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    Summary
    EudraCT Number:2007-004391-39
    Sponsor's Protocol Code Number:CTKI258A2107
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-09-30
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2007-004391-39
    A.3Full title of the trial
    A Phase I/II multi-center, open label study of TKI258 administered orally on an intermittent schedule in adult patients with advanced or metastatic Renal Cell Cancer (RCC)
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberCTKI258A2107
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberN/A
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTKI258
    D.3.2Product code TKI258
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 692737-80-7
    D.3.9.2Current sponsor codeTKI258
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 692737-80-7
    D.3.9.2Current sponsor codeTKI258
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    advanced or metastatic renal cell carcinoma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10050513
    E.1.2Term Metastatic renal cell carcinoma
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Dose escalation phase (Phase I)
    • To determine the MTD based on the incidence of the DLT of TKI258, administered orally on a 5 days on/2 days off schedule to adult patients with advanced or metastatic RCC whose diseases have progressed despite standard therapy or for whom no standard anticancer therapy exists.

    Dose expansion phase (Phase II)
    • To assess anti-tumor activity of TKI258 in patients who have been previously treated with VEGF receptor tyrosine kinase inhibitor (sunitinib and/or sorafenib) mTOR inhibitor and have measurable histologically or cytologically confirmed progressive advanced or metastatic RCC with predominant clear cell histology (>50%) based on the proportion of patients experiencing clinical response (CR and PR) and no clinical benefit at 8 weeks post-treatment
    E.2.2Secondary objectives of the trial
    Secondary objectives (both escalation and expansion parts)
    • To assess the safety profile of TKI258 administered orally on a 5 days on/2 days off schedule in this patient population.
    • To characterize the single and multiple-dose PK profiles of oral TKI258 on a 5 days on/2 days off dosing schedule schedule in all patients and a subset of patients of Asian ethnicity.
    • To assess the effect of TKI258 on plasma biomarkers pre- and post-treatment:
    • To evaluate concentrations of circulating growth factors, soluble receptors (e.g. bFGF, VEGF, PlGF, sVEGFR1 and 2).
    • To assess anti-tumor activity of TKI258 based on PFS and OS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria --
    Dose escalation phase only
    • Patients with advanced or metastatic renal cancer for whom no other therapeutic options exist (measurable lesion by RECIST is not required).

    Dose expansion phase only --
    1. Patients that must have been previously treated with VEGF receptor tyrosin kinase inhibitor(sunitinib and/or sorafenib) and mTOR inhibitor. However, patients previously treated with other therapies (e.g. IL-2, IF-α) are also allowed to be enrolled and treated to determine the effect of TKI258 in patients who had not been treated with VEGF receptor tyrosine kinase inhibitor and mTOR therapy.
    2. Patients of Asian ethnicity: who failed standard treatment or for whom no standard treatment exists.
    3. Patients with at least one measurable lesion at baseline as per the RECIST criteria, either on physical exam or as determined by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI).

