Clinical trial NCT01140347: A Study of Ramucirumab (IMC-1121B) Drug Product (DP) and Best Supportive Care (BSC) Versus Placebo and BSC as 2nd-Line Treatment in Participants With Hepatocellular Carcinoma After 1st-Line Therapy With Sorafenib
Official title: A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib (REACH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular carcinoma (HCC)
recombinant human immunoglobulin G
subclass 1 (IgG1) monoclonal antibody (MAb)
Hepatocellular Carcinoma (HCC) following First-Line Therapy With Sorafenib
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2010-06-09
Enrollment: 565
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 3 multicenter, randomized study evaluating the safety and efficacy of ramucirumab DP plus BSC as a double-blind, placebo-controlled (placebo plus BSC) comparison.

Approximately 544 participants, at least 18 years of age, with Child-Pugh score \< 7 and diagnosed with hepatocellular carcinoma will be randomized. Participants must have received sorafenib as first-line systemic treatment for hepatocellular carcinoma (HCC), and must have discontinued sorafenib prior to entering the study.

Hypothesis: This sample size will allow differentiation of the expected increase in median overall survival (OS), from 8 months in the placebo arm to 10.67 months in the ramucirumab arm.

Upon registration and completion of screening procedures, eligible participants with HCC who have disease progression during or following first-line therapy with sorafenib, or were intolerant to this agent, will be randomized to receive either ramucirumab DP or placebo.

The treatment regimen will be continued until radiographic or symptomatic progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the participant, or investigator decision.


Eligibility criteria: Inclusion criteria:

* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
* Child-Pugh score of \<7 (Child-Pugh Class A only)
* Barcelona Clinic Liver Cancer (BCLC) Stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy
* Diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or cytologic confirmation
* There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis
* Has a liver mass measuring at least 2 centimeters (cm) with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium
* At least 1 measurable or evaluable lesion that is viable \[that is (i.e.), is vascularized\], and has not been previously treated with locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable progression following locoregional therapy
* Previously treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. Participants may have experienced:

  * Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or
  * Discontinuation of sorafenib due to an adverse drug reaction, despite dose reduction by 1 level and BSC
* The participant has received sorafenib as the only systemic therapeutic intervention. Any hepatic locoregional therapy that has been administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites \[for example (e.g.), bone\] following sorafenib therapy is permitted.
* Resolution of clinically significant toxicity of any anti-cancer therapy to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events volume 4.0 (NCI-CTCAE v. 4.0).

Adequate Organ Function defined as:

* Total bilirubin \<3.0 milligrams/deciliter (mg/dL) \[51.3 micromole/liter (µmol/L)\], aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN)
* Serum creatinine ≤1.2 × ULN or calculated creatinine clearance \>50 milliliters/minute (mL/min)
* Absolute neutrophil count (ANC) ≥1.0 × 10\^3/microliter (μL) (1.0 × 10\^9/liter (L)\]), hemoglobin ≥9 grams/deciliter (g/dL) \[5.58 millimoles/liter (mmol/L)\], and platelets ≥75 × 10\^3/µL (75 × 10\^9/L)
* International Normalized Ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤5 seconds above ULN. Participants receiving prophylactic low-dose anticoagulant therapy are eligible provided that INR ≤1.5 and PTT ≤5 seconds above the ULN
* The participant's urinary protein is ≤1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates ≥2+ proteinuria, then a 24-hour urine must be collected and must demonstrate \<1000 milligrams (mg) of protein in 24 hours to allow participation in the study

Exclusion criteria:

* Major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization
* Hepatic locoregional therapy within 28 days prior to randomization
* Radiation to any nonhepatic (e.g., bone) site within 14 days prior to randomization
* Sorafenib within 14 days prior to randomization
* Received any investigational therapy or non-approved drug within 28 days prior to randomization
* Received any previous systemic therapy with vascular endothelial growth factor (VEGF) inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors (including investigational agents) other than sorafenib for treatment of HCC
* Fibrolamellar carcinoma
* Received any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior to randomization
* Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Participants receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and PTT ≤5 seconds above the ULN) are met
* Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal). Aspirin (ASA) at doses up to 100 milligrams/day (mg/day) is permitted
* Symptomatic congestive heart failure, unstable angina pectoris, 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 systolic ≥150 / diastolic ≥90 millimeters of mercury (mm Hg) despite standard medical management
* Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention (participants with any bleeding episode considered life-threatening during the 3 months prior to randomization are excluded, regardless of transfusion or intervention status)
* Esophageal or gastric varices that require immediate intervention (e.g., banding, sclerotherapy) or represent a high bleeding risk. Participants with evidence of portal hypertension (including splenomegaly) or any prior history of variceal bleeding must have had endoscopic evaluation within the 3 months immediately prior to randomization. Participants with evidence of portal hypertension are eligible for study participation if endoscopic evaluation does not indicate esophageal or gastric varices that require immediate intervention or represent a high bleeding risk; however, these eligible participants must receive supportive therapy (e.g., beta blocker therapy) according to institutional standards and clinical guidelines during study participation
* Central nervous system (CNS) metastases or carcinomatous meningitis
* History of or current hepatic encephalopathy or current clinically meaningful ascites

