A Study of LY2157299 in Participants With Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to estimate the median time to progression in participants with hepatocellular carcinoma (HCC) when treated with LY2157299 as monotherapy and in combination with sorafenib or ramucirumab.

Detailed Description
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The study consists of four Parts: Part A where HCC participants with an increased alpha-fetoprotein (AFP) level will be treated with either 160 milligrams (mg) LY2157299 or 300 mg LY2157299. Part B where HCC participants with a normal AFP level will be treated with 300 mg LY2157299, Part C where treatment-naïve HCC participants will be treated with 160 mg LY2157299 + sorafenib or 300 mg LY2157299 + sorafenib, and Part D where HCC participants will be treated with either 160 mg or 300 mg LY2157299 + ramucirumab. Participants who continue to receive benefit from treatment at the time that the study is considered completed, may enter the treatment extension period and continue to receive the study treatment. The end of the study is the date of last visit or last scheduled procedure for the last active subject in the study.

Official Title
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Phase 2 Study of LY2157299 in Patients With Hepatocellular Carcinoma

Conditions
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Carcinoma, Hepatocellular

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


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 Part A: Serum alpha fetoprotein greater than or equal to 1.5 Upper Limits of Normal, Part B: Serum alpha fetoprotein less than 1.5 Upper Limits of Normal. Not applicable for Part C or D Child-Pugh Stage: A or B7 for Parts A & B, A for Part C, and D Have the presence of measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). A lesion that has been previously treated by local therapy will qualify as a measurable or evaluable lesion if there was demonstrable progression following locoregional therapy Have given written informed consent prior to any study-specific procedures Have adequate hematologic, hepatic and renal function Have a performance status of equal to or less than 1 on the Eastern Cooperative Oncology Group (ECOG) scale For Parts A & B: Have received sorafenib and have progressed or were intolerant to sorafenib or are ineligible for sorafenib treatment. For Part C: not received previous systemic treatment. For Part D: have received sorafenib and have progressed or were intolerant to sorafenib or are ineligible for sorafenib treatment or have not received prior systemic treatment. For Parts A, B, and D: have discontinued sorafenib for at least 2 weeks Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures Males and females 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 Females with childbearing potential must have had a negative serum pregnancy test less than or equal to 7 days prior to the first dose of study drug Are able to swallow capsules or tablets Exclusion Criteria: Are currently enrolled in, or discontinued within the last 28 days from a clinical trial involving an investigational drug or device or not approved use of a drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Known HCC with fibro-lamellar or mixed histology Presence of clinically relevant ascites History of liver transplant requiring increased immunosuppressive therapy. (Participants on maintenance immunosuppressive therapy after liver transplant are eligible for Part A & B) Have received more than 1 line of systemic treatment in Parts A, B and D Have moderate or severe cardiac disease: Have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension Have documented major electrocardiogram (ECG) abnormalities at the investigator's discretion Have major abnormalities documented by echocardiography with Doppler Have predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress Have serious preexisting medical conditions that, in the opinion of the investigator, that cannot be adequately controlled with appropriate therapy or would preclude participation in this study Females who are pregnant or lactating Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless in complete remission and off all therapy for that disease for a minimum of 3 years. At the discretion of the investigator, hormone-refractory prostate cancer participants who are stable on GnRH agonist therapy and breast cancer participants who are stable on antiestrogen therapy may have that treatment continued Have active infection that would interfere with the study objectives or influence study compliance For Part C, have a known hypersensitivity to sorafenib or its excipients For Part D, have a serious illness or medical condition(s), including but not limited to the following: The participant has undergone major surgery within 28 days prior to randomization or has undergone central venous access device placement within 7 days prior to randomization The participant has uncontrolled arterial hypertension ≥150 / ≥90 millimeters of mercury (mm Hg) despite standard medical management

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Cohort 1-160 milligram (mg) LY2157299<br>Per the protocol, following an interim analysis, the decision was taken to no longer randomize participants to the 160 mg LY2157299 arm. As of May 25,2012, all newly enrolled participants will receive 300 mg LY2157299. 80 mg LY2157299 given orally twice daily (BID) for 14 days followed by 14 days off (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>|
| Experimental: Part A Cohort 2 - 300 mg LY2157299<br>150 mg LY2157299 given orally BID for 14 days followed by 14 days off (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>Drug: Sorafenib<br>* Administered orally<br>|
| Experimental: Part B - 300 mg LY2157299<br>150 mg LY2157299 given orally BID for 14 days followed by 14 days off (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>|
| Experimental: Part C Cohort 1 - 160 mg LY2157299 + 800 mg Sorafenib<br>80 mg LY2157299 given orally BID on Days 1 to 14 in combination with 400 mg Sorafenib BID on days 1 to 28 (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>Drug: Sorafenib<br>* Administered orally<br>|
| Experimental: Part C Cohort 2 - 300 mg LY2157299 + 800 mg Sorafenib<br>150 mg LY2157299 given orally BID on Days 1 to 14 in combination with 400 mg Sorafenib BID on days 1 to 28 (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>Drug: Sorafenib<br>* Administered orally<br>|
| Experimental: Part D Cohort 1 - 160 mg LY2157299 + 8 mg/kg Ramucirumab<br>80 mg LY2157299 given orally BID on days 1 to 14 in combination with ramucirumab 8 mg/kilogram (kg) intravenous (IV) on days 1 and 15 (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY30098016;|
| Experimental: Part D Cohort 2 - 300 mg LY2157299 + 8 mg/kg Ramucirumab<br>150 mg LY2157299 given orally BID on days 1 to 14 in combination with ramucirumab 8 mg/kg IV on days 1 and 15 (28-day cycle). Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | Drug: LY2157299<br>* Administered orally<br>Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY30098016;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) | Biomarker response was defined as a > 20% decrease in the biomarker AFP from baseline during 8 weeks of treatment. Data presented is median overall survival of those participants who achieved the defined biomarker response. Participants enrolled in Part A had a baseline AFP level of >1.5 upper limit normal (ULN). Participants enrolled in Part B had baseline AFP level <1.5 ULN. | Baseline, discontinuation from any cause (Up to 83 months) | 
| Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) | Biomarker response was defined as a > 20% decrease in the biomarker TGF-B from baseline. Data presented is median overall survival of those participants who achieved biomarker response. | Baseline,discontinuation from any cause (Up to 83 months) | 
| Time to Progression (TTP) | TTP is measured from the date of first dose to the first date of progression of disease based on the investigator review of tumor response using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. | Randomization to date of first measured progressive disease (Up to 36 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Population Pharmacokinetics (PK) 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 | 
| Recommended Dose for Phase 3 Hepatocellular Carcinoma (HCC) Trials |  | Cycle 1 (28 Days) | 
| Overall Survival (OS) | OS duration is measured from the date of first dose to the date of death from any cause. | Randomization to date of death from any cause (Up to 83 months) | 
| Progression Free Survival (PFS) | PFS duration is measure from the date of first dose to the first date of objective progression of disease or death from any cause. Progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. | Randomization to measured progressive disease or death from any cause (Up to 45 Weeks) | 
| Percentage of Participants Achieving an Objective Response (Response Rate) | The percentage of participants who achieved best overall response of either Complete Response (CR) or Partial Response (PR). The overall response rate for each dose with be estimated by dividing the number of confirmed responders by the number of participants who received at least one dose of study drug. Per RECIST v.1.0 criteria CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 millimeter (mm). Tumor-marker results must have normalized. PR is defined as at least 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. | Randomization to measured progressive disease (Up to 36 Weeks) | 
| Duration of Tumor Response (DoR) | DoR is measured from the date of the first objective status assessment of a Complete Response (CR) or Partial Response (PR), as determined by RECIST v1.1, to the first date of objective progression of disease or death from any cause. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 millimeter (mm). Tumor-marker results must have normalized. PR is defined as at least 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression. | Time of response to measured progressive disease or death from any cause (Up to 84 Weeks) | 
| Time to Treatment Failure (TTF) | TTF is measured from the date of first dose until the date of discontinuation of study treatment due to adverse event, progression of disease, or death from any cause. | Randomization to the date of discontinuation of study treatment due to adverse event, progression of disease, or death from any cause (Up to 75 Weeks) | 
| Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72; FACT-Hep score range 1-180, and Trial-Outcome Index (TOI) score range 1-128, to assess health related quality of life in participants with cancer. Higher scores reflect a better health state. | Baseline, Day 1 Cycle 4 | 
| Time to Worsening (TTW) of Symptoms (FACT-Hep) | Time to worsening of symptoms used minimally important differences to evaluate Physical Well Being (PWB), Functional Well Being (FWB), Hepatocellular Cancer Symptoms (HCS), National Comprehensive Cancer Network (NCCN)/FACT Hepatocellular Symptoms (FHS), Trial-Outcome Index (TOI). PWB time to worsening was defined as participants who had change in a subscale of ≥ 2 point decrease from baseline; FWB time to worsening was defined as participants who had change in a subscale of ≥ 2 point decrease from baseline; HCS time to worsening was defined as participants who had change in a subscale of ≥ 5 point decrease from baseline; FHS time to worsening was defined as participants who had change in a subscale of ≥ 2 point decrease from baseline; TOI time to Worsening was defined as participants who had change in the subscale of ≥ 7 point decrease from baseline. | Baseline to the worsening of symptoms (up to 567 days) |