A Study of LY2157299 in Participants With Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as LY2157299 in participants with hepatocellular carcinoma.

Official Title
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A Randomized Phase 2 Study of LY2157299 Versus LY2157299 - Sorafenib Combination Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: LY2157299
* Drug: Sorafenib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histological evidence of a diagnosis of HCC not amenable to curative surgery. Have Child-Pugh Class A. Have the presence of measurable disease. Have adequate organ function. Have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale. If male or female with reproductive potential, must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug. If females with childbearing potential, must have had a negative serum pregnancy test 7 days prior to the first dose of study drug. Are able to swallow capsules or tablets. Have available diagnostic or biopsy tumor tissue. Exclusion Criteria: Have received previous systemic treatment for advanced disease. Have known HCC with fibro-lamellar or mixed histology. Have presence of clinically relevant ascites. Have had a liver transplant. Have moderate or severe cardiac disease. Have active or uncontrolled clinically serious hepatitis B virus or hepatitis C virus infection. Have experienced Grade 3 or 4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to enrollment requiring transfusion or endoscopic or operative intervention. Have esophageal or gastric varices that require immediate intervention or represent a high bleeding risk. Had major surgery within 4 weeks prior to the study randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 150 milligram (mg) Galunisertib Monotherapy<br>150 mg galunisertib administered orally, twice daily (BID) for 14 days followed by 14 days with no study drug (28 days cycle). | Drug: LY2157299<br>* Administered orally<br>|
| Experimental: 150 mg Galunisertib + 400 mg Sorafenib Therapy<br>150 mg galunisertib administered orally, BID for 14 days followed by 14 days with no study drug (28 days cycle). 400 mg sorafenib administered orally BID for 28 days. | Drug: LY2157299<br>* Administered orally<br>Drug: Sorafenib<br>* Administered orally<br>|
| Placebo Comparator: 400 mg Sorafenib + Placebo Therapy<br>Placebo administered orally BID for 14 days followed by 14 days with no study drug (28 days cycle). 400 mg sorafenib administered orally BID for 28 days. | Drug: Sorafenib<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS): Number of Events | OS defined as the time from the date of randomization to the date of death due to any cause. An overall survival event was defined as death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive. The number of participants with overall survival events (deaths) is reported. | Randomization to Date of Death from Any Cause (Up To 24 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Population Pharmacokinetics (PopPK): Mean Population Clearance of Galunisertib | Population mean (between-subject coefficient variance [CV %]) apparent clearance. | Cycle (C) 1: Day (D)1: Predose, 0.5-2 hours(h) Postdose; D14: Predose, 0.5-2, 3-5 h, Postdose; D15 Morning; D22 Morning; Predose C2 and C3 Predose D1 | 
| Population Pharmacokinetics (PopPK): Steady State Apparent Volume of Distribution (Vss) of Galunisertib | Population Vss [distribution of galunisertib in the body at steady state] after a single dose of galunisertib. | Cycle (C) 1: Day (D)1: Predose, 0.5-2 hours(h) Postdose; D14: Predose, 0.5-2, 3-5 h, Postdose; D15 Morning; D22 Morning; Predose C2 and C3 Predose D1 | 
| Time to Tumor Progression (TTP) | TTP at initial treatment was defined as the number of months between date of randomization and the date of first documented disease progression or the date of death due to disease under study, whichever came first. Progression was assessed by the Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.Progressive Disease (PD)is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Randomization to the Date of Objective Progressive Disease or Date of Death due to Study Disease, whichever came first (Up To 24 Months) | 
| Progression-Free Survival (PFS) | PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. | Randomization to Measured Progressive Disease or Death (Up To 24 Months) | 
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. | Randomization to Measured Progressive Disease (Up To 24 Months) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Score | EORTC QLQ-C30 consists of 30 items covered by 1 of 3 dimensions: Global health status/quality of life (2 items) with scores ranging from 1 (Very Poor) to 7 (Excellent). Functional scales (15 total items addressing either physical, role, emotional, cognitive, or social functioning), each item scores ranging from 1 (not at all) to 4 (very much). Symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhea, or financial impact), each item scores ranging from 1 (not at all) to 4 (very much). All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. | Baseline, 24 Months | 
| Change From Baseline in EORTC QLQ Hepatocellular Carcinoma (HCC-18) Questionnaire Score | The EORTC QLQ-HCC-18 was an 18-item questionnaire design used along with the 30-item EORTC QLQ-C30. EORTC QLQ-HCC 18 questionnaire included 8 symptom scales such as abdominal swelling, sex life, fatigue, body image, jaundice, nutrition, pain and fever. Each individual item ranges from 1 to 4, where 1 = not at all and 4 = very much. All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a symptom scale/item represented a high level of symptomatology/problem. | Baseline, 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transforming growth factor beta (TGF-β)