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Randomization to death from any cause (up to 37 months)
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Randomization to PD (up to 36 months)
measure: Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
timeFrame: Baseline to the date of first evidence of confirmed CR or PR (up to 37 months)
measure: Time to Radiographic Progression (TTP)
timeFrame: Randomization to PD (up to 36 months)
measure: Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
timeFrame: Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), and end of treatment (up to 34 months)
measure: Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score
timeFrame: Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), end of treatment (up to 34 months)
measure: Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died
timeFrame: Baseline to study completion (up to 37 months)
measure: Maximum Concentration (Cmax) of Ramucirumab, Cycle 1
timeFrame: 1 hour following the completion of Cycle 1 (14-day cycle) infusion
measure: Cmax of Ramucirumab, Cycle 4
timeFrame: 1 hour following completion of Cycle 4 (14-day cycles) infusion
measure: Cmax of Ramucirumab, Cycle 7
timeFrame: 1 hour following completion of Cycle 7 (14-day cycles) infusion
measure: Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)]
timeFrame: Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles)
Other outcomes:
Locations:
city: Orange
country: United States
facility: ImClone Investigational Site
state: California
city: San Francisco
country: United States
facility: ImClone Investigational Site
state: California
city: New Haven
country: United States
facility: ImClone Investigational Site
state: Connecticut
city: Jacksonville
country: United States
facility: ImClone Investigational Site
state: Florida
city: New Orleans
country: United States
facility: ImClone Investigational Site
state: Louisiana
city: Boston
country: United States
facility: ImClone Investigational Site
state: Massachusetts
city: Worcester
country: United States
facility: ImClone Investigational Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: ImClone Investigational Site
state: Michigan
city: St Louis
country: United States
facility: ImClone Investigational Site
state: Missouri
city: Newark
country: United States
facility: ImClone Investigational Site
state: New Jersey
city: New York
country: United States
facility: ImClone Investigational Site
state: New York
city: Winston-Salem
country: United States
facility: ImClone Investigational Site
state: North Carolina
city: Dayton
country: United States
facility: ImClone Investigational Site
state: Ohio
city: Philadelphia
country: United States
facility: ImClone Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: ImClone Investigational Site
state: South Carolina
city: Lubbock
country: United States
facility: ImClone Investigational Site
state: Texas
city: Seattle
country: United States
facility: ImClone Investigational Site
state: Washington
city: Milwaukee
country: United States
facility: ImClone Investigational Site
state: Wisconsin
city: Bankstown
country: Australia
facility: ImClone Investigational Site
state: New South Wales
city: Kogarah
country: Australia
facility: ImClone Investigational Site
state: New South Wales
city: Liverpool Bc
country: Australia
facility: ImClone Investigational Site
state: New South Wales
city: Kurralta Park
country: Australia
facility: ImClone Investigational Site
state: South Australia
city: Prahran
country: Australia
facility: ImClone Investigational Site
state: Victoria
city: Linz
country: Austria
facility: ImClone Investigational Site
city: Salzburg
country: Austria
facility: ImClone Investigational Site
city: Steyr
country: Austria
facility: ImClone Investigational Site
city: Vienna
country: Austria
facility: ImClone Investigational Site
city: Bonheiden
country: Belgium
facility: ImClone Investigational Site
city: Brussels
country: Belgium
facility: ImClone Investigational Site
city: Charleroi
country: Belgium
facility: ImClone Investigational Site
city: Edegem
country: Belgium
facility: ImClone Investigational Site
city: Leuven
country: Belgium
facility: ImClone Investigational Site
city: Liège
country: Belgium
facility: ImClone Investigational Site
city: Ottignies
country: Belgium
facility: ImClone Investigational Site
city: Belo Horizonte
country: Brazil
facility: ImClone Investigational Site
city: Botucatu
country: Brazil
facility: ImClone Investigational Site
city: Brasilia
country: Brazil
facility: ImClone Investigational Site
city: Campinas
country: Brazil
facility: ImClone Investigational Site
city: Ijui
country: Brazil
facility: ImClone Investigational Site
city: Ribeirao Preto
country: Brazil
facility: ImClone Investigational Site
city: Rio De Janeiro
country: Brazil
facility: ImClone Investigational Site
city: Salvador
country: Brazil
facility: ImClone Investigational Site
city: Sao Jose Rio Preto
country: Brazil
facility: ImClone Investigational Site
city: São Paulo
country: Brazil
facility: ImClone Investigational Site
city: Plovdiv
country: Bulgaria
facility: ImClone Investigational Site
city: Sofia
country: Bulgaria
facility: ImClone Investigational Site
city: Varna
country: Bulgaria
facility: ImClone Investigational Site
city: Ottawa
country: Canada
facility: ImClone Investigational Site
state: Ontario
city: Brib
country: Czech Republic
facility: ImClone Investigational Site
city: Hradec Kralove
country: Czech Republic
facility: ImClone Investigational Site
city: Olomouc
country: Czech Republic
facility: ImClone Investigational Site
city: Prague
country: Czech Republic
facility: ImClone Investigational Site
city: Helsinki
country: Finland
facility: ImClone Investigational Site
city: Amiens
country: France
facility: ImClone Investigational Site
city: Angers
country: France
facility: ImClone Investigational Site
city: Avignon
country: France
facility: ImClone Investigational Site
city: Besancon
country: France
facility: ImClone Investigational Site
city: Bordeaux
country: France
facility: ImClone Investigational Site
city: Clermont-Ferrand
country: France
facility: ImClone Investigational Site
city: La Roche Sur Yon
country: France
facility: ImClone Investigational Site
city: Limoges
country: France
facility: ImClone Investigational Site
city: Marseille
country: France
facility: ImClone Investigational Site
city: Nice
country: France
facility: ImClone Investigational Site
city: Paris
country: France
facility: ImClone Investigational Site
city: Poitiers
country: France
facility: ImClone Investigational Site
city: Reims
country: France
facility: ImClone Investigational Site
city: Saint-Etienne
country: France
facility: ImClone Investigational Site
city: Berlin
country: Germany
facility: ImClone Investigational Site
city: Bielefeld
country: Germany
facility: ImClone Investigational Site
city: Bonn
country: Germany
facility: ImClone Investigational Site
city: Düsseldorf
country: Germany
facility: ImClone Investigational Site
city: Essen
country: Germany
facility: ImClone Investigational Site
city: Frankfurt
country: Germany
facility: ImClone Investigational Site
city: Freiburg
country: Germany
facility: ImClone Investigational Site
city: Hamburg
country: Germany
facility: ImClone Investigational Site
city: Hannover
country: Germany
facility: ImClone Investigational Site
city: Homburg
country: Germany
facility: ImClone Investigational Site
city: Leipzig
country: Germany
facility: ImClone Investigational Site
city: Magdeburg
country: Germany
facility: ImClone Investigational Site
city: Munich
country: Germany
facility: ImClone Investigational Site
city: Münster
country: Germany
facility: ImClone Investigational Site
city: Tübingen
country: Germany
facility: ImClone Investigational Site
city: Ulm
country: Germany
facility: ImClone Investigational Site
city: Weiden
country: Germany
facility: ImClone Investigational Site
city: Kowloon
country: Hong Kong
facility: ImClone Investigational Site
city: Pokfulam
country: Hong Kong
facility: ImClone Investigational Site
city: Shatin
country: Hong Kong
facility: ImClone Investigational Site
city: Budapest
country: Hungary
facility: ImClone Investigational Site
city: Beer Sheva
country: Israel
facility: ImClone Investigational Site
city: Petah Tiqva
country: Israel
facility: ImClone Investigational Site
city: Tel Aviv
country: Israel
facility: ImClone Investigational Site
city: Bari
country: Italy
facility: ImClone Investigational Site
city: Benevento
country: Italy
facility: ImClone Investigational Site
city: Bologna
country: Italy
facility: ImClone Investigational Site
