Clinical Trials Register

Summary
EudraCT Number:	2006-002893-23
Sponsor's Protocol Code Number:	H8Z-MC-JACS
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-01-19
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2006-002893-23

A.3

Full title of the trial

An Open Label Single Arm Phase 1b/2 Study with Pharmacokinetic Sampling to Evaluate LY2181308 in Patients with Advanced Hepatocellular Carcinoma

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

H8Z-MC-JACS

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Eli Lilly and Company
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LY2181308 Sodium
D.3.2	Product code	LY2181308
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Information not present in EudraCT

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hepatocellular Carcinoma (HCC)

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Main objective :

Phase 1b: To determine the recommended dose for the Phase 2 portion of this trial for patients with advanced hepatocellular cancer (HCC) with no other standard curative or palliative therapeutic option.

Phase 2: To estimate the time to progression (TTP) for patients with advanced HCC who have received LY2181308.

E.2.2

Secondary objectives of the trial

Secondary objectives:

-To estimate overall survival time and progression-free survival.

-To evaluate the safety of LY2181308 in the HCC patient population.

-To evaluate response rate based on RECIST criteria modified for HCC.

-To evaluate LY2181308 PK in the HCC patient population.

-To evaluate the effect of LY2181308 on the number of circulating tumor cells and survivin expression in these cells.

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

Protocol Sample Banking Addendum H8Z-MC-JACS (1): An Open Label, Single Arm, Phase 2 Study with Pharmacokinetic Sampling to Evaluate LY2181308 in Patients with Advanced Hepatocellular Carcinoma.
Protocol Addendum (1) Approved by Lilly: 21 July 2006
Objectives: For patients with Advanced Hepatocellular Carcinoma (HCC), current treatments offer only modest improvements in overall survival. The analysis of patient-derived blood, plasma, and serum provides an opportunity to identify key genetic factors in the pathogenesis of advanced HCC. A better understanding of HCC tumor signatures may lead to discovery of novel biomarkers and molecular targets, which could be used to advance cancer therapy.

E.3

Principal inclusion criteria

Patients may be included in the study only if they meet all of the following criteria:

1. Patients previously diagnosed with HCC. Primary HCC diagnoses may be
histopathological, cytological, or clinically confirmed. Patients with only a
clinical diagnosis of HCC are acceptable, if diagnosis was made following the
AASLD-EASL diagnostic consensus. Patients entering the trial after
progression from a previous liver cancer therapy do not need to be rebiopsied.
Progression, per modified RECIST criteria (Attachment JACS.7),
should be documented before entering the trial.

2. HCC in a BCLC (refer to Protocol Attachment JACS.5) stage at the time of
entering the trial of either intermediate (B) or advanced (C) groups. Early stage
tumors (A) can be enrolled if any of the potentially curative standard therapies
for these cases [i.e. liver transplantation, surgical resection, transcatheter
arterial chemoembolization (TACE) or percutaneous embolization] is excluded
due to tumor localization, patient’s underlying conditions or because of tumor
recurrence.

3. Patients must have discontinued and recovered from the acute effects of all
previous therapies for their cancer (e.g., sorafenib, chemotherapy,
radiotherapy, or other investigational therapy) for at least 2 weeks prior to
enrollment (3 weeks in the case of cytotoxics).

4. For Phase 2 only: Measurable disease by modified RECIST criteria for HCC
(See Attachment JACS.7). Patient should have at least one lesion which has
not been previously treated locally with percutaneous or transcatheter arterial
chemoembolization (TACE).

5. Liver function determined in Child-Pugh class A or B of 7 points (refer to
Protocol Attachment JACS.6).

6. Performance status 0-1 on the Eastern Cooperative Oncology Group (ECOG)
performance status scale. (refer to Protocol Attachment JACS.3)

7. The following laboratory results:
• Hematology
Neutrophils ≥1.5 x 10E9/L
Hemoglobin ≥9g/dL
Platelets ≥100 x 10E9/L
• Hepatic
Any bilirubin and albumin values that are within the acceptable range per
the Child Pugh Score will be eligible for participation (See inclusion criteria #5)
Alanine Aminotransferase (ALT) ≤10 times ULN
Aspartate Aminotransferase (AST) ≤10 times ULN
Alkaline Phosphatase (AP) ≤5 times ULN
Coagulation: Activated partial thromboplastin time (aPTT) ≤1.5 times ULN
and International Normalized Ratio (INR) of prothrombin time <1.7
Patients on treatment with less than 40 mg/day of furosemide and 100
mg/day of spironolactone for ascites control (or equivalent).
• Renal
Calculated creatinine clearance by Cockcroft-Gault formula ≥50 mL/min
(refer to Protocol Attachment JACS.8).

