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    Summary
    EudraCT Number:2008-005180-33
    Sponsor's Protocol Code Number:CNTO328STM2001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-04-09
    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 ConcernedUK - MHRA
    A.2EudraCT number2008-005180-33
    A.3Full title of the trial
    A Phase 1/2, Multiple-dose, Dose-escalation Study to Assess the Safety, Efficacy, and Pharmacokinetics of Intravenous CNTO 328, an Anti-interleukin 6 (IL-6) Monoclonal Antibody, in Subjects with Solid Tumors
    A.4.1Sponsor's protocol code numberCNTO328STM2001
    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 SponsorJanssen Biologics B.V.
    B.1.3.4CountryNetherlands
    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 nameCNTO328
    D.3.2Product code CNTO328
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeCNTO328
    D.3.9.3Other descriptive namechimeric murine-human monoclonal antibody against IL-6.
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    D.3.11.13.1Other medicinal product typeMonoclonal antibody
    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
    Malignant solid tumors
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the Phase 1 portion of the study is to determine a recommended dose for Phase 2 (RP2D) of CNTO 328 monotherapy.

    The primary objective of the Phase 2 portion of the study is to estimate the clinical benefit rate (CR + PR + SD > 6 weeks) of CNTO 328 monotherapy in subjects with ovarian cancer and with K-Ras mutant tumors.
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    The secondary objectives of the Phase 1 portion of the study are to assess:
    • Safety profile, including the AE profile and dose limiting toxicities (DLTs)
    • Pharmacokinetic profile
    • Immune response
    • Pharmacodynamic effects associated with IL-6 pathway and mechanisms of anemia
    • Clinical effects of CNTO 328

    The secondary objectives of the Phase 2 portion of the study are to assess:
    • Safety profile of CNTO 328
    • Pharmacodynamic effects on biomarkers of IL-6, mechanisms of anemia and correlation with K-Ras mutations
    • Pharmacokinetics
    • Immune response
    • Patient-reported outcomes (PRO) for ovarian cancer subjects
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for the study, subjects must meet all of the following criteria:

    1. Age ≥ 18 years old.

    2. Have capacity to understand and provide signed and dated informed consent prior to any study specific-procedures and agree to comply with all protocol-specified procedures.

    3. Histologic or cytologic documentation of malignancy as follows:

    a. Phase 1 Pharmacokinetic (Cohort 1) and dose-escalation (Cohorts 2 through 4): Subjects with malignant solid tumors that have progressed on or after standard therapy, or for which there is no effective therapy.

    b. Phase 1 expansion Cohort 5: Subjects with solid tumors of the subtypes
    described.

    1) Epithelial ovarian cancer subject who progressed on or after standard therapy. Subjects should be platinum resistant and taxane resistant, defined as, progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy.

    2) Subjects with known K-Ras mutant tumors or pancreatic cancer, or NSCLC, CRC or head and neck (H&N) cancer that are refractory or resistant to anti-EGFR therapy. All subjects must have received at least 1 line of standard chemotherapy.

    c. Phase 2 ovarian cancer cohort: Subjects with epithelial ovarian cancer, who progressed on or after standard therapy. Subjects should be platinum resistant and taxane resistant, defined as progression on or within 6 months of completing therapy with taxane and platinum either alone or in combination (unless contraindications for taxane or platinum exist), and for which there is no effective therapy.

    d. Phase 2 K-Ras mutant cohort: Subjects with known K-Ras mutant tumors or subjects with pancreatic cancer, or subjects with NSCLC, CRC or head and neck (H&N) cancer that are refractory or resistant to anti-EGFR therapy. All subjects must have received at least 1 line of standard chemotherapy.

    4. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2.

    5. Subjects must have recovered from reversible toxicity of previous treatment to ≤ Grade 1 or an acceptable baseline.

    6. Subjects of childbearing potential must use adequate birth control measures. Negative pregnancy test (urinary beta human chorionic gonadotropin [β-HCG]) at screening (applicable to women of child bearing potential who are sexually active).

    7. Adequate bone marrow, liver, and renal function:

    a. Hb ≥ 9.0 g/dL (5.6 mmol/L; 90 g/L)

    b. Absolute neutrophil count ≥ 1.5 x 109/L (1500/mm3)

    c. Platelets ≥ 75 x 109/L

    d. CrCL > 20 mL/min estimated by formula

    e. Liver function tests:

    1) Aspartate transaminase [AST], alanine transaminase [ALT]): ≤ 2.5 x upper limit of normal [ULN] if no liver metastasis; ≤ 5 x ULN with liver metastasis
    2) Total bilirubin ≤ 1.5 x ULN or ≤ 3x ULN if due to tumor obstruction
    3) Alkaline phosphatase ≤ 3 x ULN if no liver metastasis or bone involvement, and ≤ 5 x ULN with liver metastasis or bone involvement

    f. Coagulation prothrombin time/international normalized ratio (PT/INR) and
    activated partial thromboplastin time (aPTT) within 1.5 x ULN

    8. For the expansion Cohort 5 and Phase 2 ovarian cancer and K-Ras mutant tumor cohorts: evaluable or measurable disease (defined by RECIST, as applicable)
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria may not be enrolled in the study:

    1. Received any prior systemic therapy:
    • Bevacizumab: within 12 weeks prior to the first CNTO 328 administration
    • Nitrosoureas and mitomycin C: within 6 weeks prior to the first CNTO 328
    administration
    • All other prior systemic therapy or major surgery for the cancer under study:
    within 4 weeks prior to the first CNTO 328 administration.
    Concomitant use of immunotherapy, biotherapy, radiotherapy, chemotherapy,
    investigative therapy, immunosuppressive therapy, or IL-6 modulating agents is
    prohibited during the study except for stable low-dose steroids or luteinizing
    hormone-releasing hormone (LHRH) agonists in prostate cancer subjects.
    2. Previous anti IL-6 targeted therapy.

    3. Serious concurrent illness or history of uncontrolled heart disease such as: unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality.

    4. Subjects with known allergies or clinically significant reactions to murine,
    chimeric, or human proteins.

    5. For the dose expansion Cohort 5, ovarian cancer and K-Ras mutant tumor cohorts: Prior malignancy (other than the 1 under study) except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or other cancer for which the subject has been disease-free for ≥ 5 years).

    6. Clinically significant active infection within 2 weeks prior to the first CNTO 328
    administration.

    7. Evidence of bleeding disorder.

    8. Pregnant or lactating women.

    9. Any uncontrolled medical condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk by participating in the study or confounds the ability to interpret data from the study.

    10. Known central nervous system (CNS) metastases.

    11. Known infection with human immunodeficiency virus (HIV), known hepatitis C infection or known to be hepatitis B surface antigen positive.

    12. Subjects cannot be vaccinated with live, attenuated vaccines during the following time period: Within 4 weeks of the first administration of CNTO 328 and from the first administration of study agent to 12 weeks after the last administration of CNTO 328.
    E.5 End points
    E.5.1Primary end point(s)
    The primary safety endpoints include:
    Dose-limiting Toxicity: A DLT is defined as any of the following events occurring up to 3 weeks after the first administration of CNTO 328:

    • Grade 3 or greater nonhematologic AEs with the exception of:
    − Nausea and vomiting, which is controllable with antiemetics
    − Diarrhea, which is controllable with adequate anti-diarrheal treatment
    − Grade 3 hypertension, which is controllable with medication
    − Hypersensitivity reactions unless there are 2 or more occurrences of ≥ Grade 3
    hypersensitivity reactions within a cohort.
    • Clinically relevant hematologic toxicity such as Grade 4 neutropenia lasting > 1 week, febrile neutropenia, Grade 4 thrombocytopenia lasting more than 1 week or associated with hemorrhage.
    • Any other CNTO 328-related toxicity that in the judgment of the SET is considered to be dose limiting.

    A toxicity that is determined to be clearly unrelated to the investigational agent (eg, injury from motor vehicle accident in which the subject is a passenger) will not be considered a DLT. In such cases, confirmation by the SET is required at the next scheduled meeting.

    The safety endpoints include:
    • Incidence of DLT
    • Incidence of all AEs and reasonably related AEs
    • Incidence of all Grade 3 or higher AEs and reasonably related Grade 3 or higher AEs
    • Incidence of all SAEs and reasonably related SAEs
    • Incidence of infusion reactions, including ≥ Grade 3 allergic reactions/hypersensitivity (including drug fever) and ≥ Grade 3 cytokine release syndrome/acute infusion reaction
    • Incidence of clinically significant abnormal safety-related laboratory parameters
    • Incidence of antibodies to CNTO 328

    The primary efficacy endpoint is the clinical benefit rate. The major secondary efficacy endpoints include overall response rate, tumor marker response, and changes in hemoglobin. Additional efficacy endpoints include progression-free survival (PFS), and overall survival (OS).
    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 No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Patient Reported Outcomes
    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 Escalation
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Information not present in EudraCT
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 90
    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 Decision2009-05-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-06-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-04-11
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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