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    Summary
    EudraCT Number:2004-001716-31
    Sponsor's Protocol Code Number:20040124
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-01-20
    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 ConcernedGermany - BfArM
    A.2EudraCT number2004-001716-31
    A.3Full title of the trial
    A Phase 1/2 Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Weekly Doses of Palifermin (Recombinant Human Keratinocyte Growth Factor, rHuKGF) for the Reduction of Oral Mucositis in Subjects with Locally Advanced Head and Neck Cancer (HNC) Receiving Postoperative Radiotherapy with Concurrent Chemotherapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the effects of palifermin in reducing mouth ulceration in subjects with locally advanced head and neck cancer
    A.4.1Sponsor's protocol code number20040124
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorSwedish Orphan Biovitrum AB (publ.)
    B.1.3.4CountrySweden
    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 supportSwedish Orphan Biovitrum AB (publ.)
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmgen (EUROPE) GmbH
    B.5.2Functional name of contact pointIHQ Medical Info - Clinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressDammstrasse 23, P.O. Box 1557
    B.5.3.2Town/ cityZug
    B.5.3.3Post codeCH-6300
    B.5.3.4CountrySwitzerland
    B.5.6E-mailMedinfoInternational@amgen.com
    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 namePalifermin (kepivance)
    D.3.2Product code V03A F08
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for solution for injection
    D.8.4Route of administration of the placeboIntravenous bolus use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Oral Mucositis
    E.1.1.1Medical condition in easily understood language
    Mouth Ulcers
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10028130
    E.1.2Term Mucositis oral
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the pharmacokinetic profile and biological activity on buccal mucosae of palifermin administered at the dose of 120 μg/kg IV in a cohort of at least 16 (3 palifermin : 1 placebo) locally advanced HNC subjects receiving RT with concurrent CT as adjuvant treatment for their disease (post-operative setting).
    To evaluate the safety and tolerability of palifermin when administered at the dose of 120 μg/kg weekly for up to 8 consecutive weeks to patients with locally advanced HNC receiving RT with concurrent CT as adjuvant treatment for their disease (post-operative setting).
    E.2.2Secondary objectives of the trial
    To assess the preliminary efficacy of 120 μg/kg palifermin in reducing the incidence and duration of severe oral mucositis (OM) (Adapted RTOG/EORTC grade ≥3)
    To assess the preliminary efficacy of palifermin on the clinical sequelae of OM and Patient-reported mouth and throat soreness (MTS)
    To evaluate long-term effects of palifermin on disease outcome and survival.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Signed informed consent
    • ≥18 years of age
    • History of newly diagnosed histologically confirmed squamous cell carcinoma (AJCC Stage II, III, IVA, or IVB) involving either the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx, post surgical resection (R0, R1) and candidates for adjuvant RT/CT
    • High-risk subject defined by presence of at least one of the following: R1 resection margins; T3 or T4 tumor stage; 3 or more positive lymph node metastases; <3 lymph node metastases with extracapsular extension of the disease
    • Scheduled to receive adjuvant concurrent chemoradiation treatment within 12 weeks of surgery
    • Radiation treatment field to receive planned dose of at least 50Gy to areas of the oral cavity/oropharynx mucosa that can be visualized (Subjects with larynx or hypopharynx tumors are eligible only if the radiation oncologist anticipates a significant part of the oral mucosa to receive a total dose of 50Gy or
    more.
    • Karnofsky performance status ≥ 70
    • Planned interval < 6 calendar days between randomization and the first dose of RT
    • Baseline laboratory assessments:
    − Hemoglobin (Hgb) ≥ 10g/dL
    − White blood count (WBC) > 3.5 x 109/L or absolute neutrophil count (ANC) > 1.5 x 109/L
    − Platelet count ≥ 100 x 109/L
    − Serum bilirubin ≤ 1.5 x institutional upper limits of normal (ULN)
    − Serum creatinine ≤ 2.0 mg/dL; Subjects with a serum creatinine ≥ 1.4 mg/dL and ≤ 2.0 mg/dL need to demonstrate a 24-hr urinary creatinine clearance ≥ 50 mL/min
    − Females of childbearing potential: negative serum or urine pregnancy test
    E.4Principal exclusion criteria
    • Tumors of the lips, paranasal sinuses, salivary glands, or of unknown primary tumors
    • Metastatic disease (M1) / Stage IV C
    • Presence or history of any other primary malignancy
    • History of pancreatitis
    • Prior radiotherapy to the site of disease
    • Prior chemotherapy
    • Other investigational procedures
    • Thirty days or less since receiving an investigational product or device in another clinical trial. Current enrollment in another clinical trial is not permitted unless the sole purpose of the trial is for long-term follow-up/survival data.
    • Pregnant or breast-feeding women permitted unless the sole purpose of the trial is for long-term follow-up/survival data.
    • Refusal to use adequate contraceptive devices during treatment phase
    • Known sensitivity to any of the products administered during dosing, including E coli-derived products
    • Known to be sero-positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
    • Previous treatment on this study or with other keratinocyte growth factors
    • Compromised ability of the subject to give written informed consent and/or to comply with study procedures
    • Refusal to give written informed consent to participate in this study and to sign the hospital information release form
    • Unwilling or unable to complete the patient-reported outcome questionnaires
    • Psychological, social, familial, or geographical reasons that would prevent regular follow-up.
    E.5 End points
    E.5.1Primary end point(s)
    Pharmacokinetic endpoints:
    PK endpoints will include, but are not limited to:
    • systemic clearance (CL)
    • volume of distribution at steady state (Vss)
    • estimated initial concentration (C0)
    • area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC(0-t)) and to infinity (AUC(0-∞))
    • terminal half-life (t1/2,z)
    • mean residence time (MRT)

    Pharmacodynamics Endpoints
    The primary PD endpoint will be cell proliferation assayed by staining for cell cycle proliferation marker Ki67.

    Safety and Efficacy Endpoints:
    Proportion of subjects with protocol-specific limiting toxicity
    • Incidence of adverse events and laboratory abnormalities using the CTCAE v.3.0 toxicity scales
    • Incidence (%) and duration (days) of severe oral mucositis (Adapted RTOG/EORTC) grade ≥3
    • Time (days) to onset of severe oral mucositis (Adapted RTOG/EORTC grade ≥3)
    • Incidence (%) and duration (days) of oral mucositis (Adapted RTOG/EORTC grade ≥2)
    • Time (days) to onset of oral mucositis (Adapted RTOG/EORTC grade ≥2)
    • Opioid analgesics use (incidence, total dose of morphine equivalents)
    • Incidence of unplanned RT and CT breaks
    • Changes in performance status and body weight (kg)

    Long-term Safety Endpoints
    • Incidence of second primary tumors
    • Incidence of other malignancies
    • Progression-free survival (PFS)
    • Overall survival (OS)
    • Incidence of leukoplakia
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluations of oral mucosal surfaces (mucositis assessments) occur daily (weekdays) throughout CT/RT, then 2 times weekly thereafter until mucositis has resolved to Grade ≤ 2, once mucositis has resolved to Grade ≤ 2 subjects will return to the clinic for mucositis assessments once a week until mucositis has resolved to grade ≤ 1. If OM does not resolve to Grade ≤ 1 by week 15, subjects should continue to have a once weekly assessment until resolution to Grade ≤ 1 but not beyond week 24 / month 6.
    E.5.2Secondary end point(s)
    Exploratory endpoints
    Evaluation of potential biomarkers with respect to chemo/radiotherapy-induced oral mucositis and treatment regimen
    Evaluation of genetic variation as related to presence of mucositis and patient response to treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluations of oral mucosal surfaces (mucositis assessments) occur daily (weekdays) throughout CT/RT, then 2 times weekly thereafter until mucositis has resolved to Grade ≤ 2, once mucositis has resolved to Grade ≤ 2 subjects will return to the clinic for mucositis assessments once a week until mucositis has resolved to grade ≤ 1. If OM does not resolve to Grade ≤ 1 by week 15, subjects should continue to have a once weekly assessment until resolution to Grade ≤ 1 but not beyond week 24 / month 6.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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.7.1.3.1Other 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    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
    All subjects will be followed for up to 10 years from the last subject randomized or until death or loss to follow-up.
    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 months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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.1.2.1Number of subjects for this age range: 3
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state40
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    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 Decision2005-03-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-05-25
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