Carcinoma, Hepatocellular
Conditions
Brief summary
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
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.
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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: 1. 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 2. Have documented major electrocardiogram (ECG) abnormalities at the investigator's discretion 3. Have major abnormalities documented by echocardiography with Doppler 4. 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: 1. 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 2. The participant has uncontrolled arterial hypertension ≥150 / ≥90 millimeters of mercury (mm Hg) despite standard medical management
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) | Baseline, discontinuation from any cause (Up to 83 months) | 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. |
| Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) | Baseline,discontinuation from any cause (Up to 83 months) | 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. |
| Time to Progression (TTP) | Randomization to date of first measured progressive disease (Up to 36 Weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Randomization to measured progressive disease or death from any cause (Up to 45 Weeks) | 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. |
| Percentage of Participants Achieving an Objective Response (Response Rate) | Randomization to measured progressive disease (Up to 36 Weeks) | 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. |
| Duration of Tumor Response (DoR) | Time of response to measured progressive disease or death from any cause (Up to 84 Weeks) | 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. |
| Population Pharmacokinetics (PK) Mean Population Clearance 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 | Population mean (between-subject coefficient variance \[CV %\]) apparent clearance. |
| Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | Baseline, Day 1 Cycle 4 | 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. |
| Time to Worsening (TTW) of Symptoms (FACT-Hep) | Baseline to the worsening of symptoms (up to 567 days) | 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. |
| Time to Treatment Failure (TTF) | 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) | 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. |
| Recommended Dose for Phase 3 Hepatocellular Carcinoma (HCC) Trials | Cycle 1 (28 Days) | — |
| Overall Survival (OS) | Randomization to date of death from any cause (Up to 83 months) | OS duration is measured from the date of first dose to the date of death from any cause. |
Countries
Australia, France, Germany, Italy, New Zealand, Spain, United States
Participant flow
Pre-assignment details
Participants who had progressive disease or death are defined as completed. Per the protocol, following an interim analysis, the decision was taken to no longer randomize participants to the 160 mg LY2157299 arm.
Participants by arm
| Arm | Count |
|---|---|
| Part A Cohort 1 - 160 mg LY2157299 80 mg LY2157299 given orally BID for 14 days followed by 14 days off (28-day cycle).. | 37 |
| Part A Cohort 2 - 300 mg LY2157299 150mg LY2157299 given orally BID for 14 days followed by 14 days off (28-day cycle). | 72 |
| Part B - 300 mg LY2157299 150 mg LY2157299 given orally BID for 14 days followed by 14 days off (28-day cycle). | 40 |
| Part C Cohort 1 - 160 mg LY2157299 + Sorafenib 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). | 3 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib 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). | 44 |
| Part D Cohort 1 - 160 mg LY2157299 + Ramucirumab 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). | 3 |
| Part D Cohort 2 - 300 mg LY2157299 + Ramucirumab 150 mg LY2157299 given twice BID on days 1 to 14 in combination with ramucirumab 8 mg/kg IV on days 1 and 15 (28-day cycle). | 5 |
| Total | 204 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 3 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 4 | 3 | 0 | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | Part C Cohort 1 - 160 mg LY2157299 + Sorafenib | Part B - 300 mg LY2157299 | Part A Cohort 2 - 300 mg LY2157299 | Total | Part D Cohort 2 - 300 mg LY2157299 + Ramucirumab | Part A Cohort 1 - 160 mg LY2157299 | Part D Cohort 1 - 160 mg LY2157299 + Ramucirumab | Part C Cohort 2 - 300 mg LY2157299 + Sorafenib |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 70.3 years STANDARD_DEVIATION 4.7 | 68.1 years STANDARD_DEVIATION 9.6 | 63.3 years STANDARD_DEVIATION 10.8 | 64.3 years STANDARD_DEVIATION 10.5 | 63.2 years STANDARD_DEVIATION 11.2 | 63.4 years STANDARD_DEVIATION 10.8 | 54.0 years STANDARD_DEVIATION 11.3 | 63.7 years STANDARD_DEVIATION 9.8 |
