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    EudraCT Number:2009-012417-22
    Sponsor's Protocol Code Number:CTKI258A2204
    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:2009-12-29
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2009-012417-22
    A.3Full title of the trial
    A phase II, multi-center, non-randomized, open-label study of TKI258 in patients with relapsed or refractory multiple myeloma, who are with or without t(4;14) translocation
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberCTKI258A2204
    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.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.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.3.2Product 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.3.9.2Current 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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    Patients with relapsed or refractory multiple myeloma, who are with or without
    t(4;14) translocation
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the extended overall response rates of orally administered TKI258,
    at 500 mg/day, on a five days on and two days off dosing schedule, in groups
    of patients with relapsed or refractory multiple myeloma who are
    • with t(4;14) translocation (Group 1).
    • without t(4;14) translocation (Group 2).
    E.2.2Secondary objectives of the trial
    • To assess the safety profile of TKI258 dosing schedule, in the two groups.
    • To assess the overall response rates as per IMWG in the two groups.
    • To evaluate PFS in the two groups.
    • To evaluate plasma exposure of TKI258 in all patients who receive single
    agent TKI258.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Cytopathologically or histologically confirmed diagnosis of multiple myeloma previously requiring systemic treatment.
    2. Evidence of relapsed or refractory disease as documented from the prior treatment history (Refractory myeloma is defined as disease that is non-responsive while on salvage therapy, or progresses within 60 days of last therapy. Relapsed myeloma is defined as previously treated myeloma which after a period of being off-therapy requires the initiation of salvage therapy. Detailed definitions provided in the PTS-1).
    3. Have received at least 2 prior treatment regimens for multiple myeloma including
    chemotherapy, autologous transplantation, immunotherapy, or other investigational agents. Pre-planned induction followed by transplant and maintenance should be
    considered as one regimen.
    4. Presence of measurable disease as defined by at least one of the following;
    • Serum M-protein ≥ 1g/dL (measurable disease)
    • Urine M-protein ≥ 200mg/24 hours by protein electrophoresis (measurable disease)
    5. Age ≥ 18 years.
    6. WHO (World Health Organization) performance status of ≤ 2.
    7. Must have the following baseline laboratory values;
    • Absolute neutrophil count ≥ 1000/mm3 (or ≥ 750/mm3 if neutropenia is clinically
    related to progressive myeloma with bone marrow infiltration) [SI units, 1.0x109/L,and 0.75x109/L, respectively)
    • Platelet count ≥ 75,000/mm3 (or ≥ 50,000/mm3 if thrombocytopenia is clinically
    indicated to progressive myeloma with bone marrow infiltration) [SI units, 75x109/L,and 50x109/L, respectively) (transfusion support allowed)
    • Hemoglobin (Hgb) ≥ 8 g/dl (transfusion support allowed)
    • AST and ALT ≤ 3.0 x ULN
    • Serum bilirubin ≤ 1.5 x ULN
    • Electrolyte levels ≥ LLN (i.e., potassium, magnesium, phosphorus), correction with
    supplements allowed
    • Serum creatinine ≤ 2.0 x ULN (or 24-hour creatinine clearance ≥ 50 ml/min)
    8. Willing and able to undergo bone marrow aspirations and bone marrow biopsies as per the study center’s practice and protocol requirements.
    9. Life expectancy of ≥12 weeks.
    10. Must provide written informed consent to participate in this study.
    E.4Principal exclusion criteria
    1. Patients with non-secretory, or oligosecretory, multiple myeloma.
    2. Patients with symptomatic amyloidosis, or with plasma cell leukemia.
    3. Patients who have received allogeneic stem cell transplantation and who show evidence of active graft-versus-host disease that requires immunosuppressive therapy.
    4. Patients with history of another malignancy within the last three years prior to study entry, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.
    5. Patients who have received the last administration of anticancer therapy (for example chemotherapy, immunotherapy, hormonal therapy, and targeted therapy), less than 2 weeks prior to the start of this study drug, and who have not recovered from the side effects of such therapy. 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.
    6. Patients who received the last administration of an anti-cancer monoclonal antibody ≤ 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
    7. 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.
    8. Patients who have received wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 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.
    9. Patients who have undergone a major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
    10. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
    • History or presence of serious uncontrolled cardiac arrhythmias
    • Clinically significant resting bradycardia
    • LVEF assessed by 2-D echocardiogram (ECHO) or Multiple gated acquisition
    scanning (MUGA) < 45 %
    11. Any of the following within 6 months prior to study entry: 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).
    12. Uncontrolled hypertension defined by SBP ≥160 mmHg and/or DBP ≥100 mmHg, with or without anti-hypertensive medication.
    13. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of TKI258 (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
    14. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory).
    15. Patients who are currently receiving anticoagulation treatment with therapeutic doses of warfarin.
    16. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
    17. Pregnant or breast-feeding women.
    18. Male and female patients 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. women who have 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.5.1Primary end point(s)
    Extended overall response rate (Extended ORR) as defined by the rate of patients with best overall response of CR, VGPR (very good partial response) or PR (IMWG ORR), plus patients with best overall response MR as defined according to IMWG. Serum or urine M-protein levels will be measured at the end of each cycle. Confirmation of certain responses may require plasma cell count, evaluation of
    soft tissue plasmacytoma, or lytic bone lesions.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    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 months5
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 36
    F.4.2.2In the whole clinical trial 80
    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 Decision2010-01-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-04-29
    P. End of Trial
    P.End of Trial StatusCompleted
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