmin of ramucirumab [ Time Frame: Baseline, pre- and post-infusions at cycles 3 and 5, and at 30-day follow-up ]
• Change in EuroQol EQ-5D [ Time Frame: Every 2 cycles through cycle 14, then every 4 cycles ]

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

Descriptive Information

• Brief Title: A Study in Second Line Metastatic Colorectal Cancer
• Official Title: A Randomized, Double-blind, Multicenter Phase 3 Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-Line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine
• Brief Summary: The purpose of this study is to compare overall survival in participants with metastatic colorectal cancer treated with either ramucirumab and FOLFIRI or placebo and FOLFIRI.
• 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: Colorectal Cancer

Intervention

• Biological: Ramucirumab
  8 milligrams / kilogram (mg/kg) administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision
  Other Names:

  • LY3009806
  • IMC-1121B
• Biological: Placebo
  Administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision
• Drug: Irinotecan
  180 milligrams/square meter (mg/m^2) administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision
• Drug: Folinic Acid
  400 mg/m^2 administered intravenously every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision
  Other Name: leucovorin
• Drug: 5-Fluorouracil
  400 mg/m^2 bolus immediately followed by 2400 mg/m^2 continuous infusion every 2 weeks until disease progression, unacceptable toxicity, noncompliance or withdrawal of consent by the participant or investigator decision

Study Arms

• Experimental: FOLFIRI + Ramucirumab
  Interventions:

  • Biological: Ramucirumab
  • Drug: Irinotecan
  • Drug: Folinic Acid
  • Drug: 5-Fluorouracil
• Placebo Comparator: FOLFIRI + Placebo
  Interventions:

  • Biological: Placebo
  • Drug: Irinotecan
  • Drug: Folinic Acid
  • Drug: 5-Fluorouracil

Publications *

• 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.
• Taniguchi H, Yoshino T, Yamaguchi K, Yamazaki K, Nixon AB, Tabernero J, Van Cutsem E, Robling KR, Abada PB, Hozak RR, Siegel R, Fill JA, Wijayawardana S, Walgren RA, Giles B, Jones A, Pitts KR, Drove N, Muro K. Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study. Curr Med Res Opin. 2021 Oct;37(10):1769-1778. doi: 10.1080/03007995.2021.1940908. Epub 2021 Jul 28.
• Lim HH, Hopkins AM, Rowland A, Yuen HY, Karapetis CS, Sorich MJ. Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab. Target Oncol. 2019 Dec;14(6):743-748. doi: 10.1007/s11523-019-00683-z.
• Yoshino T, Portnoy DC, Obermannova R, Bodoky G, Prausova J, Garcia-Carbonero R, Ciuleanu T, Garcia-Alfonso P, Cohn AL, Van Cutsem E, Yamazaki K, Lonardi S, Muro K, Kim TW, Yamaguchi K, Grothey A, O'Connor J, Taieb J, Wijayawardana SR, Hozak RR, Nasroulah F, Tabernero J. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study. Ann Oncol. 2019 Jan 1;30(1):124-131. doi: 10.1093/annonc/mdy461.
• Grothey A, Yoshino T, Bodoky G, Ciuleanu T, Garcia-Carbonero R, Garcia-Alfonso P, Van Cutsem E, Muro K, Mytelka DS, Li L, Lipkovich O, Hsu Y, Sashegyi A, Ferry D, Nasroulah F, Tabernero J. Association of baseline absolute neutrophil counts and survival in patients with metastatic colorectal cancer treated with second-line antiangiogenic therapies: exploratory analyses of the RAISE trial and validation in an electronic medical record data set. ESMO Open. 2018 Apr 24;3(3):e000347. doi: 10.1136/esmoopen-2018-000347. eCollection 2018.
• Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Prausova J, Muro K, Siegel RW, Konrad RJ, Ouyang H, Melemed SA, Ferry D, Nasroulah F, Van Cutsem E. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol. 2018 Mar 1;29(3):602-609. doi: 10.1093/annonc/mdx767.
• Obermannova R, Van Cutsem E, Yoshino T, Bodoky G, Prausova J, Garcia-Carbonero R, Ciuleanu T, Garcia Alfonso P, Portnoy D, Cohn A, Yamazaki K, Clingan P, Lonardi S, Kim TW, Yang L, Nasroulah F, Tabernero J. Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression. Ann Oncol. 2016 Nov;27(11):2082-2090. doi: 10.1093/annonc/mdw402. Epub 2016 Aug 29.
• Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausova J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F; RAISE Study Investigators. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12. Erratum In: Lancet Oncol. 2015 Jun;16(6):e262.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 19, 2015): 1072
• Original Estimated Enrollment (submitted: August 17, 2010): 1050
• Actual Study Completion Date: June 20, 2016
• Actual Primary Completion Date: July 17, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed colorectal cancer, excluding primary tumors of appendiceal origin (participants are eligible to enroll irrespective of KRAS mutation status)
• Confirmed metastatic colorectal cancer (Stage IV)
• The participant has received first-line combination therapy of bevacizumab, oxaliplatin, and a fluoropyrimidine for metastatic disease and, a) Experienced radiographic disease progression during first-line therapy, or b) Experienced radiographic disease progression ≤6 months after the last dose of first-line therapy, or c) Discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression ≤6 months after the last dose of first-line therapy. Note that a participant must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy; in addition, a participant must have received at least 1 cycle of first-line therapy that included bevacizumab, oxaliplatin and a fluoropyrimidine in the same cycle. Note that a participant must not have received more than 2 different fluoropyrimidines as part of a first-line regimen; disease progression is not an acceptable reason for discontinuing 1 fluoropyrimidine and starting a second fluoropyrimidine
• Receipt of no more than 2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted). For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen. Note that rechallenge with oxaliplatin is permitted and will be considered part of the first-line regimen for metastatic disease, both initial oxaliplatin treatment and subsequent rechallenge are considered as 1 regimen
• Measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Adequate hematologic, renal and hepatic function
• Adequate coagulation function [International Normalized Ratio (INR) ≤1.5 and Partial Thromboplastin Time (PTT) or activated PTT (aPTT) ≤1.5 x upper limit of normal (ULN)). Participants on full-dose anticoagulation must be on a stable dose of anticoagulant therapy and if on oral anticoagulation, must have an INR ≤3 and have no clinically significant active bleeding or pathological condition that carries a high risk of bleeding
• Consent to provide a historical colorectal cancer tissue sample for assessment of biomarkers and the tumor tissue sample is available
• Ability to provide signed informed consent

