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    Summary
    EudraCT Number:2015-002066-24
    Sponsor's Protocol Code Number:PrE0204
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-20
    Trial 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 ConcernedAustria - BASG
    A.2EudraCT number2015-002066-24
    A.3Full title of the trial
    A Multi-Institutional, Single Arm, Two-Stage Phase II Trial of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients with Advanced or Metastatic Cholangiocarcinoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II Study of Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients with Advanced or Metastatic Cholangiocarcinoma
    A.4.1Sponsor's protocol code numberPrE0204
    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 SponsorThe All Ireland Cooperative Oncology Research Group (ICORG)
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPrECOG
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedizinische Universität Wien
    B.5.2Functional name of contact pointProf. Werner Scheithauer
    B.5.3 Address:
    B.5.3.1Street AddressWähringer-Gürtel 18-20
    B.5.3.2Town/ cityWien
    B.5.3.3Post code1090
    B.5.3.4CountryAustria
    B.5.6E-mailwerner.scheithauer@meduniwien.ac.at
    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 Yes
    D.2.1.1.1Trade name Abraxane
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Limited, Uxbridge, UK
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameNab-Paclitaxel
    D.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) 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 No
    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 typeThe IMP contains an excipient of biological origin, albumin, a non-active stabilising agent. It is derived from human blood subject to approved donor screening and product manufacturing processes.
    D.IMP: 2
    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 Yes
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameGemcitabine
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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) 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 No
    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 cholangiocarcinoma
    E.1.1.1Medical condition in easily understood language
    Cholangiocarcinoma is cancer of the biliary tract system, involving the bile ducts which connect the liver and gall bladder to the small bowel.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the efficacy of gemcitabine and nab-paclitaxel in patients with advanced CCA as measured by improvement in 6-month Progression Free Survival .
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    1. Evaluate clinical efficacy by assessment of median OS, PFS, TTP as well as best ORR and disease control rate (DCR).
    2. Describe the safety and toxicity profile of nab-paclitaxel and gemcitabine.
    3. Correlate change in CA 19-9 with ORR, DCR, median PFS, TTP and OS.
    Exploratory Objectives:
    1. Correlate change in Circulating Tumor Cells (CTCs) to ORR, DCR and median PFS, TTP and OS. Perform targeted gene expression analysis on CTCs and correlate with CCA pathology, PFS, TTP, ORR and OS.
    2. Correlate stromal SPARC (high versus low) expression and fibrosis (low, intermediate and high) by trichrome staining with ORR, DCR and median PFS, TTP and OS.
    3. Correlate CDA (high versus low) and hENT1 (high versus low) expression with ORR, DCR and median PFS, TTP and OS.
    4. Optional specimen banking of patient blood specimens and fixed left-over tissue specimens when available for possible future molecular, pharmacogenomic, and/or proteomic testing.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have a histologically-confirmed diagnosis of cholangiocarcinoma American Joint Committee on Cancer (AJCC) Stage II, III, or IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are not allowed.
    2. Must have radiographically measurable disease (RECIST Version 1.1) in at least one site not previously treated with radiation, chemoembolization, radioembolization, or other local ablative procedures (i.e. must have at least one measurable target lesion, either within the liver or in a measurable metastatic site); a new area of tumor progression within or adjacent to a previously-treated lesion, if clearly measurable by a Radiologist, is acceptable. Appropriate imaging should have been completed ≤ 4 weeks prior to registration.
    3. May have received prior radiation, chemoembolization, radioembolization, or other local ablative therapies, or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to ≤ grade 1 toxicity.
    NOTE: Measurable disease (as required above) must still be present.
    4. May have received prior radiation for bone or brain metastases if patient is now asymptomatic and has completed all radiation and steroid therapy (if applicable) ≥ 2 weeks prior to registration.
    5. Age ≥ 18 years.
    6. Child-Pugh score of A or B with ≤ 7 points (Appendix I of protocol).
    7. ECOG performance status of 0-1 (Appendix II) of protocol).
    8. Ability to understand and willingness to sign IRB-approved informed consent.
    9. Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
    10. Must be able to tolerate CT and/or MRI with contrast.
    11. Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks prior to registration:
    • Absolute Neutrophil Count (ANC) ≥ 1500/mm3
    • Hemoglobin ˃9.0 g/dL
    • Platelets ˃100,000/mm3
    • Serum Creatinine ≤ 1.5x Upper Limit Normal (ULN)
    • Creatinine Clearance ≥ 50 mL/min
    • Albumin ≥ 2.8 g/dL
    • Total Bilirubin ≤ 1.5 mg/dL or ≤ 1.5x ULN
    • AST/ALT ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
    • INR <1.5x the ULN [INR ≥ 1.5 is allowed if anticoagulation is used. Patient must be on a stable dose of anticoagulant (i.e. Coumadin) for ≥ 2 weeks at time of randomization.]

