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A Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (REACH-2)

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ClinicalTrials.gov Identifier: NCT02435433
Recruitment Status : Recruiting
First Posted : May 6, 2015
Last Update Posted : August 3, 2018
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Tracking Information
First Submitted Date  ICMJE May 1, 2015
First Posted Date  ICMJE May 6, 2015
Last Update Posted Date August 3, 2018
Actual Study Start Date  ICMJE July 2015
Actual Primary Completion Date March 15, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 1, 2015)
Overall Survival (OS) [ Time Frame: Baseline to Death from Any Cause (Approximately 28 Months) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02435433 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2017)
  • Progression Free Survival (PFS) [ Time Frame: Baseline to Objective Progression or Death from Any Cause (Approximately 28 Months) ]
  • Time to Radiographic Progression [ Time Frame: Baseline to Objective Progression (Approximately 28 Months) ]
  • Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Baseline to Objective Progression (Approximately 28 Months) ]
  • Pharmacokinetics (PK): Serum Concentration of Ramucirumab [ Time Frame: Predose Cycle 1 through Follow Up (Approximately 28 Months) ]
  • Number of Participants with Anti-Ramucirumab Antibodies [ Time Frame: Predose Cycle 1 through Follow Up (Approximately 28 Months) ]
  • Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) [ Time Frame: Baseline through End of Study (Approximately 28 Months) ]
  • EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire [ Time Frame: Baseline through End of Study (Approximately 28 Months) ]
  • Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: Baseline through End of Study (Approximately 28 Months) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 1, 2015)
  • Progression Free Survival (PFS) [ Time Frame: Baseline to Objective Progression or Death from Any Cause (Approximately 28 Months) ]
  • Time to Radiographic Progression [ Time Frame: Baseline to Objective Progression (Approximately 28 Months) ]
  • Percentage of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Baseline to Objective Progression (Approximately 28 Months) ]
  • Pharmacokinetics (PK): Serum Concentration of Ramucirumab [ Time Frame: Predose Cycle 1 through Follow Up (Approximately 28 Months) ]
  • Number of Participants with Anti-Ramucirumab Antibodies [ Time Frame: Predose Cycle 1 through Follow Up (Approximately 28 Months) ]
  • Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) [ Time Frame: Baseline through End of Study (Approximately 28 Months) ]
  • EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire [ Time Frame: Baseline through End of Study (Approximately 28 Months) ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein
Official Title  ICMJE Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Therapy With Sorafenib
Brief Summary The purpose of this study is to evaluate the safety and efficacy of ramucirumab in participants with hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein. Participants will be randomized to ramucirumab or placebo in a 2:1 ratio (Main Global Cohort and China Maximized Extended Enrollment {ME2} Cohort). Participants may also receive ramucirumab if eligible to be enrolled in Open-Label Expansion (OLE) Cohort.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma
Intervention  ICMJE
  • Drug: Ramucirumab
    Administered IV
    Other Names:
    • Cyramza
    • LY3009806
  • Drug: Placebo
    Administered IV
Study Arms
  • Experimental: Ramucirumab
    8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
    Intervention: Drug: Ramucirumab
  • Placebo Comparator: Placebo

    Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.

    Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.

    Interventions:
    • Drug: Ramucirumab
    • Drug: Placebo
  • Experimental: Open Label Ramucirumab
    8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
    Intervention: Drug: Ramucirumab
  • Experimental: Ramucirumab ME2 Cohort
    8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
    Intervention: Drug: Ramucirumab
  • Placebo Comparator: Placebo ME2 Cohort

    Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.

    Participants still on treatment at the time of study completion may have the option to crossover to the ramucirumab arm.