Exclusion Criteria:

• Receipt of bevacizumab ≤28 days prior to randomization
• Receipt of any investigational therapy for non-oncology clinical indication ≤28 days prior to randomization
• Receipt of any previous systemic therapy, other than a combination of bevacizumab, oxaliplatin, and a fluoropyrimidine, for first-line treatment of metastatic colorectal cancer
• Known leptomeningeal disease or brain metastases or uncontrolled spinal cord compression (currently or in the past)
• Experience of any arterial thrombotic or arterial thromboembolic events, including, but not limited to, myocardial infarction, transient ischemic attack, or cerebrovascular accident, ≤12 months prior to randomization
• Pregnant (confirmed by serum beta human chorionic gonadotropin (ß HCG) test ≤7 days prior to randomization) or lactating
• History of inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization
• Acute or subacute bowel obstruction or history of chronic diarrhea which is considered clinically significant in the opinion of the investigator
• Grade 3 or higher bleeding event ≤3 months prior to randomization
• Experience of any of the following during first-line therapy with a bevacizumab-containing regimen: an arterial thrombotic/thromboembolic event, Grade 4 hypertension, Grade 3 proteinuria, a Grade 3-4 bleeding event, or bowel perforation
• Known history or clinical evidence of Gilbert's Syndrome, or is known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28
• Known allergy to any of the study treatment components, including any components used in the preparation of ramucirumab, or other contraindication to receive the study treatments
• Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinical meaningful ascites resulting from cirrhosis; Clinically meaningful ascites is defined as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis

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, Australia, Austria, Belgium, Brazil, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Netherlands, Portugal, Puerto Rico, Romania, Slovenia, Spain, Sweden, Taiwan, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01183780
• Other Study ID Numbers: 13856; I4T-MC-JVBB ( Other Identifier: Eli Lilly and Company ); CP12-0920 ( Other Identifier: ImClone LLC Trial Number ); 2010-021037-32 ( EudraCT Number ); CTRI/2011/07/001900 ( 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 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

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