Clinical Trials Register

Summary
EudraCT Number:	2008-006430-10
Sponsor's Protocol Code Number:	CTKI258A2202
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-05-28
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

France - ANSM

A.2

EudraCT number

2008-006430-10

A.3

Full title of the trial

A multi-center, open label Phase II trial of TKI258 in FGFR1 amplified and non-amplified metastatic HER2 negative breast cancer.

A.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

CTKI258A2202

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

N/A

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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.3.2	Product code	TKI258
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	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	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	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.3.2	Product code	TKI258
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	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)	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	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

In female patients with FGFR1 amplified and non-amplified metastatic HER2 negative breast cancer.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To determine the Overall Response Rate (ORR) in 4 groups of patients with (FGFR1+, HR+),(FGFR1+, HR-),(FGFR1-, HR+) or (FGFR1-, HR-) breast tumors treated with TKI258.

E.2.2

Secondary objectives of the trial

• To determine Disease Control Rate (DCR), defined according to RECIST, (CR, PR and Stable Disease (SD) ≥ 24 weeks after start of TKI258 treatment) in the 4 groups of patients
• Progression Free Survival (PFS), defined according to RECIST, in the 4 groups of patients.
• To characterize the safety and tolerability of TKI258 treatment.
• To characterize the single- and repeated-dose pharmacokinetic (PK) profile of TKI258.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female patients with histological confirmation of adenocarinoma of the breast, presenting with metastatic disease.
2. The primary tumor, metastatic axillary lymph nodes or biopsy of metastatic tumor must have been locally tested by FISH/CISH for FGFR1 amplification. Tumor material must be available for central testing.
3. HER2 and hormone receptors (ER/PgR) status of breast cancer must have been previously determined.
4. Patients must have HER2 negative breast cancer.
5. Patients must have a documented disease progression as defined by RECIST at baseline.
6. Patients with HR+ disease must have received adjuvant endocrine therapy and at least one line and no more that three lines of chemotherapy in the metastatic setting.
• Patients with newly diagnosed metastatic disease must have received at least one line endocrine therapy and chemotherapy for metastatic disease.
7. Patients with HR- disease must have received:
• Adjuvant chemotherapy and at least one line and no more than three lines of chemotherapy in metastatic setting
• Patients who did not receive adjuvant chemotherapy must have received two lines of chemotherapy in the metastatic setting.
8. Patient must be ≥ 18 years old.
9. Patient’s WHO performance status equal to 0, 1 or 2.
Required baseline laboratory values:
10. Electrolytes (Ca2+, Na+, Mg2+, K+, phosphorous) level within normal limit
11. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
12. Hemoglobin ≥ 9 g/dl
13. Platelets ≥ 100 x 109/L
14. Serum creatinine ≤ 1.5 x ULN
15. AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present
16. Serum bilirubin ≤ 1.5 x ULN
17. All patients must have signed and dated an informed consent form.

E.4

Principal exclusion criteria

1. Patients with known 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 history of another malignancy within the last 5 years prior to study entry, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.
3. Patients who have received the last administration of chemotherapy or immunotherapy ≤ the timeframe defined below after the end of the cycle of the last treatment, prior to starting study drug, or who have not recovered from the side effects of such therapy: patients who have received the last administration of chemotherapy/immunotherapy in a daily schedule ≤ 7 days prior to starting study drug; patients who have received the last administration of chemotherapy/immunotherapy in a weekly schedule ≤ 2 weeks prior to starting study drug; patients who have received the last administration of chemotherapy/immunotherapy in a 2-weekly schedule ≤ 3 weeks prior to starting study drug; patients who have received the last administration of chemotherapy/immunotherapy in a 3-weekly schedule ≤ 4 weeks prior to starting study drug; patients who have received the last administration of chemotherapy/ immunotherapy in a 4-weekly schedule ≤ 5 weeks prior to starting study drug.
Patients who have received the last administration of nitrosourea, mitomycin-C ≤ 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
4. Patients who received a continuous dosing small molecule therapeutic ≤ 7 days prior to starting study drug or who have not recovered from the side effects of such therapy
5. Patients who received the last administration of biologic therapy ≤ 6 weeks prior to starting study drug or who have not recovered from the side effects of such therapy
6. Patients who have received any other investigational agents ≤ 4 weeks prior to starting study drug or who have not recovered from the side effects of such therapy
7. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
8. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study :
9. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• Congenital long QT syndrome
• History or presence of ventricular arrhythmias or presence of atrial fibrilation
• Clinically significant resting bradycardia (< 50 beats per minute)
• QTc > 480 msec on screening ECG.
• LVEF assessed by 2-D echocardiogram (ECHO) or Multiple gated acquisition scanning (MUGA), < 45 %.
10. Any of the following within 6 months prior to study entry: myocardial infarction, severe/unstable angina, CABG, Congestive Heart Failure, Cerebrovascular Accident, Transient Ischemic Attack, Pulmonary Embolism
11. Uncontrolled hypertension defined by a SBP > 150 mm Hg and/or DBP > 100 mm Hg, with or without anti-hypertensive medication.
12. Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring two or more interventions/month.
13. Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of TKI258.
14. Known diagnosis of HIV infection (HIV testing is not mandatory).
15. History of alcoholism, drug addiction, or any psychiatric or psychological condition which, in the opinion of the investigator, would impair study compliance.
16. Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin.
17. Other concurrent severe and/or uncontrolled concomitant medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol.
18. Pregnant or breast-feeding woman.
19. Women of child-bearing potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial and one month after the end of 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 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months), must have a negative serum pregnancy test ≤ 72 hours prior to starting TKI258.

E.5 End points

E.5.1

Primary end point(s)

• Overall Response (Complete responses (CR) or partial response (PR)) Rate. CR and PR will be defined according to RECIST.

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

Yes

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

Information not present in EudraCT

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

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

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

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Information not present in EudraCT
F.1.3	Elderly (>=65 years)	Information not present in EudraCT
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	No
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	30
F.4.2	For a multinational trial
F.4.2.1	In the EEA	60
F.4.2.2	In the whole clinical trial	200

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

2009-07-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-06-16

P. End of Trial
P.	End of Trial Status	Completed

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