| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Carcinoma, hepatocellular |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019829 |
| E.1.2 | Term | Hepatocellular carcinoma recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To characterize both the time-to-progression (TTP) distributions and the
effect on transforming growth factor beta (TGF-b)-associated serum
biomarkers (for example, TGF-b, alpha-fetoprotein (AFP), E-cadherin) of
study treatment in patients with hepatocellular carcinoma (HCC). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety of LY2157299 as monotherapy and in combination with sorafenib
- To evaluate the population PK of LY2157299 as monotherapy and in combination with sorafenib
- To recommend which doses of LY2157299 as monotherapy and in combination with sorafenib to use in future trials with HCC patients
- To characterize other time-to-event distributions, such as PFS, OS
- To estimate antitumor efficacy using response rate
- To assess PRO measures of disease-specific symptoms and healthrelated quality of life.
- To explore E-cadherin, pSMAD, and b-integrin and other markers presence in the original diagnostic tumor tissue and optional posttreatment tumor tissue and the correlation of this with both clinical efficacy endpoints and biomarker response
- To explore the utility of exploratory imaging techniques to assess treatment effect with LY2157299 as monotherapy or in combination with sorafenib when possible
- To explore fibrosis-related biomarkers, such as Fibrotest |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
GERMANY Site 401 (Johannes Gutenberg Universität) ONLY:
Protocol addendum H9H-MC-JBAK (2) 14Jun12
This addendum is only applicable to site 401 in Germany
For this addendum, analysis of peripheral blood mononuclear cells (PBMC) and tumor tissue collected from patients with hepatocellular carcinoma (HCC) enrolled in Study JBAK will be part of a ongoing study at Johannes Gutenberg University to establish a relationship between genetic signatures and clinical outcome. The site will obtain comprehensive genetic information by means of Next Generation Sequencing, microarray analysis, and immunohistochemistry. Results from these high-throughput analyses will be subject to comparison to clinical data of response and adverse events.
Participation in this addendum is optional for all patients enrolled in Study JBAK at the Johannes Gutenberg University site in Germany.
The following analyses and experiments will be performed:
1. Evaluation of genetic signatures from PBMC of patients with HCC under LY2157299 treatment by means of Next Generation Sequencing and comparison to clinical course
2. Microarray analysis of HCC tissue from patients with HCC under LY2157299 treatment and comparison to clinical course
3. Analysis of cancer stem cell markers in HCC tissue of patients with HCC under LY2157299 treatment and comparison to clinical course
Sample collection will be as follows:
• Tumor biopsies will be collected before Cycle 1 Day 1.
• Blood samples will be collected at baseline for PBMC analysis.
• Additional blood samples may be taken during the course of treatment, if needed.
Analysis of these samples will occur at Johannes Gutenberg University following the institutional procedures.
FRANCE ONLY: Protocol Addendum H9H-MC-JBAK(1)
Randomized Phase 2 Study of LY2157299 in Patients with Hepatocellular Carcinoma who Have Had Disease
Progression on Sorafenib or Are Not Eligible to Receive
Sorafenib
This addendum to is for French sites participating
in Study H9H-MC-JBAK. The inclusion/exclusion criteria
were modified as requested by the Agence française de sécurité sanitaire des produits de santé
(AFSSAPS) through communication dated 11 March 2011(AFSSAPS A110036-41 for Clinical
Trial EudraCT 2010-022338-10).
Modifications and additions to the protocol are as follows.
Modifications:
8.1. Inclusion Criteria
[9] Have either:
- received sorafenib and have progressed or were intolerant to sorafenib, or
- are ineligible for sorafenib: contraindication to sorafenib are preexisting conditions
such as palmar-plantar erythrodysesthesia, hemorrhage, or elderly population, or
- patients who have received other treatments in first line
8.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply:
[20] Have moderate or severe cardiac disease:
a) Have the presence of cardiac disease, including a myocardial infarction, unstable
angina pectoris, New York Heart Association Class III/IV congestive heart failure,
or uncontrolled hypertension
b) Have documented major electrocardiogram (ECG) abnormalities: symptomatic or
sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular
block, bundle-branch blocks, ventricular hypertrophy, or myocardial infarction
c) Have organic valvulopathies
d) Have abnormalities documented by echocardiography with Doppler
e) Have predisposing conditions that are consistent with development of
aneurysms of the ascending aorta or aortic stress (for example, family
history of aneurysms, Marfan Syndrome, bicuspid aortic valve, evidence
of damage to the large vessels of the heart documented by computerized
tomography [CT] scan with contrast)
Addition:
8.2. Exclusion Criteria
Potential study patients may not be included in the study if any of the following apply:
[25] Patients eligible for a treatment with chemoembolization |
|
| E.3 | Principal inclusion criteria |
- Have histological evidence of a diagnosis of HCC not amenable to
curative surgery
- Have serum alpha fetoprotein:
• ≥1.5 Upper Limit of Normal (Part A)
• <1.5 Upper Limit of Normal (Part B)
- Child-Pugh Class:
• Parts A and B: A or B7
• Part C: A
- 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
- Age ≥18 years
- Have given written informed consent prior to any study-specific
procedures
- Have adequate hematologic, hepatic and renal function
- Have a performance status of ≤1 on the Eastern Cooperative Oncology
Group (ECOG) scale
- Have received sorafenib and have progressed or were intolerant to
sorafenib or are ineligible for sorafenib treatment (Parts A and B)
- Have not received previous systemic treatment (Part C)
- 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 ≤7 days prior to the first dose of study drug
- Are able to swallow capsules or tablets
- Child-Pugh Class:
• Parts A and B: A or B7
• Part C: A
- 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
- Age ≥18 years
- Have given written informed consent prior to any study-specific
procedures
- Have adequate hematologic, hepatic and renal function
- Have a performance status of ≤1 on the Eastern Cooperative Oncology
Group (ECOG) scale
- Have received sorafenib and have progressed or were intolerant to
sorafenib or are ineligible for sorafenib treatment (Parts A and B)
- Have not received previous systemic treatment (Part C)
- 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 ≤7 days prior to the first dose of study drug
- Are able to swallow capsules or tablets |
|
| E.4 | Principal 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 ascitis
- Liver transplant requiring increased immunosuppressive therapy.
(Patients on maintenance immunosuppressive therapy after liver
transplant are eligible for Parts A and B. Rapamycin analogues are not
allowed.)
- Have received > 1 line of systemic treatment (Parts A and B)
- Have moderate or severe cardiac disease:
a. 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
b. Have documented major ECG abnormalities at the investigator's
discretion
c. Have major abnormalities documented by echocardiography with
Doppler.
d. 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 patients who are
stable on GnRH agonist therapy and breast cancer patients who are
stable on antiestrogen therapy (for example, an aromatase inhibitor)
may have that treatment continued while they are enrolled in this study.
- 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Relationship of change in response biomarker to clinical benefit;
2. Time to progression
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline through discontinuation from any cause
2. Baseline to measured progressive disease or date of death from any cause
|
|
| E.5.2 | Secondary end point(s) |
1. Population Pharmacokinetics
2. Recommended dose for Phase 3 HCC trials
3. Overall Survival
4. Progression Free Survival
5. Proportion of patients achieving an objective response (Response Rate)
6. Duration of tumor Response
7. Time to Treatment Failure
8. Change from baseline in Functional Assessment of Cancer Therapy, Hepatobiliary (FACT-Hep) sub-scores and total score
9. Time to worsening of symptoms (FACT-Hep) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Baseline through cycle 1
2. Baseline to end of study
3. Randomization to date of death from any cause
4. Randomization to measured progressive disease or death from any cause
5. Randomization to measured progressive disease
6. Time of response to measured progressive disease or death from any cause
7. Randomization to the date of discontinuation of study treatment due to adverse event, progression of disease, or death from any cause
8. Baseline through the end of the study
9. Baseline through the end of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Patients enrolled after 25 May 2012 are not randomized and will receive 300mg/day LY2157299 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| New Zealand |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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