| Alpha-Fetoprotein 200 - 400 (µg/L) | 0 Participants | 0 Participants | 5 Participants | 12 Participants | 0 Participants | 3 Participants | 0 Participants | 4 Participants |
| Alpha-Fetoprotein < 200 nanograms per Liter (µg/L) | 2 Participants | 28 Participants | 23 Participants | 85 Participants | 2 Participants | 9 Participants | 1 Participants | 20 Participants |
| Alpha-Fetoprotein > 400 (µg/L) | 1 Participants | 0 Participants | 43 Participants | 87 Participants | 2 Participants | 23 Participants | 2 Participants | 16 Participants |
| Alpha-Fetoprotein Unknown/Not reported | 0 Participants | 12 Participants | 1 Participants | 20 Participants | 1 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 7 Participants | 21 Participants | 4 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 3 Participants | 9 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 2 Participants | 9 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 2 Participants | 15 Participants | 0 Participants | 0 Participants | 1 Participants | 9 Participants |
| Race (NIH/OMB) White | 2 Participants | 35 Participants | 58 Participants | 149 Participants | 0 Participants | 34 Participants | 0 Participants | 20 Participants |
| Region of Enrollment Australia | 0 Participants | 2 Participants | 3 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment France | 0 Participants | 16 Participants | 27 Participants | 69 Participants | 0 Participants | 12 Participants | 0 Participants | 14 Participants |
| Region of Enrollment Germany | 2 Participants | 4 Participants | 7 Participants | 21 Participants | 0 Participants | 4 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Italy | 0 Participants | 9 Participants | 15 Participants | 40 Participants | 0 Participants | 12 Participants | 0 Participants | 4 Participants |
| Region of Enrollment New Zealand | 0 Participants | 4 Participants | 5 Participants | 23 Participants | 0 Participants | 2 Participants | 0 Participants | 12 Participants |
| Region of Enrollment Spain | 0 Participants | 1 Participants | 3 Participants | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 Participants | 4 Participants | 12 Participants | 41 Participants | 5 Participants | 6 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 13 Participants | 27 Participants | 0 Participants | 5 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 36 Participants | 59 Participants | 177 Participants | 5 Participants | 32 Participants | 3 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 33 / 37 | 63 / 72 | 26 / 40 | 3 / 3 | 36 / 44 | 2 / 3 | 5 / 5 |
| other Total, other adverse events | 32 / 37 | 64 / 72 | 38 / 40 | 3 / 3 | 44 / 44 | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 15 / 37 | 36 / 72 | 16 / 40 | 3 / 3 | 28 / 44 | 1 / 3 | 2 / 5 |
Outcome results
Primary
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.
Time frame: Baseline, discontinuation from any cause (Up to 83 months)
Population: All participants who received at least one dose of study drug, achieved a \>20% reduction in biomarker AFP, and had evaluable post-baseline biomarker data. Due to low enrollment into Part C Cohort - 160 mg reporting group, Kaplan Meier analysis for OS was not conducted in this subgroup. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) | 19.0 Months |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) | 21.5 Months |
| Part B LY2157299 | Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) | 24.2 Months |
| Part C LY2157299 | Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) | 17.9 Months |
Primary
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.
Time frame: Baseline,discontinuation from any cause (Up to 83 months)
Population: All participants who received at least one dose of study drug, achieved a \>20% reduction in biomarker TGF-β and had evaluable post-baseline biomarker data. Due to low enrollment in Part C Cohort 1 - 160 mg reporting group, Kaplan Meier analysis for OS was not conducted in this subgroup. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) | 11.9 Months |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) | 10.1 Months |
| Part B LY2157299 | Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) | 21.9 Months |
| Part C LY2157299 | Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) | 22.88 Months |
Primary
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.
Time frame: Randomization to date of first measured progressive disease (Up to 36 Weeks)
Population: All participants who receive at least one dose of study drug. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Time to Progression (TTP) | 12.1 Weeks |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Progression (TTP) | 7.1 Weeks |
| Part B LY2157299 | Time to Progression (TTP) | 18.0 Weeks |
| Part C LY2157299 | Time to Progression (TTP) | 36.0 Weeks |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Time to Progression (TTP) | 17.9 Weeks |
Secondary
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.
