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

Hepatocellular Carcinoma Clinical Trial

— REACH  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01140347
• Other study ID #: 13895
• Secondary ID: CP12-0919I4T-IE-
• Status: Completed
• Phase: Phase 3
• First received: June 2, 2010
• Last updated: November 24, 2015
• Start date: October 2010
• Est. completion date: March 2015

Study information

• Verified date: November 2015
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustria: Agency for Health and Food SafetyBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: National Health Surveillance AgencyBulgaria: Bulgarian Drug AgencyCanada: Health CanadaChina: Food and Drug AdministrationCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Finland: Finnish Medicines AgencyGermany: Paul-Ehrlich-InstitutHong Kong: Department of HealthHungary: National Institute of PharmacyIndonesia: National Agency of Drug and Food ControlIsrael: Ministry of HealthItaly: The Italian Medicines AgencyJapan: Pharmaceuticals and Medical Devices AgencyMalaysia: Ministry of HealthNetherlands: Ministry of Health, Welfare and SportNew Zealand: MedsafeNorway: Norwegian Medicines AgencyPhilippines: Bureau of Food and DrugsPoland: Ministry of HealthPortugal: National Pharmacy and Medicines InstituteRomania: National Medicines AgencySingapore: Ministry of HealthSpain: Agencia Española de Medicamentos y Productos SanitariosSouth Korea: Korea Food and Drug Administration (KFDA)Sweden: Medical Products AgencySwitzerland: SwissmedicTaiwan: Department of HealthThailand: Food and Drug AdministrationTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 565
• Est. completion date: March 2015
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Biological:
• Placebo
8 mg/kg IV every 2 weeks
• Ramucirumab DP (IMC-1121B)
8 milligrams/kilogram (mg/kg) intravenous (IV) every 2 weeks

Other:
• BSC
Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.