    E.4Principal exclusion criteria
    1. Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine may harm the fetus or child. All females of childbearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks prior to registration.
    2. Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 3 months following completion of study therapy. Method of contraception must be documented.
    NOTE: Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
    3. Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for this cancer.
    NOTE: Prior systemic cytotoxic therapy for other diagnoses is permitted if the last dose was >6 months prior, any prior toxicity has recovered to ≤ grade 1, and treatment was not discontinued for toxicity.
    4. Must not be receiving treatment with other investigational agents and must not have received any other investigational agent’s ≤ 4 weeks prior to registration.
    5. Must not have a pre-existing >grade 2 peripheral neuropathy.
    6. Must not be receiving immunosuppressive medications, including systemic corticosteroids, aside from the following exceptions: used for adrenal replacement, appetite stimulation, acute therapy for asthma or bronchitis exacerbation (≤ 2 weeks), or anti-emesis.
    7. No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) seropositivity. The risk for potential toxicities secondary to Hepatitis B, Hepatitis C or HIV (e.g., increased risk for fatal opportunistic infection) may confound the toxicity profile of the chemotherapy regimen. Testing is not required in absence of clinical suspicion.
    8. Must not have undergone liver transplantation.
    9. Must not have symptomatic brain or bone metastases (Section 3.4 for additional requirements).
    10. Must not have serious non-healing wound, ulcer, bone fracture, or abscess.
    11. Must not have undergone a major surgical procedure <4 weeks prior to registration.
    12. Must not have possible histories of pneumonitis or pneumonitis risk factors (Section 5.3.5).
    13. Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
    NOTE: Patients with history of malignancy are not considered to have a “currently active” malignancy if they have completed therapy and are now considered by their physician to be at less than 30% risk for relapse.
    14. Must have no ongoing or active, uncontrolled infections (afebrile for ≥ 48 hours off antibiotics).
    15. Must have no evidence of significant, uncontrolled concomitant diseases including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months, uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, connective tissue disease including lupus.
    16. Must not have any history of allergic reaction(s) attributed to compounds of similar composition to nab-paclitaxel or gemcitabine.
    17. Must not require prohibited medications with the potential for serious interactions with protocol therapy, and who cannot have therapeutic substitution (Section 5.4).
    18. Must not have a psychiatric illness, other significant medical illness, or social situation which, in the investigator’s opinion, would limit compliance or ability to comply with study requirements.

    E.5 End points
    E.5.1Primary end point(s)
    PFS at 6 months will be calculated in months from date of first dose of protocol therapy to date of documented disease progression or death from any cause, whichever comes first. PFS will be censored at the date of study discontinuation for evaluable patients other than progression or death. Eligible patients who receive at least one dose of nab-paclitaxel and gemcitabine will be included in the analysis of PFS.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 6 months and censored at the date of study discontinuation for evaluable patients other than progression or death.
    E.5.2Secondary end point(s)
    Overall Survival (OS) is defined as the time from enrollment until death or last patient contact, whichever comes first.

    Clinical Efficacy Endpoints:
    Stable disease (SD), complete response (CR), partial response (PR) and progressive disease (PD) will be defined as per the response evaluation criteria in solid tumors (RECIST) Version 1.1 guidelines to calculate ORR (PR + CR) and DCR (SD + PR + CR).

    Safety Endpoints:
    A patient will be considered for safety endpoints if the patient is eligible and one of the following occurs: (1) receives one dose of protocol therapy; (2) death on protocol therapy for a reason considered possibly, probably or likely related to protocol therapy; or (3) are removed from protocol therapy because of an adverse experience possibly, probably or likely related to one of the agents. Review will be performed by Data Safety and Monitoring Board (DSMB) approximately every 6 months.

    Exploratory Endpoints:
    -Immunohistochemical staining of CCA tumors will be performed for SPARC, CDA and hENT1.
    -Tumor Fibrosis Evaluation: Available tissue will be stained with trichrome to evaluate for fibrosis.
    -Optional Specimens for Testing and Banking: Blood specimens (whole blood) will be requested from the patient to test for Circulating Tumor Cells [CTCs]. Correlation of change in CTCs to ORR, DCR and median PFS, TTP and OS will be completed. Targeted gene expression analysis will be performed on CTCs for correlation with CCA pathology, PFS, TTP, ORR and OS.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall Survival: at death or last patient contact, whichever comes first.

    Clinical efficacy: Radiographic assessments will be performed every 8 weeks to evaluate response to treatment.

    Safety: Will be assessed every study visit until 30 days after last dose of study medication.

    Exploratory:
    -Pre-treatment, diagnostic pathology specimens obtained in the course of standard biopsy or surgery. Formalin-Fixed Paraffin-Embedded (FFPE) blocks or up to 15 FFPE slides plus H&E slide will be required. Procurement of tissue will be mandatory for enrollment, but if additional tissue from initial biopsy is not available, repeat biopsy will not be required.
    -Optional blood specimens will be collected at Cycle 1, Day 1, Cycle 1 Day 8, Cycle 3, Day 1 (only) and at Off Treatment.
    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 No
    E.6.7Pharmacodynamic No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Single-arm
    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.8.2.4Number of treatment arms in the trial1
    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 No
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    United States
    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
    LVLS
    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 months8
    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 months8
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 15
    F.4.2.2In the whole clinical trial 70
    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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation PrECOG
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation ICORG (All Ireland Co-operative Oncology Research Group)
    G.4.3.4Network Country Ireland
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-08-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-02-27
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