Time frame: Baseline, Day 1 Cycle 4
Population: All participants with baseline and one post-baseline FACT-Hep Questionnaire in Cycles 2, 3, or 4. Per protocol, Part D collected safety data only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | PWB | 0.06 units on a scale | Standard Deviation 3.6 |
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | TOI | 1.34 units on a scale | Standard Deviation 13.3 |
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FACT-Hep | 2.04 units on a scale | Standard Deviation 1.53 |
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | EWB | 0.55 units on a scale | Standard Deviation 2.7 |
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | SWB | 0.96 units on a scale | Standard Deviation 2.9 |
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FWB | -0.02 units on a scale | Standard Deviation 5.3 |
| Part A Cohort 1 - 160 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | HCS | 1.93 units on a scale | Standard Deviation 7.6 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | HCS | 1.40 units on a scale | Standard Deviation 7.8 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FWB | 0.84 units on a scale | Standard Deviation 3.6 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | SWB | 0.24 units on a scale | Standard Deviation 3.4 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | PWB | -0.16 units on a scale | Standard Deviation 5 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FACT-Hep | 1.50 units on a scale | Standard Deviation 17.5 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | EWB | 1.17 units on a scale | Standard Deviation 3.9 |
| Part A Cohort 2 - 300 mg LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | TOI | 1.14 units on a scale | Standard Deviation 14.6 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FWB | 1.20 units on a scale | Standard Deviation 4.7 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | PWB | 0.04 units on a scale | Standard Deviation 3.4 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | SWB | 0.37 units on a scale | Standard Deviation 4.5 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | EWB | 1.13 units on a scale | Standard Deviation 4.1 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | HCS | 0.89 units on a scale | Standard Deviation 6.8 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FACT-Hep | 0.58 units on a scale | Standard Deviation 18.2 |
| Part B LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | TOI | 1.17 units on a scale | Standard Deviation 12.2 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | EWB | 2.87 units on a scale | Standard Deviation 2.8 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | HCS | 1.08 units on a scale | Standard Deviation 6 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | SWB | -1.11 units on a scale | Standard Deviation 2.8 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | TOI | -1.92 units on a scale | Standard Deviation 7.7 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FACT-Hep | -0.50 units on a scale | Standard Deviation 6.5 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | PWB | -1.67 units on a scale | Standard Deviation 1.5 |
| Part C LY2157299 | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FWB | -1.00 units on a scale | Standard Deviation 1 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | EWB | 0.85 units on a scale | Standard Deviation 2.5 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | TOI | -8.28 units on a scale | Standard Deviation 13.7 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FACT-Hep | -8.54 units on a scale | Standard Deviation 17 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | HCS | -3.79 units on a scale | Standard Deviation 7.3 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | SWB | 0.41 units on a scale | Standard Deviation 3.6 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | PWB | -1.75 units on a scale | Standard Deviation 4.4 |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score | FWB | -1.19 units on a scale | Standard Deviation 4.6 |
Secondary
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 frame: Time of response to measured progressive disease or death from any cause (Up to 84 Weeks)
Population: All participants who received at least one dose of study drug with assessment of CR or PR. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part B LY2157299 | Duration of Tumor Response (DoR) | 37.6 Weeks |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Duration of Tumor Response (DoR) | 40.2 Weeks |
Secondary
Overall Survival (OS)
OS duration is measured from the date of first dose to the date of death from any cause.
Time frame: Randomization to date of death from any cause (Up to 83 months)
Population: All participants who received at least one dose of study drug. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Overall Survival (OS) | 39.1 Weeks |
| Part A Cohort 2 - 300 mg LY2157299 | Overall Survival (OS) | 29.6 Weeks |
| Part B LY2157299 | Overall Survival (OS) | 73.0 Weeks |
| Part C LY2157299 | Overall Survival (OS) | 30.3 Weeks |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Overall Survival (OS) | 89.6 Weeks |
Secondary
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.
