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A Study of LY2157299 in Participants With Hepatocellular Carcinoma

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ClinicalTrials.gov Identifier: NCT01246986
Recruitment Status : Completed
First Posted : November 24, 2010
Results First Posted : August 7, 2020
Last Update Posted : January 12, 2021
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

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.

Condition or disease Intervention/treatment Phase
Carcinoma, Hepatocellular Drug: LY2157299 Drug: Sorafenib Drug: Ramucirumab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 204 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of LY2157299 in Patients With Hepatocellular Carcinoma
Actual Study Start Date : March 30, 2011
Actual Primary Completion Date : June 6, 2019
Actual Study Completion Date : December 24, 2019

Arm Intervention/treatment
Experimental: Part A Cohort 1-160 milligram (mg) LY2157299

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
Administered orally

Experimental: Part A Cohort 2 - 300 mg LY2157299

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
Administered orally

Drug: Sorafenib
Administered orally

Experimental: Part B - 300 mg LY2157299

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
Administered orally

Experimental: Part C Cohort 1 - 160 mg LY2157299 + 800 mg 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).

Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met.

Drug: LY2157299
Administered orally

Drug: Sorafenib
Administered orally

Experimental: Part C Cohort 2 - 300 mg LY2157299 + 800 mg 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).

Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met.

Drug: LY2157299
Administered orally

Drug: Sorafenib
Administered orally

Experimental: Part D Cohort 1 - 160 mg LY2157299 + 8 mg/kg 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).

Participants will continue to receive until disease progression, unacceptable toxicity, or another withdrawal criterion is met.

Drug: LY2157299
Administered orally

Drug: Ramucirumab
Administered IV
Other Name: LY30098016

Experimental: Part D Cohort 2 - 300 mg LY2157299 + 8 mg/kg Ramucirumab

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
Administered orally

Drug: Ramucirumab
Administered IV
Other Name: LY30098016




Primary Outcome Measures :
  1. Change From Baseline in Relationship of Biomarker Alpha-fetoprotein (AFP) to Overall Survival (OS) [ Time Frame: 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.

  2. Change From Baseline in Relationship of Biomarker Transforming Growth Factor - Beta (TGF-β) to Overall Survival (OS) [ Time Frame: 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.

  3. Time to Progression (TTP) [ Time Frame: 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 Outcome Measures :
  1. Population Pharmacokinetics (PK) Mean Population Clearance of Galunisertib [ 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 mean (between-subject coefficient variance [CV %]) apparent clearance.

  2. Recommended Dose for Phase 3 Hepatocellular Carcinoma (HCC) Trials [ Time Frame: Cycle 1 (28 Days) ]
  3. Overall Survival (OS) [ Time Frame: 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.

  4. Progression Free Survival (PFS) [ Time Frame: 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.

  5. Percentage of Participants Achieving an Objective Response (Response Rate) [ Time Frame: 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.

  6. Duration of Tumor Response (DoR) [ Time Frame: 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.

  7. Time to Treatment Failure (TTF) [ 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) ]
    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.

  8. Change From Baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) Sub-scores and Total Score [ Time Frame: 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.

  9. Time to Worsening (TTW) of Symptoms (FACT-Hep) [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01246986


Locations
Show Show 40 study locations
Sponsors and Collaborators
Eli Lilly and Company
Investigators
Layout table for investigator information
Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:
Study Protocol  [PDF] August 18, 2016
Statistical Analysis Plan  [PDF] October 11, 2013

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01246986    
Other Study ID Numbers: 13665
H9H-MC-JBAK ( Other Identifier: Eli Lilly and Company )
2010-022338-10 ( EudraCT Number )
First Posted: November 24, 2010    Key Record Dates
Results First Posted: August 7, 2020
Last Update Posted: January 12, 2021
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
URL: https://vivli.org/
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Sorafenib
Ramucirumab
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action