    Interventions:
    • Drug: Ramucirumab
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 28, 2017)
383
Original Estimated Enrollment  ICMJE
 (submitted: May 1, 2015)
399
Estimated Study Completion Date June 2020
Actual Primary Completion Date March 15, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • A diagnosis of HCC based on histopathologic findings, or a diagnosis of cirrhosis and a tumor with classical HCC imaging characteristics.
  • Sorafenib was the only systemic therapy for HCC and was discontinued for disease progression or intolerance (Main Global and ME2 Cohorts only).
  • The participant received one prior systemic therapy regimen, excluding prior sorafenib, for the treatment of HCC (OLE Cohort only).
  • ≥1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 that has not been previously treated with locoregional therapy. A participant with a lesion(s) that has previously been treated with locoregional therapy is also eligible, if the lesion has documented progression after locoregional treatment and is measureable.
  • Child-Pugh score <7 (Child-Pugh Class A).
  • Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.
  • Baseline AFP ≥400 nanograms/milliliter.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Resolution of all clinically significant toxic effects of prior therapy.
  • Total bilirubin ≤1.5 times upper limit of normal value (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤5 × ULN.
  • Creatinine clearance ≥60 milliliters/minute.
  • Urinary protein is ≤1+ on dipstick or routine urinalysis or 24-hour urine demonstrating <1 gram of protein.
  • Absolute neutrophil count ≥1.0 × 10^9/Liter, hemoglobin ≥9 grams/deciliter, and platelets ≥75 × 10^9/Liter.
  • International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤5 seconds above the ULN.
  • Surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method.
  • If a woman of childbearing potential, a negative serum pregnancy test prior to randomization.
  • Willing to provide blood for research.

Exclusion Criteria:

  • Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
  • Concurrent malignancy. Participants with carcinoma in situ of any origin and participants with prior malignancies in remission may be eligible with sponsor approval.
  • Previous brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
  • History of or current hepatic encephalopathy or clinically meaningful ascites.
  • Ongoing or recent hepatorenal syndrome.
  • Liver transplant.
  • Hepatic locoregional therapy following prior systemic therapy or within 28 days prior to randomization.
  • Major surgical procedure, traumatic injury, non-healing wound, or peptic ulcer ≤28 days prior to randomization.
  • Placement of a subcutaneous venous access device within 7 days prior to the first dose of study treatment unless the procedure is judged of low risk of bleeding.
  • Enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or in medical research judged not to be scientifically or medically compatible with this study.
  • Discontinued from study treatment from another clinical trial within 28 days prior to randomization.
  • Known allergy to any of the treatment components.
  • Uncontrolled hypertension.
  • Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, <6 months prior to randomization.
  • Any bleeding episode considered life-threatening, or any Grade 3 or 4 gastrointestinal bleeding episode in the 3 months prior to randomization requiring intervention.
  • Esophageal or gastric varices that require intervention or represent high bleeding risk. Participants with evidence of portal hypertension or prior bleeding must have had endoscopic evaluation within 3 months prior to randomization.
  • Gastrointestinal perforation or fistulae within 6 months prior to randomization.
  • Symptomatic congestive heart failure (New York Heart Association II-IV), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia.
  • Pregnant or breast-feeding.
  • Any medical or psychiatric condition that may increase the risk associated with study participation or may interfere with the interpretation of study results. Conditions include but are not limited to:

    • Human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
    • Active or uncontrolled clinically serious infection. (Participants with chronic viral hepatitis are eligible.)
    • Ongoing or recent history of drug abuse.
    • Uncontrolled hereditary or acquired thrombotic or bleeding disorder.
  • Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection.
  • Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or similar agents.
  • Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted.
  • The participant received prior immunotherapy and is experiencing or has experienced any of the following (OLE cohort only):

    • Any clinically significant Grade ≥3 immune-related adverse event (irAE)
    • Any grade neurologic or ocular irAE
    • Any grade immune-related pneumonitis, cardiomyopathy, or hepatitis
  • The participant received prior immunotherapy and at the time of study enrollment, requires steroids or other immunosuppressive agents (OLE cohort only).
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE
Contact: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   China,   Czechia,   France,   Germany,   Hong Kong,   Israel,   Italy,   Japan,   Korea, Republic of,   Poland,   Spain,   Switzerland,   Taiwan,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02435433
Other Study ID Numbers  ICMJE 15755
I4T-MC-JVDE ( Other Identifier: Eli Lilly and Company )
2014-005068-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Yes
Plan Description:

Lilly provides access to the individual patient data from studies on approved medicines and indications as defined by the sponsor specific information on ClinicalStudyDataRequest.com.

This access is provided in a timely fashion after the primary publication is accepted. Researchers need to have an approved research proposal submitted through ClinicalStudyDataRequest.com. Access to the data will be provided in a secure data sharing environment after signing a data sharing agreement.

Responsible Party Eli Lilly and Company
Study Sponsor  ICMJE Eli Lilly and Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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 August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP