Clinical Trials Register

Summary
EudraCT Number:	2010-018739-17
Sponsor's Protocol Code Number:	OSI-906-206
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-06-22
Trial results	View 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

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2010-018739-17

A.3

Full title of the trial

A Randomized, Placebo-controlled, Double-blind Phase 2 Study of Second-line Treatment with OSI-906 in Patients with Advanced Hepatocellular Carcinoma (HCC) after Failure of First-line Treatment with Sorafenib

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study in liver cancer investigating whether a new product has beneficial effects

A.4.1

Sponsor's protocol code number

OSI-906-206

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01101906

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Astellas Pharma Global Development, Inc.
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	Astellas Pharma Global Development, Inc.
B.4.2	Country	United States
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	OSI-906 150 mg
D.3.2	Product code	OSI-906
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	linsitinib
D.3.9.1	CAS number	867160-71-2
D.3.9.2	Current sponsor code	OSI-906
D.3.9.3	Other descriptive name	OSI-906 150 mg
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	No
D.IMP: 2
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	OSI-906 100 mg
D.3.2	Product code	OSI-906
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	linsitinib
D.3.9.1	CAS number	867160-71-2
D.3.9.2	Current sponsor code	OSI-906
D.3.9.3	Other descriptive name	OSI-906 100 mg
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	No
D.IMP: 3
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	OSI-906 25 mg
D.3.2	Product code	OSI-906
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	linsitinib
D.3.9.1	CAS number	867160-71-2
D.3.9.2	Current sponsor code	OSI-906
D.3.9.3	Other descriptive name	OSI-906 25 mg
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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)	No
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	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
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	No
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	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hepatocellular Carcinoma

E.1.1.1

Medical condition in easily understood language

liver cancer

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	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10019829
E.1.2	Term	Hepatocellular carcinoma recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

The primary objective of this study is to determine the time to progression (TTP) based on investigator assessment of OSI 906 in HCC patients who have failed first-line treatment with sorafenib, compared with placebo.

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate:
• Overall survival (OS);
• Safety (including safety review for first 18 patients);
• Progression-free survival (PFS);
• Disease control rate (DCR);
• Overall response rate (ORR);
• TTP, PFS, OS, and ORR in patients with hepatitis B and/or C;
• Pharmacokinetics;
• Potential relationships between exploratory biomarkers associated with the IGF-1R and IR signaling axes and other predictive and prognostic markers related to clinical outcomes; and
• TTP based on the following definition analyzed as exploratory analyses:
– TTPc: defined as time from randomization to progression (either radiological disease progression based on RECIST version 1.1 or symptomatic clinical progression as assessed by investigator).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically confirmed diagnosis of advanced HCC. Clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic patients is acceptable. For patients without cirrhosis histological confirmation is mandatory;
• Patient has received their last dose of sorafenib at least 14 days prior to randomization;
• Patient has recovered from sorafenib or investigational agent related toxicity to </= grade 2;
• Measurable disease according to RECIST (version 1.1);
• ECOG PS 0 – 1;
• Age >/= 18 years;
• Child-Pugh Status A or B;
• Barcelona Clinic Liver Cancer (BCLC) stage B/C;
• Previous local therapy (eg, surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) is permitted if >/= 21 days before randomization;
• Fasting glucose </= 150 mg/dL (8.3 mmol/L). Concurrent use of non-insulinotropic oral antihyperglycemic therapy is permitted if the dose has been stable for >/= 4 weeks at the time of randomization;
• Following laboratory parameters (determined by local laboratory):
– Platelet count >/= 60 x 10^9/L;
– Hemoglobin >/= 8.5 g/dL;
– ANC >/= 1.5 x 10^9/L;
– Potassium within normal limits (supplementation is permitted);
– PTT </= 2.3 x ULN;
– Magnesium within normal limits (supplementation is permitted); and
– Calcium within normal limits (supplementation is permitted).
• Adequate organ function (for a HCC population):
– LFT </= 5 x ULN;
– Albumin >/= 2.8 g/dL;
– Total bilirubin </= 2.8 mg/dL;
– Creatinine </= 1.5 x ULN;
• Estimated Life Expectancy >/= 12 weeks based on an investigator assessment of recent changes in laboratory values, performance status, and other clinical criteria;
• Patients – both males and females – with reproductive potential (ie, menopausal for less than 1 year and not surgically sterilized) must agree to practice effective contraceptive measures throughout the study. Women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to randomization;
• Patients must provide written informed consent to participate in the study;
• Prior radiation therapy is permitted provided patients have recovered from the acute, toxic effects of radiotherapy prior to randomization. A minimum of 21 days must have elapsed between the end of radiotherapy and randomization; and
• Prior surgery is permitted provided that the surgery was done >/= 28 days prior to randomization and adequate wound healing has occurred prior to randomization.

E.4

Principal exclusion criteria

• Child-Pugh B (8 – 9) or C;
• Patients who are candidates for potentially curative intervention (ie, surgical resection or transplantation);
• Type 1 diabetes mellitus or Type 2 diabetes mellitus currently requiring insulinotropic or insulin therapy;
• Prior IGF-1R therapy;
• Patients requiring interferon;
• Patients with uncontrolled symptomatic ascites;
• Prior investigational agent within 21 days prior to randomization;
• History of poorly controlled gastrointestinal disorders that could affect the absorption of study drug (eg, Crohn’s disease, ulcerative colitis, etc);
• History of organ allograft including liver transplant;
• Malignancy other than HCC within the past 3 years:
Exceptions: resected basal cell or squamous cell carcinoma of the skin; cured in situ cervical carcinoma; cured ductal carcinoma in situ of the breast; and/or cured superficial bladder cancer.
• History (within last 6 months) of significant cardiovascular disease unless the disease is well-controlled. Significant cardiac disease includes second/third degree heart block; clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea).
• History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (>/= grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded;
• QTcF interval at screening >/=450 msec;
• Use of drugs that have a risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to randomization;
• Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded;
• History of cerebrovascular accident (CVA) within 6 months prior to randomization or that resulted in ongoing neurologic instability;
• Active infection or serious underlying medical condition (including any type of active seizure disorder within 12 months prior to randomization) that would impair the ability of the patient to receive study drug;
• History of human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS)-related illness or serious acute or chronic illness;
• History of any psychiatric or neurologic condition that might impair the patient’s ability to understand or to comply with the requirements of the study or to provide informed consent;
• Pregnant or breast-feeding females;
• Symptomatic brain metastases that are not stable, require steroids, are potentially life threatening, or that have required radiation within 28 days prior to randomization; and/or
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drug.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is time to progression. The secondary efficacy variables include: OS, PFS, DCR, ORR, and TTPc, and responses of the HBV and/or HCV subpopulations.

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

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

Yes

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

The end of the study will be deemed as the date of the last visit of the last patient participating in the clinical trial. The study will be unblinded approximately 1 month after the date when at least 96 OS events have occurred in patients participating in this clinical trial.

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

E.8.9.2

In all countries concerned by the trial days

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

132

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)

Any patients still on study drug at the time overall survival results become available will be allowed to continue at the discretion of the investigator and provided the criteria for study drug discontinuation are not met.

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

2010-08-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-10-08

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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