Time frame: Randomization to measured progressive disease (Up to 36 Weeks)
Population: All participants who received at least one dose of study drug. Per protocol, Part D collected safety data only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Complete Response | 0 percentage of participants |
| Part A Cohort 1 - 160 mg LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Partial Response | 0 percentage of participants |
| Part A Cohort 2 - 300 mg LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Complete Response | 0 percentage of participants |
| Part A Cohort 2 - 300 mg LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Partial Response | 0 percentage of participants |
| Part B LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Complete Response | 0 percentage of participants |
| Part B LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Partial Response | 3.7 percentage of participants |
| Part C LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Partial Response | 0 percentage of participants |
| Part C LY2157299 | Percentage of Participants Achieving an Objective Response (Response Rate) | Complete Response | 0 percentage of participants |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Percentage of Participants Achieving an Objective Response (Response Rate) | Complete Response | 0 percentage of participants |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Percentage of Participants Achieving an Objective Response (Response Rate) | Partial Response | 2.3 percentage of participants |
Secondary
Population Pharmacokinetics (PK) Mean Population Clearance of Galunisertib
Population mean (between-subject coefficient variance \[CV %\]) apparent clearance.
Time frame: 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: All participants who received at least one dose of study drug, regardless of dose, with evaluable PK data. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Population Pharmacokinetics (PK) Mean Population Clearance of Galunisertib | 33.6 Liter per hour (L/hr) | Geometric Coefficient of Variation 48 |
Secondary
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.
Time frame: Randomization to measured progressive disease or death from any cause (Up to 45 Weeks)
Population: All participants who received at least one dose of study drug. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Progression Free Survival (PFS) | 12 Weeks |
| Part A Cohort 2 - 300 mg LY2157299 | Progression Free Survival (PFS) | 6.6 Weeks |
| Part B LY2157299 | Progression Free Survival (PFS) | 13.4 Weeks |
| Part C LY2157299 | Progression Free Survival (PFS) | 28.4 Weeks |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Progression Free Survival (PFS) | 28.4 Weeks |
Secondary
Recommended Dose for Phase 3 Hepatocellular Carcinoma (HCC) Trials
Time frame: Cycle 1 (28 Days)
Population: All participants in Part A and Part B.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Recommended Dose for Phase 3 Hepatocellular Carcinoma (HCC) Trials | 300 milligrams (mg) |
Secondary
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.
Time frame: 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)
Population: All participants who received at least one dose of study drug. Per protocol, Part D collected safety data only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Time to Treatment Failure (TTF) | 13.4 Weeks |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Treatment Failure (TTF) | 9.9 Weeks |
| Part B LY2157299 | Time to Treatment Failure (TTF) | 19.3 Weeks |
| Part C LY2157299 | Time to Treatment Failure (TTF) | 26.3 Weeks |
| Part C Cohort 2 - 300 mg LY2157299 + Sorafenib | Time to Treatment Failure (TTF) | 49.3 Weeks |
Secondary
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.
Time frame: Baseline to the worsening of symptoms (up to 567 days)
Population: All participants who completed a baseline and one post-baseline FACT-Hep TTW questionnaire. Due to low enrollment in Part C Cohort 1 - 160 mg reporting group, time-to-event analysis for TTW was not conducted for this subgroup. Per protocol, Part D collected safety data only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A Cohort 1 - 160 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FHS | 55.0 Days |
| Part A Cohort 1 - 160 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FWB | 57.0 Days |
| Part A Cohort 1 - 160 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | TOI | 114.0 Days |
| Part A Cohort 1 - 160 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | HCS | 114.0 Days |
| Part A Cohort 1 - 160 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | PWB | 114.0 Days |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | HCS | 113.0 Days |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FHS | 57.0 Days |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | TOI | 113.0 Days |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FWB | 88.0 Days |
| Part A Cohort 2 - 300 mg LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | PWB | 113.0 Days |
| Part B LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | HCS | 170.0 Days |
| Part B LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | PWB | 113.0 Days |
| Part B LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FWB | 64.0 Days |
| Part B LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FHS | 57.0 Days |
| Part B LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | TOI | 179.0 Days |
| Part C LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FHS | 30.0 Days |
| Part C LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | FWB | 30.0 Days |
| Part C LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | PWB | 30.0 Days |
| Part C LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | HCS | 31.0 Days |
| Part C LY2157299 | Time to Worsening (TTW) of Symptoms (FACT-Hep) | TOI | 30.0 Days |