Locations

Country	Name	City	State
Australia	ImClone Investigational Site	Bankstown	New South Wales
Australia	ImClone Investigational Site	Kogarah	New South Wales
Australia	ImClone Investigational Site	Kurralta Park	South Australia
Australia	ImClone Investigational Site	Liverpool Bc	New South Wales
Australia	ImClone Investigational Site	Prahran	Victoria
Austria	ImClone Investigational Site	Linz
Austria	ImClone Investigational Site	Salzburg
Austria	ImClone Investigational Site	Steyr
Austria	ImClone Investigational Site	Vienna
Belgium	ImClone Investigational Site	Bonheiden
Belgium	ImClone Investigational Site	Brussels
Belgium	ImClone Investigational Site	Charleroi
Belgium	ImClone Investigational Site	Edegem
Belgium	ImClone Investigational Site	Leuven
Belgium	ImClone Investigational Site	Liège
Belgium	ImClone Investigational Site	Ottignies
Brazil	ImClone Investigational Site	Belo Horizonte
Brazil	ImClone Investigational Site	Botucatu
Brazil	ImClone Investigational Site	Brasilia
Brazil	ImClone Investigational Site	Campinas
Brazil	ImClone Investigational Site	Ijui
Brazil	ImClone Investigational Site	Ribeirao Preto
Brazil	ImClone Investigational Site	Rio De Janeiro
Brazil	ImClone Investigational Site	Salvador
Brazil	ImClone Investigational Site	Sao Jose Rio Preto
Brazil	ImClone Investigational Site	São Paulo
Bulgaria	ImClone Investigational Site	Plovdiv
Bulgaria	ImClone Investigational Site	Sofia
Bulgaria	ImClone Investigational Site	Varna
Canada	ImClone Investigational Site	Ottawa	Ontario
Czech Republic	ImClone Investigational Site	Brib
Czech Republic	ImClone Investigational Site	Hradec Kralove
Czech Republic	ImClone Investigational Site	Olomouc
Czech Republic	ImClone Investigational Site	Prague
Finland	ImClone Investigational Site	Helsinki
France	ImClone Investigational Site	Amiens
France	ImClone Investigational Site	Angers
France	ImClone Investigational Site	Avignon
France	ImClone Investigational Site	Besancon
France	ImClone Investigational Site	Bordeaux
France	ImClone Investigational Site	Clermont-Ferrand
France	ImClone Investigational Site	La Roche Sur Yon
France	ImClone Investigational Site	Limoges
France	ImClone Investigational Site	Marseille
France	ImClone Investigational Site	Nice
France	ImClone Investigational Site	Paris
France	ImClone Investigational Site	Poitiers
France	ImClone Investigational Site	Reims
France	ImClone Investigational Site	Saint-Etienne
Germany	ImClone Investigational Site	Berlin
Germany	ImClone Investigational Site	Bielefeld
Germany	ImClone Investigational Site	Bonn
Germany	ImClone Investigational Site	Düsseldorf
Germany	ImClone Investigational Site	Essen
Germany	ImClone Investigational Site	Frankfurt
Germany	ImClone Investigational Site	Freiburg
Germany	ImClone Investigational Site	Hamburg
Germany	ImClone Investigational Site	Hannover
Germany	ImClone Investigational Site	Homburg
Germany	ImClone Investigational Site	Leipzig
Germany	ImClone Investigational Site	Magdeburg
Germany	ImClone Investigational Site	Munich
Germany	ImClone Investigational Site	Münster
Germany	ImClone Investigational Site	Tübingen
Germany	ImClone Investigational Site	Ulm
Germany	ImClone Investigational Site	Weiden
Hong Kong	ImClone Investigational Site	Kowloon
Hong Kong	ImClone Investigational Site	Pokfulam
Hong Kong	ImClone Investigational Site	Shatin
Hungary	ImClone Investigational Site	Budapest
Israel	ImClone Investigational Site	Beer Sheva
Israel	ImClone Investigational Site	Petah Tiqva
Israel	ImClone Investigational Site	Tel Aviv
Italy	ImClone Investigational Site	Bari
Italy	ImClone Investigational Site	Benevento
Italy	ImClone Investigational Site	Bologna
Italy	ImClone Investigational Site	Genova
Italy	ImClone Investigational Site	Lecce
Italy	ImClone Investigational Site	Milano
Italy	ImClone Investigational Site	Modena
Italy	ImClone Investigational Site	Padova
Italy	ImClone Investigational Site	Palermo
Italy	ImClone Investigational Site	Pavia
Italy	ImClone Investigational Site	Rome
Italy	ImClone Investigational Site	Udine
Japan	ImClone Investigational Site	Chiba
Japan	ImClone Investigational Site	Fukuoka
Japan	ImClone Investigational Site	Hyogo
Japan	ImClone Investigational Site	Ishikawa
Japan	ImClone Investigational Site	Kanagawa
Japan	ImClone Investigational Site	Kochi
Japan	ImClone Investigational Site	Kyoto
Japan	ImClone Investigational Site	Miyagi
Japan	ImClone Investigational Site	Osaka
Japan	ImClone Investigational Site	Osaka-Pref
Japan	ImClone Investigational Site	Saga
Japan	ImClone Investigational Site	Tochigi
Japan	ImClone Investigational Site	Tokushima
Japan	ImClone Investigational Site	Tokyo
Korea, Republic of	ImClone Investigational Site	Anyang
Korea, Republic of	ImClone Investigational Site	Incheon
Korea, Republic of	ImClone Investigational Site	Seodaemun-Gu
Korea, Republic of	ImClone Investigational Site	Seoul
Netherlands	ImClone Investigational Site	Amsterdam
Netherlands	ImClone Investigational Site	Rotterdam
Norway	ImClone Investigational Site	Oslo
Philippines	ImClone Investigational Site	Quezon City
Portugal	ImClone Investigational Site	Lisbon
Portugal	ImClone Investigational Site	Santa Maria Da Feira
Romania	ImClone Investigational Site	Bucharest
Romania	ImClone Investigational Site	Cluj-Napoca
Romania	ImClone Investigational Site	Craiova
Spain	ImClone Investigational Site	Avila
Spain	ImClone Investigational Site	Girona
Spain	ImClone Investigational Site	Madrid
Spain	ImClone Investigational Site	Ourense
Spain	ImClone Investigational Site	Valencia
Sweden	ImClone Investigational Site	Stockholm
Switzerland	ImClone Investigational Site	Bern
Taiwan	ImClone Investigational Site	Changhua
Taiwan	ImClone Investigational Site	Kuei Shan Hsiang
Taiwan	ImClone Investigational Site	Liouying/Tainan
Taiwan	ImClone Investigational Site	Niaosung
Taiwan	ImClone Investigational Site	Taichung
Taiwan	ImClone Investigational Site	Tainan
Taiwan	ImClone Investigational Site	Taipei
Thailand	ImClone Investigational Site	Bangkok
Thailand	ImClone Investigational Site	Hat Yai
United States	ImClone Investigational Site	Ann Arbor	Michigan
United States	ImClone Investigational Site	Boston	Massachusetts
United States	ImClone Investigational Site	Charleston	South Carolina
United States	ImClone Investigational Site	Dayton	Ohio
United States	ImClone Investigational Site	Jacksonville	Florida
United States	ImClone Investigational Site	Lubbock	Texas
United States	ImClone Investigational Site	Milwaukee	Wisconsin
United States	ImClone Investigational Site	New Haven	Connecticut
United States	ImClone Investigational Site	New Orleans	Louisiana
United States	ImClone Investigational Site	New York	New York
United States	ImClone Investigational Site	Newark	New Jersey
United States	ImClone Investigational Site	Orange	California
United States	ImClone Investigational Site	Philadelphia	Pennsylvania
United States	ImClone Investigational Site	San Francisco	California
United States	ImClone Investigational Site	Seattle	Washington
United States	ImClone Investigational Site	St Louis	Missouri
United States	ImClone Investigational Site	Winston-Salem	North Carolina
United States	ImClone Investigational Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Czech Republic,  Finland,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Norway,  Philippines,  Portugal,  Romania,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the end of the follow-up period or were lost to follow-up were censored on the last date the participant was known to be alive.	Randomization to death from any cause (up to 37 months)	No
Secondary	Progression-Free Survival (PFS)	PFS was defined as time from date of randomization until date of objectively determined progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death from any cause. PD was defined as =20% increase in sum of diameters (SOD) of target lesions, taking as reference smallest sum on study (including baseline sum if it was smallest). Sum must show a =5 millimeter (mm) increase. Appearance of =1 new lesions and unequivocal progression of existing non-target lesions were considered progression. In primary analysis, participants alive and without PD were censored at day of last adequate tumor assessment; progression or deaths without progression occurring immediately after =2 missed tumor assessments, were censored at day of the last adequate tumor assessment prior to missing assessments; participants who began new anticancer therapy were censored at day of the last adequate tumor assessment prior to start of new anticancer therapy.	Randomization to PD (up to 36 months)	No
Secondary	Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]	ORR was defined, using RECIST v1.1 criteria, as the percentage of participants who achieved a best overall response of CR or PR. CR was defined as the disappearance of all lesions and any intratumor arterial enhancement in target lesions, the normalization of the tumor marker level and all lymph nodes short axis reduced to <10 mm. PR was defined as =30% decrease in the SOD of target lesions, including the short axes of any target lymph nodes, taking as reference the baseline SOD of target lesions, no new lesions and stable nontarget lesions. Percentage of participants was calculated as: (number of participants with CR or PR / number of participants randomized) * 100.	Baseline to the date of first evidence of confirmed CR or PR (up to 37 months)	No
Secondary	Time to Radiographic Progression (TTP)	TTP was defined as the time from randomization to the first radiographically documented PD. PD was defined, using RECIST v1.1 criteria, as =20% increase in SOD of target lesions, taking as reference smallest sum on study (including baseline sum if it was the smallest). Sum must show an absolute increase of =5 mm. Appearance of =1 new lesions and unequivocal progression of existing non-target lesions were considered progression. Participants without PD were censored at the day of the last adequate tumor assessment. Progression occurred immediately after =2 missed tumor assessments and were censored at the day of the last adequate tumor assessment prior to the missing assessments. Participants who began new anticancer therapy were censored at the day of their last adequate tumor assessment prior to start of new anticancer therapy.	Randomization to PD (up to 36 months)	No
Secondary	Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)	The FHSI-8 is a self-administered 8-item questionnaire that measures a participant's symptoms in the domains of jaundice, stomach pain/discomfort weight loss, and fatigue. Participants rated each item on a 5-point scale from 0 (not at all) to 4 (very much). Item scores were calculated as outlined in the FACIT manual. FHSI-8 total score was the sum of each item's score with a total score ranging from 0 (highly symptomatic) to 32 (asymptomatic).	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)	No
Secondary	Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score	The EQ-5D is a self-reported, 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire related to the participant's current health state. Each question was scored using a 3 level scale (no problems, some problems, or extreme problems). EQ-5D health state was defined by combining responses from each of the 5 dimensions into a weighted health-state index score according to the United Kingdom (UK) population based algorithm where 0 = death and 1 = perfect health.	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)	No
Secondary	Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died	The number of participants with serious AEs (SAEs), other non-serious AEs and participants who died. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.	Baseline to study completion (up to 37 months)	No
Secondary	Maximum Concentration (Cmax) of Ramucirumab, Cycle 1		1 hour following the completion of Cycle 1 (14-day cycle) infusion	No
Secondary	Cmax of Ramucirumab, Cycle 4		1 hour following completion of Cycle 4 (14-day cycles) infusion	No
Secondary	Cmax of Ramucirumab, Cycle 7		1 hour following completion of Cycle 7 (14-day cycles) infusion	No
Secondary	Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)]	Participants were considered positive for anti-ramucirumab antibodies [anti-drug antibodies (ADA)] if the post-treatment sample had an increase of at least 4-fold in titer from the pretreatment values. If the pretreatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence of ADA.	Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles)	No