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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
Results First Posted : May 17, 2019
Last Update Posted : May 17, 2019
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

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.

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 292 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 20, 2015
Actual Primary Completion Date : March 15, 2018
Estimated Study Completion Date : June 15, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Ramucirumab

Arm Intervention/treatment
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.
Drug: Ramucirumab
Administered IV
Other Names:
  • Cyramza
  • LY3009806

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.

Drug: Ramucirumab
Administered IV
Other Names:
  • Cyramza
  • LY3009806

Drug: Placebo
Administered IV

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.
Drug: Ramucirumab
Administered IV
Other Names:
  • Cyramza
  • LY3009806

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.
Drug: Ramucirumab
Administered IV
Other Names:
  • Cyramza
  • LY3009806

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.

Drug: Ramucirumab
Administered IV
Other Names:
  • Cyramza
  • LY3009806

Drug: Placebo
Administered IV




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From Date of Randomization to Death from Any Cause (Up to 28 Months) ]
    OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive.


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months) ]
    Progression-free survival is defined as time from the date of randomization to the date of first observation of objective progression or death from any cause. Progressive disease (PD) is referenced as the smallest measurements recorded since the treatment started.

  2. Time to Radiographic Progression [ Time Frame: From Randomization to Objective Progression (Up to 28 Months) ]
    Time to radiographic progression is defined as the time from the date of randomization to the date of first observation of objective progression. Progressive disease (PD) is referenced as the smallest measurements recorded since the treatment started.

  3. Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: From Randomization to Objective Progression (Up to 28 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 normalisation 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.

  4. Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion [ Time Frame: Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before Infusion (14-Day Cycles) ]
    PK Cmin of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.

  5. PK: Serum Concentration Maximum (Cmax) After 1st, 2nd, 4th, 7th and 10th Ram Infusion [ Time Frame: Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles) ]
    PK Cmax of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations.

  6. Percentage of Participants With Anti-Ramucirumab Antibodies [ Time Frame: Predose Cycle 1: 7 Days prior to First Infusion, Cycle 4: 3 Days Prior to Infusion, Cycle 7 through Follow Up (Up to 28 Months) ]
    Percentage of participants with positive treatment emergent anti-drug antibodies was summarized by treatment group. A treatment-emergent ADA (TEADA) was defined as: having a negative ADA at baseline and an ADA titer greater than or equal to 1:20 (that is (i.e.), greater than 2-fold from the minimal required dilution of 1:10) any time post baseline (i.e., treatment-induced); or a 4-fold or greater change in ADA titer from baseline for participants that had a detectable ADA titer at baseline (i.e., treatment boosted).

  7. Time to Deterioration of Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) [ Time Frame: From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months) ]
    The FACT Hepatobiliary Symptom Index (FHSI-8) is a instrument with specific focus regarding the most frequent and concerning symptoms experienced by participants with hepatobiliary malignancies, including lack of energy, nausea, pain, weight loss, pain in back, fatigue, jaundice, stomach pain or discomfort. The (FHSI-8) questionnaire was used to assess the time to deterioration of FSHI-8 total score issued from the date of randomization to the first date observing deterioration, with the deterioration threshold defined as a decrease ≥ 3-points from baseline. In case of no deterioration, the participants were censored at the time of the last FSHI-8 item recording. FHSI-8 total score ranges from 0 to 32 where "0" is a severely symptomatic participant and the highest score indicates an asymptomatic participant. Kaplan-Meier method Hazard ratio was used to estimate (Ramucirumab versus Placebo) and 95% Confidence Interval (CI) (Wald) were estimated from un-stratified/stratified Cox model.

  8. Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire [ Time Frame: From Randomization through End of Study (Up to 28 Months) ]
    The EQ-5D-5L is a nonspecific and standardized instrument for use as a measure of self-reported health status (EuroQol Group 1990; Herdman et al. 2011). Participants completed the 5-level (no problems, slight problems, moderate problems, severe problems, and extreme problems), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. A unique EQ-5D-5L health state scale ranges from 0 to 100 and is defined by combining 1 level from each of the 5 dimensions. Participants indicated their current health status by marking on a continuum ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).

  9. Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months) ]
    Time to deterioration in ECOG PS is defined as the time from the date of randomization to the first date observing ECOG PS 2 (ie, deterioration from baseline status of 0 [fully active] or 1 [restricted in physically strenuous activity but ambulatory and able to carry out light work]). Participants without PS deterioration were censored at their last documented assessments of 0 or 1. Assessments included ECOG Performance Status (PS): 2- Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours, 3 -Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours, 4 -Completely disabled, cannot carry on any self-care. Totally confined to bed or chair, 5- Dead.



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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:

  • 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. The participant has provided signed informed consent prior to any study specific procedures and is amenable to compliance with protocol schedules and testing.

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.
  • Received radiation to any nonhepatic (for example, bone) site within 14 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 unapproved 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).

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): NCT02435433


Contacts
Layout table for location contacts
Contact: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559

  Show 131 Study Locations
Sponsors and Collaborators
Eli Lilly and Company
Investigators
Layout table for investigator information
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] April 24, 2017
Statistical Analysis Plan  [PDF] December 21, 2017


Additional Information:
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02435433     History of Changes
Other Study ID Numbers: 15755
I4T-MC-JVDE ( Other Identifier: Eli Lilly and Company )
2014-005068-13 ( EudraCT Number )
First Posted: May 6, 2015    Key Record Dates
Results First Posted: May 17, 2019
Last Update Posted: May 17, 2019
Last Verified: April 2019
Individual Participant Data (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.

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: 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:
liver cancer

Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Ramucirumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs