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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01140347




Registration number
NCT01140347
Ethics application status
Date submitted
2/06/2010
Date registered
9/06/2010
Date last updated
28/12/2015

Titles & IDs
Public title
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
Scientific 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)
Secondary ID [1] 0 0
CP12-0919
Secondary ID [2] 0 0
13895
Universal Trial Number (UTN)
Trial acronym
REACH
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatocellular Carcinoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Placebo
Treatment: Other - Ramucirumab DP (IMC-1121B)
Other interventions - BSC

Experimental: Ramucirumab DP and BSC -

Placebo comparator: Placebo and BSC -


Treatment: Other: Placebo
8 mg/kg IV every 2 weeks

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

Other interventions: 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.
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
Randomization to death from any cause (up to 37 months)
Secondary outcome [1] 0 0
Progression-Free Survival (PFS)
Timepoint [1] 0 0
Randomization to PD (up to 36 months)
Secondary outcome [2] 0 0
Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
Timepoint [2] 0 0
Baseline to the date of first evidence of confirmed CR or PR (up to 37 months)
Secondary outcome [3] 0 0
Time to Radiographic Progression (TTP)
Timepoint [3] 0 0
Randomization to PD (up to 36 months)
Secondary outcome [4] 0 0
Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
Timepoint [4] 0 0
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)
Secondary outcome [5] 0 0
Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score
Timepoint [5] 0 0
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)
Secondary outcome [6] 0 0
Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died
Timepoint [6] 0 0
Baseline to study completion (up to 37 months)
Secondary outcome [7] 0 0
Maximum Concentration (Cmax) of Ramucirumab, Cycle 1
Timepoint [7] 0 0
1 hour following the completion of Cycle 1 (14-day cycle) infusion
Secondary outcome [8] 0 0
Cmax of Ramucirumab, Cycle 4
Timepoint [8] 0 0
1 hour following completion of Cycle 4 (14-day cycles) infusion
Secondary outcome [9] 0 0
Cmax of Ramucirumab, Cycle 7
Timepoint [9] 0 0
1 hour following completion of Cycle 7 (14-day cycles) infusion
Secondary outcome [10] 0 0
Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)]
Timepoint [10] 0 0
Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles)

Eligibility
Key inclusion 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/10/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/03/2015
Sample size
Target
Accrual to date
Final
565
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
ImClone Investigational Site - Bankstown
Recruitment hospital [2] 0 0
ImClone Investigational Site - Kogarah
Recruitment hospital [3] 0 0
ImClone Investigational Site - Liverpool Bc
Recruitment hospital [4] 0 0
ImClone Investigational Site - Kurralta Park
Recruitment hospital [5] 0 0
ImClone Investigational Site - Prahran
Recruitment postcode(s) [1] 0 0
2200 - Bankstown
Recruitment postcode(s) [2] 0 0
2217 - Kogarah
Recruitment postcode(s) [3] 0 0
1871 - Liverpool Bc
Recruitment postcode(s) [4] 0 0
5037 - Kurralta Park
Recruitment postcode(s) [5] 0 0
3181 - Prahran
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
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United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
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Washington
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Linz
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Steyr
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Ulm
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Bari
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Benevento
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Italy
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Bologna
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Italy
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Genova
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Italy
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Lecce
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Milano
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Modena
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Padova
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Palermo
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Pavia
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Rome
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Kochi
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Kyoto
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Miyagi
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Osaka-Pref
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Osaka
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Saga
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Craiova
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Avila
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Girona
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Valencia
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Stockholm
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Bern
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Changhua
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Taiwan
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Kuei Shan Hsiang
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Taiwan
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Liouying/Tainan
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Taiwan
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Niaosung
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Taiwan
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Taichung
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Tainan
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Taiwan
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Taipei
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Thailand
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Bangkok
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Thailand
State/province [139] 0 0
Hat Yai

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Eli Lilly and Company
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01140347
Trial related presentations / publications
Llovet JM, Singal AG, Villanueva A, Finn RS, Kudo M, Galle PR, Ikeda M, Callies S, McGrath LM, Wang C, Abada P, Widau RC, Gonzalez-Gugel E, Zhu AX. Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials. Clin Cancer Res. 2022 Jun 1;28(11):2297-2305. doi: 10.1158/1078-0432.CCR-21-4000.
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.
Zhu AX, Finn RS, Kang YK, Yen CJ, Galle PR, Llovet JM, Assenat E, Brandi G, Motomura K, Ohno I, Daniele B, Vogel A, Yamashita T, Hsu CH, Gerken G, Bilbruck J, Hsu Y, Liang K, Widau RC, Wang C, Abada P, Kudo M. Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab. Br J Cancer. 2021 Apr;124(8):1388-1397. doi: 10.1038/s41416-021-01260-w. Epub 2021 Feb 3.
Reig M, Galle PR, Kudo M, Finn R, Llovet JM, Metti AL, Schelman WR, Liang K, Wang C, Widau RC, Abada P, Zhu AX. Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab. Liver Int. 2021 Mar;41(3):598-607. doi: 10.1111/liv.14731. Epub 2020 Dec 5.
Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. doi: 10.1136/esmoopen-2020-000797.
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Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01140347