8. Female patients of child-bearing potential must have a negative pregnancy
test at the time of enrollment based on a serum pregnancy test. Male and
female patients must agree to use a reliable method of birth control during
and for 3 months following the last dose of study drug.

9. Patient must be reliable, compliant with study procedures, and willing to be
available for all study visits for the duration of the study.

10. Patient must sign an Institutional Review Board approved informed consent
document prior to study procedures being performed.

11. Patient must be at least 18 years of age.

E.4

Principal exclusion criteria

Patients will be excluded from the study if they meet any of the following criteria:

1. HCC that could be treated with potentially curative or effective palliative
therapies (e.g., surgical resection, liver transplant, percutaneous ablation,
transcatheter arterial embolization (TACE), sorafenib and/or other proven
effective therapies).

2. Patients who have received a liver transplant.

3. Second primary malignancy except in situ carcinoma of the cervix or
adequately treated non-melanomatous carcinoma of the skin or other
malignancy treated at least 5 years previously with no evidence of recurrence;
prior low grade [Gleason score ≤6] localized prostate cancer is allowed.

4. Previous systemic antisense oligonucleotide treatment.

5. Hepatic encephalopathy of any degree or requirement for chronic treatment to
control (it is acceptable to enroll patients with one or more previous events that
were short-lived which remained without treatment).

6. Concurrent chronic infection with Human Immunodeficiency Virus (HIV).

7. Patients who have received treatment within the last 30 days with a drug that
has not received regulatory approval for any indication at the time of study
entry.

8. Patients with active alcohol abuse or illicit drug use.

9. Patients with serious concomitant systemic disorders that, in the opinion of the
investigator, would compromise the safety of the patient or compromise the
patient’s ability to complete the study.

10. Female patients who are pregnant or breast-feeding.

11. Symptomatic or proven central nervous system (CNS) neoplasm.

12. Concomitant anticancer therapy or anticoagulant therapy (with the exception of
the use of heparinized saline to maintain patency of central venous catheters).

13. Patients taking acetylsalicylic acid (ASA, aspirin) and NSAIDS less than one
week prior to treatment.

14. Patients taking G-CSF (Growth-Colony Stimulating Factor) less than 24 hours
prior to the start of therapy.

15. Patients who require palliative radiotherapy at the time of study entry.

16. Patients with more than 2 previous systemic chemotherapy treatments
(excluding tamoxifen).

E.5 End points

E.5.1

Primary end point(s)

In this study, the primary objective is to estimate TTP median and its 90% confidence
intervals (CI). Time-to-progression is defined as the time from the date of first treatment dose to the first date of progressive disease. For patients not known to have disease progression as of the data cut-off date, the TTP date will be censored as the last contact date or at the date of death. The analysis will be performed using the Kaplan-Meier method (Kaplan and Meier 1958). For this single-arm trial, hypothesis tests comparing the time-to-progression median from this study with historical values are not planned.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

The phase 1b safety dose escalation component is to determine the phase 2 dose.

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Information not present in EudraCT

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

E.8.7

Trial has a data monitoring committee

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

Given that time to progression is the primary objective, with secondary objectives of overall survival time and progression free survival, each patient will be followed for survival and progression of their disease. Based upon a median time to progression of 7.5 months and a recruitment rate of 3 patients per month, a 15 month enrolment period with a 6 month follow-up period is anticipated.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Long term follow-up visits will occur every 30 days until the patient dies, has progressive disease, or receives another treatment for his/her disease. If in the judgement of the treating physician the patient is benefiting from the treatment, then the study drug may be continued after the 6th cycle and after the approval by the Lilly clinical research physician. However, after the termination of the trial patients will be in medical care by their treating physician.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-07-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-09-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-08-08

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials