I4T-MC-JVDE

Eli Lilly and Company

Lilly Corporate Center, Indianapolis, IN, United States, 46285

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,

Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,

No

No

No

Final

19 Nov 2021

No

Yes

19 Nov 2021

No

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 [MEE] Cohort). Participants may also receive ramucirumab if eligible to be enrolled in Open-Label Expansion (OLE) Cohort.

This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

20 Jul 2015

No

Yes

Austria: 2

France: 51

Poland: 5

Australia: 3

Brazil: 9

Canada: 2

China: 76

Hong Kong: 22

Israel: 1

Japan: 59

Korea, Republic of: 38

Taiwan: 76

United States: 23

Czechia: 6

Germany: 23

Italy: 22

Spain: 5

Switzerland: 5

Belgium: 4

United Kingdom: 11

443

118

0

0

0

0

0

0

266

174

3

Overall Study (overall period)

Randomised - controlled

Yes

Ramucirumab

Cyramza,LY3009806

Solution for infusion

Intravenous use

Administered IV

Placebo

Solution for infusion

Intravenous use

Administered IV

Ramucirumab

Cyramza,LY3009806

Solution for infusion

Intravenous use

Administered IV

Ramucirumab

Cyramza,LY3009806

Solution for infusion

Intravenous use

Administered IV

Placebo

Solution for infusion

Intravenous use

Administered IV

Ramucirumab + BSC

Placebo + BSC

Open Label Ramucirumab + BSC

Ramucirumab MEE Cohort

Placebo MEE Cohort

Placebo + Best Supportive Care (BSC)

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.

Ramucirumab + Best Supportive Care (BSC)

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.

Ramucirumab + BSC

8 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.

Ramucirumab + BSC

Placebo + BSC

Open Label Ramucirumab + BSC

Ramucirumab MEE Cohort

Placebo MEE Cohort

Placebo + Best Supportive Care (BSC)

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.

Ramucirumab + Best Supportive Care (BSC)

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.

Ramucirumab + BSC

8 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.

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. Analysis Population Description (APD): All randomized participants. Participants were censored in Ramucirumab arm = 50 and Placebo arm = 21. All randomized participants (including the censored participants) were included in the analyses.

Primary

From Date of Randomization to Death from Any Cause (Up to 28 Months)

Placebo + BSC v Ramucirumab + Best Supportive Care (BSC)

292

Pre-specified

0.71

2-sided

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. APD: All randomized participants. Participants were censored in the Ramucirumab arm = 25 and in the Placebo arm = 9. All randomized participants (including the censored participants) were included in the analyses.

Secondary

From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months)

Ramucirumab + BSC v Placebo + BSC

292

Pre-specified

0.452

2-sided

Time to radiographic progression is defined as the time from the date of randomization to the date of first observation of objective progression. APD: All randomized participants.

Secondary

From Randomization to Objective Progression (Up to 28 Months)

Ramucirumab + BSC v Placebo + BSC

292

Pre-specified

0.427

2-sided

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. APD: All randomized participants who received at least one dose of study drug.

Secondary

From Randomization to Objective Progression (Up to 28 Months)

Ramucirumab + BSC v Placebo + BSC

292

Pre-specified

4.6

2-sided

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. APD: All randomized participants who received at least one dose of study drug.

Secondary

Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before 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. APD: All randomized participants who received at least one dose of study drug.

Secondary

Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles)

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). APD: All randomized participants who received at least one dose of study drug and had evaluable anti-ramucirumab data.

Secondary

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)

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 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. APD: All randomized participants who had evaluable FHSI-8 data.

Secondary

From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months)

Ramucirumab + BSC v Placebo + BSC

292

Pre-specified

0.799

2-sided

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). APD: All randomized participants and had evaluable EQ-5D-5L data.

Secondary

From Randomization through End of Study (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. APD: All randomized participants and had evaluable ECOG data. Censored participants without any post baseline assessments at randomization date were in the Ramucirumab + BSC arm = 141 and the Placebo + BSC arm =75.

Secondary

From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months)

Baseline up to 3.2 years

All participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly.

25.0

Ramucirumab + BSC

Placebo+BSC

Ramucirumab MEE Cohort

Placebo MEE Cohort

Open Label Ramucirumab + BSC