Clinical Trials Register

Summary
EudraCT Number:	2011-002445-36
Sponsor's Protocol Code Number:	0001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2011-08-31
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

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2011-002445-36

A.3

Full title of the trial

Neo-adjuvant dovitinib in patients with hepatocellular carcinoma prior to local treatment: a phase II study

A.3.1

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

Treatment with dovitinib in patients with liver cancer before local treatment: a phase II study

A.3.2

Name or abbreviated title of the trial where available

Neo-adjuvant dovitinib in HCC

A.4.1

Sponsor's protocol code number

0001

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	Department of Clinical Oncology, Leiden University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Clinical Oncology, Leiden University Medical Center
B.5.2	Functional name of contact point	prof. dr. S. Osanto
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31715263464
B.5.5	Fax number	31715266760
B.5.6	E-mail	s.osanto@lumc.nl

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	TKI258
D.3.2	Product code	TKI258
D.3.4	Pharmaceutical form	Capsule
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	dovitinib
D.3.9.1	CAS number	915769-50-5
D.3.9.2	Current sponsor code	TKI258
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.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, not metastatic

E.1.1.1

Medical condition in easily understood language

Liver cancer that has not spread to other parts of the body

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	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10019830
E.1.2	Term	Hepatocellular carcinoma resectable
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10019828
E.1.2	Term	Hepatocellular carcinoma non-resectable
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. Toxicity and Safety of TKI 258 (all grades, and grade 3 or 4 toxicities).
2. Tumor response according to RECIST criteria (version 1.1) after 4 weeks of treatment as determined by CT-imaging and changes in intratumoral blood flow as measured by CT perfusion imaging.
3. Histopathology of HCC specimens obtained following 4 weeks of treatment with TKI258 (comparison with pre-treatment biopsy, parameters: e.g. tumor necrosis, percentage of vital tumor cells, vascular density).

E.2.2

Secondary objectives of the trial

1. Progression free survival of local relapse.
2. Immunohistochemistry: changes in FGFR1, FGFR2, FGFR3, FGFR4, bFGF, FGF19, HGF, PLGF, cleaved caspase-3, Ki-67, CD31, pERK, M30/M65, and correlation with clinical data.
3. Changes in plasma levels of VEGF, basic FGF, soluble VEGFR1, soluble VEGFR2, FGF2, FGF23, FGF19, HGF, cKit, and inhibition of ERK (extracellular receptor kinase) phosphorylation in PBMC’s (pre-treatment, day 15, day 26, and 1 month after local treatment) and correlation with clinical data.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histological or cytological confirmed HCC or HCC diagnosed by the Barcelona criteria.
2. HCC stage A or B according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (appendix 2; Llovet et al, 2008a).
3. Patients eligible for local therapy, i.e. RF-ablation, chemo-embolization, or surgical resection
4. ECOG (WHO) performance status 0, 1, or 2
5. Age ≥ 18 years old
6. At least one uni-dimensional measurable lesion. Lesions must be measured by CT-scan or MRI-scan
7. Patients must have adequate bone marrow, liver and renal function as assessed by the following laboratory requirements:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 75 x 109/L
• Hemoglobin (Hgb) ≥ 6.0 mmol/L
• Serum total bilirubin: ≤ 1.5 x ULN
• Child-Pugh score of up to 6 points, i.e. Child-Pugh classe A (appendix 3), with no encephalopathy. Child-Pugh status must be calculated based on clinical findings and laboratory results during the baseline/screening period
• ALT and AST ≤ 3.0 x ULN (with or without liver metastases)
• Serum creatinine ≤ 1.5 x ULN or serum creatinine >1.5 – 3 x ULN if calculated creatinine clearance (CrCl) is ≥ 30 mL/min using the Cockroft-Gault equation, see formula below:
CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)]
(if patient is female multiply the above by 0.85)
8. Life expectancy of at least 3 months
9. Patients who give a written informed consent obtained according to local guidelines

E.4

Principal exclusion criteria

1. Patients with brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases
2. Patients with another primary malignancy within 3 years prior to starting study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, skin cancer (such as basal cell carcinoma, squamous cell carcinoma, or non-melanomatous skin cancer), or superficial bladder tumors (Ta, Tis, and T1)
3. Patients who have received the last administration of an anticancer therapy including chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding nitrosurea, mitomycin-C, targeted therapy and radiation) ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
4. Patients who have received the last administration of nitrosurea or mitomycin-C ≤ 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
5. Patients who have received targeted therapy (e.g. sunitinib, sorafenib, pazopanib) ≤ 2 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
6. Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or ≤ 2 weeks prior to starting study drug in the case of localized radiotherapy (e.g. for analgesic purpose or for lytic lesions at risk of fracture), or who have not recovered from radiotherapy toxicities
7. Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures, percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
8. Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
a. History or presence of serious uncontrolled ventricular arrhythmias
b. Clinically significant resting bradycardia
c. LVEF assessed by 2-D echocardiogram (ECHO) < 50% or lower limit of normal (which ever is higher) or multiple gated acquisition scan (MUGA) < 45% or lower limit of normal (which ever is higher)
d. Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE)
e. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s)
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dovitinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory)
• Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
9. Pregnant or breast-feeding women
10. Women of child-bearing potential, who are biologically able to conceive, not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicidal jelly, foam suppository or film, diaphragm with spermicide) must be used by both sexes during the study and must be continued for 8 weeks after the end of study treatment. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study treatment and must use two forms of highly effective contraception (also applicable to their partners who are biologically able to conceive).
11. Fertile males not willing to use contraception, as stated above
12. Patients unwilling or unable to comply with the protocol

E.5 End points

E.5.1

Primary end point(s)

1. Toxicity and Safety of TKI258 (all grades, and grade 3 or 4 toxicities).
2. Tumor response according to RECIST criteria (version 1.1) after 4 weeks of treatment as determined by CT-imaging and changes in intratumoral blood flow as measured by CT perfusion imaging.
3. Histopathology of HCC specimens obtained following 4 weeks of treatment with TKI258 (comparison with pre-treatment biopsy, parameters: e.g. tumor necrosis, percentage of vital tumor cells, vascular density).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 4 weeks of treatment with TKI258, at the time of local treatment and one month after local treatment of the hepatocellular carcinoma

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

For 1: 1,5 year after inclusion of the first patient into this study.
For 2 and 3: At the time of local treatment of the hepatocellualr carcinoma.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

Last patient last visit

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.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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.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)

Normal treatment of that condition

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-10-31

P. End of Trial
P.	End of Trial Status	Ongoing

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