city: Genova
country: Italy
facility: ImClone Investigational Site
city: Lecce
country: Italy
facility: ImClone Investigational Site
city: Milano
country: Italy
facility: ImClone Investigational Site
city: Modena
country: Italy
facility: ImClone Investigational Site
city: Padova
country: Italy
facility: ImClone Investigational Site
city: Palermo
country: Italy
facility: ImClone Investigational Site
city: Pavia
country: Italy
facility: ImClone Investigational Site
city: Rome
country: Italy
facility: ImClone Investigational Site
city: Udine
country: Italy
facility: ImClone Investigational Site
city: Chiba
country: Japan
facility: ImClone Investigational Site
city: Fukuoka
country: Japan
facility: ImClone Investigational Site
city: Hyogo
country: Japan
facility: ImClone Investigational Site
city: Ishikawa
country: Japan
facility: ImClone Investigational Site
city: Kanagawa
country: Japan
facility: ImClone Investigational Site
city: Kochi
country: Japan
facility: ImClone Investigational Site
city: Kyoto
country: Japan
facility: ImClone Investigational Site
city: Miyagi
country: Japan
facility: ImClone Investigational Site
city: Osaka-Pref
country: Japan
facility: ImClone Investigational Site
city: Osaka
country: Japan
facility: ImClone Investigational Site
city: Saga
country: Japan
facility: ImClone Investigational Site
city: Tochigi
country: Japan
facility: ImClone Investigational Site
city: Tokushima
country: Japan
facility: ImClone Investigational Site
city: Tokyo
country: Japan
facility: ImClone Investigational Site
city: Anyang
country: Korea, Republic of
facility: ImClone Investigational Site
city: Incheon
country: Korea, Republic of
facility: ImClone Investigational Site
city: Seodaemun-Gu
country: Korea, Republic of
facility: ImClone Investigational Site
city: Seoul
country: Korea, Republic of
facility: ImClone Investigational Site
city: Amsterdam
country: Netherlands
facility: ImClone Investigational Site
city: Rotterdam
country: Netherlands
facility: ImClone Investigational Site
city: Oslo
country: Norway
facility: ImClone Investigational Site
city: Quezon City
country: Philippines
facility: ImClone Investigational Site
city: Lisbon
country: Portugal
facility: ImClone Investigational Site
city: Santa Maria Da Feira
country: Portugal
facility: ImClone Investigational Site
city: Bucharest
country: Romania
facility: ImClone Investigational Site
city: Cluj-Napoca
country: Romania
facility: ImClone Investigational Site
city: Craiova
country: Romania
facility: ImClone Investigational Site
city: Avila
country: Spain
facility: ImClone Investigational Site
city: Girona
country: Spain
facility: ImClone Investigational Site
city: Madrid
country: Spain
facility: ImClone Investigational Site
city: Ourense
country: Spain
facility: ImClone Investigational Site
city: Valencia
country: Spain
facility: ImClone Investigational Site
city: Stockholm
country: Sweden
facility: ImClone Investigational Site
city: Bern
country: Switzerland
facility: ImClone Investigational Site
city: Changhua
country: Taiwan
facility: ImClone Investigational Site
city: Kuei Shan Hsiang
country: Taiwan
facility: ImClone Investigational Site
city: Liouying/Tainan
country: Taiwan
facility: ImClone Investigational Site
city: Niaosung
country: Taiwan
facility: ImClone Investigational Site
city: Taichung
country: Taiwan
facility: ImClone Investigational Site
city: Tainan
country: Taiwan
facility: ImClone Investigational Site
city: Taipei
country: Taiwan
facility: ImClone Investigational Site
city: Bangkok
country: Thailand
facility: ImClone Investigational Site
city: Hat Yai
country: Thailand
facility: ImClone Investigational Site
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References:
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citation: Kudo M, Hatano E, Ohkawa S, Fujii H, Masumoto A, Furuse J, Wada Y, Ishii H, Obi S, Kaneko S, Kawazoe S, Yokosuka O, Ikeda M, Ukai K, Morita S, Tsuji A, Kudo T, Shimada M, Osaki Y, Tateishi R, Sugiyama G, Abada PB, Yang L, Okusaka T, Zhu AX. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial. J Gastroenterol. 2017 Apr;52(4):494-503. doi: 10.1007/s00535-016-1247-4. Epub 2016 Aug 22.
citation: Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015 Jul;16(7):859-70. doi: 10.1016/S1470-2045(15)00050-9. Epub 2015 Jun 18.