    Dose escalation and dose expansion phase --
    • Prior therapy with any prior anti-cancer agent (i.e. IL-2, Interferon, etc.) is permitted as long as it is administered 14 days (6 weeks for nitrosoureas or mitomycin C and 4 weeks for any investigational agents and bevacizumab) prior to first administration of TKI258 (cycle 1 day 1). The only exception is made for palliative radiotherapy for symptomatic bone metastases. Patients must have recovered from adverse events (to grade 1 or less toxicity according to CTCAE 3.0) due to the prior anticancer agents(with the exception of the GI toxicities mentioned in the exclusion criteria).
    • Patients with histologically or cytologically confirmed progressive metastatic renal cell carcinoma with predominant clear cell histology (>50%).
    • Age at least 18 years.
    • ECOG performance status 0 or 1.
    • Required baseline laboratory data includes:
    • Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 [SI units 1.5 x 109/L]
    • Platelets greater than or equal to 75,000/mm3 [SI units 75 x 109/L]
    • Hemoglobin greater than or equal to 8.0 gm/dL [SI units 80 gm/L]
    • Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN)
    • Bilirubin less than or equal to 1.5 x ULN
    • AST (SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN, except for subjects with tumor involvement of the liver who must have AST and ALT less than or equal to 5 x ULN
    • Amylase, Lipase less than or equal to ULN
    • Electrolyte levels should be within normal limits
    • Urine dipstick reading: Negative for proteinuria or, if documentation of +1 results for protein on dipstick reading, then total urinary protein less than or equal to 500 mg and measured creatinine clearance greater than or equal to 50 mL/min/1.73m2 from a 24-hour urine collection
    • Life expectancy greater than or equal to 12 weeks.
    • Signed and witnessed informed consent form obtained prior to any screening procedures.
    E.4Principal exclusion criteria
    Exclusion criteria (dose escalation and dose expansion phases)
    • Concurrent therapy with any other investigational agent within 28 days prior to baseline.
    • Women of child-bearing potential who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Barrier contraceptives must be used throughout the trial in both sexes. 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 less than or equal to 72 hours prior to starting TKI258.
    • Clinically significant cardiac disease (New York Heart Association, Class III or IV) or impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
    • LVEF < 45% as determined by MUGA scan or echocardiogram
    • Complete left bundle branch block
    • Obligate use of a cardiac pacemaker
    • Congenital long QT syndrome
    • History or presence of ventricular tachyarrhythmia
    • Presence of unstable atrial fibrillation (ventricular response > 100 bpm). Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria
    • Clinically significant resting bradycardia (< 50 bpm)
    • Uncontrolled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥ 100 mmHg, with or without antihypertensive medication)
    • QTc > 480 msec on screening ECG
    • Right bundle branch block + left anterior hemiblock (bifasicular block)
    • Angina pectoris less than or equal to 3 months prior to starting study drug
    • Acute Myocardial Infarction less than or equal to 3 months prior to starting study drug
    • Other clinically significant heart disease (e.g., CHF, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
    • Uncontrolled infection.
    • Diabetes mellitus (insulin dependent or independent disease, requiring chronic medication) with signs of clinically significant peripheral vascular disease.
    • Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring two or more interventions/month (in both the dose escalation and dose expansion).
    • Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis, adrenal or thyroid glands.
    • Prior acute or chronic pancreatitis of any etiology.
    • Acute and chronic liver disease and all chronic liver impairment.
    • Malabsorption syndrome or uncontrolled gastrointestinal toxicities (nausea, diarrhea, vomiting) with toxicity greater than NCI CTCAE grade 2.
    • Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for this study.
    • Treatment with any of the medications that have a potential risk of prolonging the QT interval or inducing Torsades de Points and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
    • Use of ketoconazole, erythromycin, carbamazapine, phenobarbital, rifampin, phenytoin, and quinidine 2 weeks prior baseline.
    • Major surgery less than or equal to 28 days prior to starting study drug or who have not recovered from side effects of such therapy.
    • Known diagnosis of HIV infection (HIV testing is not mandatory).
    • History of another primary malignancy that is currently clinically significant or currently requires active intervention.
    • Patients with brain metastases as assessed by radiologic imaging (e.g. CT, MRI)
    • Alcohol or substance abuse disorder.
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints
    • Dose escalation phase: incidence of DLT.
    • Dose expansion phase: proportion of patients with clinical response and no clinical benefit at 8 weeks post treatment. Patients will be categorized into one of 3 mutually exclusive categories: clinical responders (CR and/or PR) at 8 weeks post treatment [R], patients with stable disease for at least 8 weeks excluding clinical responders [SD] and all other patients (No Clinical Benefit [NCB]).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose finding study
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial has a data monitoring committee No
    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
    Patients may continue treatmetn with TKI258 until they experience unacceptable toxicicty , disease progression and/or at the discretion of the investigator. Six months following enrollment of the last patient in this trial a continuation protocol will be implemented for those patients who are still on TKI258 treatment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 104
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-11-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-06-11
    P. End of Trial
    P.End of Trial StatusCompleted
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