A Study of LY2157299 in Participants With Hepatocellular Carcinoma

NCT01246986 | Completed Phase 2 Results

• 3 other identifiers: 13665H9H-MC-JBAK2010-022338-10
• Study Type: interventional
• Target: 204
• Locations: 7 countries
• Sites: 40

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.

Conditions

Carcinoma, Hepatocellular

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• 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

• 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)

• Progression Free Survival (PFS)

  Randomization to measured progressive disease or death from any cause (Up to 45 Weeks)

• Percentage of Participants Achieving an Objective Response (Response Rate)

  Randomization to measured progressive disease (Up to 36 Weeks)

Study Arms (7)

Part A Cohort 1-160 milligram (mg) LY2157299

EXPERIMENTAL

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

Part A Cohort 2 - 300 mg LY2157299

EXPERIMENTAL

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; Drug: Sorafenib

Part B - 300 mg LY2157299

EXPERIMENTAL

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

Part C Cohort 1 - 160 mg LY2157299 + 800 mg Sorafenib

EXPERIMENTAL

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; Drug: Sorafenib

Part C Cohort 2 - 300 mg LY2157299 + 800 mg Sorafenib

EXPERIMENTAL

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; Drug: Sorafenib

Part D Cohort 1 - 160 mg LY2157299 + 8 mg/kg Ramucirumab

EXPERIMENTAL

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; Drug: Ramucirumab

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

EXPERIMENTAL

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; Drug: Ramucirumab

Interventions

LY2157299 DRUG

Administered orally

Part A Cohort 1-160 milligram (mg) LY2157299; Part A Cohort 2 - 300 mg LY2157299; Part B - 300 mg LY2157299; Part C Cohort 1 - 160 mg LY2157299 + 800 mg Sorafenib; Part C Cohort 2 - 300 mg LY2157299 + 800 mg Sorafenib; Part D Cohort 1 - 160 mg LY2157299 + 8 mg/kg Ramucirumab; Part D Cohort 2 - 300 mg LY2157299 + 8 mg/kg Ramucirumab

Sorafenib DRUG

Administered orally

Part A Cohort 2 - 300 mg LY2157299; Part C Cohort 1 - 160 mg LY2157299 + 800 mg Sorafenib; Part C Cohort 2 - 300 mg LY2157299 + 800 mg Sorafenib

Ramucirumab DRUG

Administered IV

Also known as: LY30098016

Part D Cohort 1 - 160 mg LY2157299 + 8 mg/kg Ramucirumab; Part D Cohort 2 - 300 mg LY2157299 + 8 mg/kg Ramucirumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (40)

Highlands Oncology Group

Fayetteville, Arkansas, 72703, United States

Location

University of California, San Francisco

San Francisco, California, 94158, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

MD Anderson Cancer Center Orlando

Orlando, Florida, 32806, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Indiana Univ Melvin & Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Lahey Clinic Medical Center

Burlington, Massachusetts, 01805, United States

Location

Weill Cornell Medical College

New York, New York, 10021, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Nedlands, Western Australia, 6009, Australia

Location

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Greenslopes, 4120, Australia

Location

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Heidelberg, 3084, Australia

Location

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St Leonards, 2065, Australia

Location

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Brest, 29609, France

Location

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Caen, 14033, France

Location

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Clichy, 92110, France

Location

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Créteil, 94010, France

Location

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Lille, 59037, France

Location

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Lyon, 69317, France

Location

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Marseille, 13273, France

Location

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Montpellier, 34295, France

Location

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Paris, 75012, France

Location

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Pessac, 33604, France

Location

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Saint-Etienne, 42055, France

Location

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Saint-Herblain, 44805, France

Location

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Strasbourg, 67085, France

Location

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Vandœuvre-lès-Nancy, 54511, France

Location

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Berlin, 13353, Germany

Location

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Cologne, 50937, Germany

Location

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Erlangen, 91054, Germany

Location

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Göttingen, 37075, Germany

Location

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Mainz, 55131, Germany

Location

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Münster, 48149, Germany

Location

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Bari, 70124, Italy

Location

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Rome, 00168, Italy

Location

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Rozzano, 20089, Italy

Location

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Auckland, 1023, New Zealand

Location

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Barcelona, 08035, Spain

Location

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Madrid, 28007, Spain

Location

Related Publications (4)

• Giannelli G, Santoro A, Kelley RK, Gane E, Paradis V, Cleverly A, Smith C, Estrem ST, Man M, Wang S, Lahn MM, Raymond E, Benhadji KA, Faivre S. Biomarkers and overall survival in patients with advanced hepatocellular carcinoma treated with TGF-betaRI inhibitor galunisertib. PLoS One. 2020 Mar 25;15(3):e0222259. doi: 10.1371/journal.pone.0222259. eCollection 2020.

  PMID: 32210440 DERIVED

• Addepalli A, Kalyani S, Singh M, Bandyopadhyay D, Mohan KN. CalPen (Calculator of Penetrance), a web-based tool to estimate penetrance in complex genetic disorders. PLoS One. 2020 Jan 29;15(1):e0228156. doi: 10.1371/journal.pone.0228156. eCollection 2020.

  PMID: 31995602 DERIVED

• Faivre S, Santoro A, Kelley RK, Gane E, Costentin CE, Gueorguieva I, Smith C, Cleverly A, Lahn MM, Raymond E, Benhadji KA, Giannelli G. Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int. 2019 Aug;39(8):1468-1477. doi: 10.1111/liv.14113. Epub 2019 Jun 3.

  PMID: 30963691 DERIVED

• Li S, Yang F, Ren X. Immunotherapy for hepatocellular carcinoma. Drug Discov Ther. 2015 Oct;9(5):363-71. doi: 10.5582/ddt.2015.01054.

  PMID: 26632545 DERIVED

Related Links

• A Study of LY2157299 in Participants With Hepatocellular Carcinoma

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

LY-2157299; Sorafenib; Ramucirumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Per the protocol, following an interim analysis, the decision was taken to no longer randomize participants to the 160 mg LY2157299 arm. Per protocol, Part D collected safety data only.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company

ClinicalTrials.gov@lilly.com

800-545-5979

Study Officials

• 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 DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2010
• First Posted: November 24, 2010
• Study Start: March 30, 2011
• Primary Completion: June 6, 2019
• Study Completion: December 24, 2019
• Last Updated: January 12, 2021
• Results First Posted: August 7, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

NZ (1); AU (4); ES (2); FR (14); US (10); DE (6); IT (3)