Clinical Trial Results:
An open label, multi-center, extension study to evaluate long-term safety and tolerability of dovitinib in patients with solid tumors, who continue to receive treatment with dovitinib (TKI258) in Novartis-sponsored, single agent dovitinib studies, which have fulfilled the requirements for the primary objective, and are benefitting from continued dovitinib treatment as assessed by the investigator

Trial information Top of page
Trial identification
Sponsor protocol code	CTKI258A2X01B
Additional study identifiers
ISRCTN number	-
US NCT number	NCT02116803
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Novartis Pharma, AG
Sponsor organisation address	CH-4002, Basel, Switzerland,
Public contact	Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
Scientific contact	Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	28 Nov 2016
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	28 Nov 2016
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate long-term safety and tolerability of dovitinib in patients with solid tumors, who are currently receiving treatment with single agent dovitinib within a Novartis sponsored study which has fulfilled the requirements for the primary objective
Protection of trial subjects	The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	28 May 2014
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 1
Country: Number of subjects enrolled	Austria: 1
Country: Number of subjects enrolled	Belgium: 1
Country: Number of subjects enrolled	Denmark: 3
Country: Number of subjects enrolled	Italy: 3
Country: Number of subjects enrolled	Japan: 1
Country: Number of subjects enrolled	United States: 2
Worldwide total number of subjects	12
EEA total number of subjects	9
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	7
From 65 to 84 years	5
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	A total of 12 patients were rolled over from parent studies and randomized by the time of study completion; 10 patients to dovitinib treatment group and 2 patients to dovitinib plus fulvestrant treatment arm.
Pre-assignment
Screening details	There was no screening period for this study. Once consented, patients were evaluated for eligibility via the inclusion and exclusion criteria and immediately began study treatment.
Period 1
Period 1 title	Core Period (overall period)
Is this the baseline period?	Yes
Allocation method	Non-randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	Dovitinib
Arm description	Participants were given single agent dovitinib starting with last assigned dose and regimen which patient received in parent study. Additional dose modifications were given at the discretion of the investigator based on guidance provided in the protocol and investigative brochure (IB).
Arm type	Experimental
Investigational medicinal product name	dovitinib
Investigational medicinal product code	TKI258
Other name
Pharmaceutical forms	Capsule, Tablet
Routes of administration	Oral use
Dosage and administration details	Capsules of 100 mg strength, and tablets of 100 mg strength and taken orally.
Arm title	dovitinib + fulvestrant
Arm description	Participants were given dovitinib and fulvestrant coadministration starting with last assigned dose and regimen which patient received in parent study. Additional dose modifications were at the discretion of the investigator based on guidance provided in the protocol and IB.
Arm type	Experimental
Investigational medicinal product name	dovitinib
Investigational medicinal product code	TKI258
Other name
Pharmaceutical forms	Capsule, Tablet
Routes of administration	Oral use
Dosage and administration details	Capsules of 100 mg strength, and tablets of 100 mg strength and taken orally.
Investigational medicinal product name	fulvestrant
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection in pre-filled syringe
Routes of administration	Intravenous use
Dosage and administration details	Generally available as solution for injection in pre-filled syringes containing 250 mg of fulvestrant in 5 mL solution.
Number of subjects in period 1 Dovitinib dovitinib + fulvestrant Started 10 2 Completed 0 0 Not completed 10 2      Adverse event, serious fatal 1 -      Physician decision 1 -      Study terminated by Sponsor 2 1      Adverse event, non-fatal 2 1      Progressive disease 4 -

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Dovitinib
Reporting group description	Participants were given single agent dovitinib starting with last assigned dose and regimen which patient received in parent study. Additional dose modifications were given at the discretion of the investigator based on guidance provided in the protocol and investigative brochure (IB).
Reporting group title	dovitinib + fulvestrant
Reporting group description	Participants were given dovitinib and fulvestrant coadministration starting with last assigned dose and regimen which patient received in parent study. Additional dose modifications were at the discretion of the investigator based on guidance provided in the protocol and IB.
Reporting group values Dovitinib dovitinib + fulvestrant Total Number of subjects 10 2 12 Age categorical Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 6 1 7     From 65-84 years 4 1 5     85 years and over 0 0 0 Age continuous Units: years     median (standard deviation) 60.3 ± 10.55 72.0 ± 14.14 - Gender categorical Units: Subjects     Female 3 2 5     Male 7 0 7

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Dovitinib
Reporting group description	Participants were given single agent dovitinib starting with last assigned dose and regimen which patient received in parent study. Additional dose modifications were given at the discretion of the investigator based on guidance provided in the protocol and investigative brochure (IB).
Reporting group title	dovitinib + fulvestrant
Reporting group description	Participants were given dovitinib and fulvestrant coadministration starting with last assigned dose and regimen which patient received in parent study. Additional dose modifications were at the discretion of the investigator based on guidance provided in the protocol and IB.

End points Top of page

Primary: Severity of adverse events Top of page
End point title	Severity of adverse events [1]
End point description
End point type	Primary
End point timeframe	Until the last patient discontinued dovitinib up to 30 months
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint.
End point values Dovitinib dovitinib + fulvestrant Number of subjects analysed 10 2 Units: number of subjects     Any Primary system organ class 6 2     Blood & lymphatic system disorders 1 0     Cardiac disorders 2 1     Ear and Labyrinth disorders 0 0     Endocrine disorders 0 0     Eye disorders 0 0     Gastrointestinal disorders 1 0     General disorders & administrative site conditions 1 0     Infections and Infestations 1 0     Injury, poisoning & procedural complications 0 0     Investigations 2 0     Metabolism and nutrition disorders 1 0     Musculoskeletal & connective tissue disorders 1 0     Neoplasms benign, malignant & unspecified 0 1     Nervous system Disorders 0 0     Psychiatric disorders 0 0     Respiratory, thoracic & mediastinal disorders 1 0     Skin and subcutaneous tissue disorders 0 0     Vascular disorders 0 0
No statistical analyses for this end point

Primary: Severity of adverse events Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
Adverse event reporting additional description	Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	19.1
Reporting groups
Reporting group title	Dovitinib+Fulvestrant
Reporting group description	Dovitinib+Fulvestrant
Reporting group title	Dovitinib
Reporting group description	Dovitinib
Serious adverse events Dovitinib+Fulvestrant Dovitinib Total subjects affected by serious adverse events      subjects affected / exposed 2 / 2 (100.00%) 4 / 10 (40.00%)      number of deaths (all causes) 0 2      number of deaths resulting from adverse events 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) ADENOCARCINOMA OF COLON      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Cardiac disorders ACUTE MYOCARDIAL INFARCTION      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 BRADYCARDIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 CORONARY ARTERY DISEASE      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 MYOCARDIAL ISCHAEMIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders PLEURAL EFFUSION      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 PNEUMOTHORAX      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Infections and infestations PNEUMONIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Dovitinib+Fulvestrant Dovitinib Total subjects affected by non serious adverse events      subjects affected / exposed 2 / 2 (100.00%) 9 / 10 (90.00%) Vascular disorders ORTHOSTATIC HYPOTENSION      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences all number 1 0 General disorders and administration site conditions ASTHENIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 FACE OEDEMA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 FATIGUE      subjects affected / exposed 1 / 2 (50.00%) 2 / 10 (20.00%)      occurrences all number 1 2 OEDEMA PERIPHERAL      subjects affected / exposed 0 / 2 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 PYREXIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Respiratory, thoracic and mediastinal disorders COUGH      subjects affected / exposed 0 / 2 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 DYSPNOEA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 DYSPNOEA EXERTIONAL      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 PRODUCTIVE COUGH      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Psychiatric disorders INSOMNIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 RESTLESSNESS      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Investigations ASPARTATE AMINOTRANSFERASE INCREASED      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 BLOOD ALKALINE PHOSPHATASE INCREASED      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 BLOOD CREATININE INCREASED      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 GAMMA-GLUTAMYLTRANSFERASE INCREASED      subjects affected / exposed 0 / 2 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 INTERNATIONAL NORMALISED RATIO INCREASED      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 LYMPHOCYTE COUNT DECREASED      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 PLATELET COUNT DECREASED      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Injury, poisoning and procedural complications CONTUSION      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Cardiac disorders ANGINA PECTORIS      subjects affected / exposed 1 / 2 (50.00%) 2 / 10 (20.00%)      occurrences all number 1 2 Nervous system disorders HEADACHE      subjects affected / exposed 0 / 2 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 NEURALGIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Blood and lymphatic system disorders ANAEMIA      subjects affected / exposed 0 / 2 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 LEUKOPENIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 INCREASED TENDENCY TO BRUISE      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 NEUTROPENIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Ear and labyrinth disorders VERTIGO      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences all number 1 0 Eye disorders EYE OEDEMA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Gastrointestinal disorders ABDOMINAL PAIN      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 CONSTIPATION      subjects affected / exposed 0 / 2 (0.00%) 3 / 10 (30.00%)      occurrences all number 0 3 ABDOMINAL PAIN UPPER      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences all number 1 0 DIARRHOEA      subjects affected / exposed 1 / 2 (50.00%) 3 / 10 (30.00%)      occurrences all number 1 3 DRY MOUTH      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 DYSPEPSIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 GASTROOESOPHAGEAL REFLUX DISEASE      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 NAUSEA      subjects affected / exposed 1 / 2 (50.00%) 1 / 10 (10.00%)      occurrences all number 1 1 Skin and subcutaneous tissue disorders PRURITUS      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 SEBACEOUS GLAND DISORDER      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences all number 1 0 RASH      subjects affected / exposed 0 / 2 (0.00%) 3 / 10 (30.00%)      occurrences all number 0 3 SKIN LESION      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Endocrine disorders HYPOTHYROIDISM      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 Musculoskeletal and connective tissue disorders ARTHRALGIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 ARTHRITIS      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 MUSCLE SPASMS      subjects affected / exposed 1 / 2 (50.00%) 1 / 10 (10.00%)      occurrences all number 1 1 MUSCULOSKELETAL PAIN      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 PAIN IN EXTREMITY      subjects affected / exposed 0 / 2 (0.00%) 3 / 10 (30.00%)      occurrences all number 0 3 Infections and infestations BRONCHITIS      subjects affected / exposed 1 / 2 (50.00%) 0 / 10 (0.00%)      occurrences all number 1 0 HERPES ZOSTER      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 INFLUENZA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 NASOPHARYNGITIS      subjects affected / exposed 0 / 2 (0.00%) 2 / 10 (20.00%)      occurrences all number 0 2 Metabolism and nutrition disorders DECREASED APPETITE      subjects affected / exposed 0 / 2 (0.00%) 5 / 10 (50.00%)      occurrences all number 0 5 HYPERKALAEMIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 HYPERTRIGLYCERIDAEMIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1 HYPOCALCAEMIA      subjects affected / exposed 0 / 2 (0.00%) 1 / 10 (10.00%)      occurrences all number 0 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
23 Oct 2013	Amendment 1 allowed the enrollment of patients who were currently receiving dovitinib in combination with fulvestrant.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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