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    Summary
    EudraCT Number:2017-001625-40
    Sponsor's Protocol Code Number:AX-CL-PANC-PI-008619
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-03-20
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-001625-40
    A.3Full title of the trial
    A MULTICENTER, PHASE I/II STUDY OF SEQUENTIAL EPIGENETIC AND IMMUNE TARGETING IN COMBINATION WITH NAB-PACLITAXEL/GEMCITABINE IN PATIENTS WITH ADVANCED PANCREATIC DUCTAL ADENOCARCINOMA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-center clinical study with patients suffering from pancreatic cancer who will receive a consecutive epigenetic and immune targeted treatment in combination with nab-Paclitaxel/Gemcitabine
    A.3.2Name or abbreviated title of the trial where available
    SEPION
    A.4.1Sponsor's protocol code numberAX-CL-PANC-PI-008619
    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 SponsorGWT-TUD GmbH
    B.1.3.4CountryGermany
    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 supportCelgene International II Sàrl
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportAstraZeneca GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGWT-TUD GmbH
    B.5.2Functional name of contact pointMedical Consulting
    B.5.3 Address:
    B.5.3.1Street AddressFreiberger Str. 33
    B.5.3.2Town/ cityDresden
    B.5.3.3Post code01067
    B.5.3.4CountryGermany
    B.5.4Telephone number+4935125933100
    B.5.5Fax number+4935125933198
    B.5.6E-mailmelanie.hoffmann@gwtonline.de
    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 Vidaza®
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe B.V.
    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.3.4Pharmaceutical form Powder for suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.4EV Substance CodeSUB05624MIG
    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) 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.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 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 nameRomidepsin
    D.3.4Pharmaceutical form Powder and solvent 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 INNROMIDEPSIN
    D.3.9.2Current sponsor code128517-07-7
    D.3.9.4EV Substance CodeSUB26362
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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.IMP: 3
    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 B.V.
    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.3.4Pharmaceutical 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.3.9.3Other descriptive namePACLITAXEL ALBUMIN-BOUND
    D.3.9.4EV Substance CodeSUB127678
    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) 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 stabilizing agent. It is derived from human blood subject to approved donor screening and product manufacturing processes.
    D.IMP: 4
    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 AuthorisationGermany
    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/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38
    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.IMP: 5
    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 IMFINZI
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    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.3.2Product code MEDI4736
    D.3.4Pharmaceutical form Concentrate 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 INNDURVALUMAB
    D.3.9.3Other descriptive nameMEDI4736
    D.3.9.4EV Substance CodeSUB176342
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 6
    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 REVLIMID®
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe BV
    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.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Pancreatic Ductal Adenocarcinoma (PDAC)
    duktales Pankreaskarzinom
    E.1.1.1Medical condition in easily understood language
    Pancreatic cancer
    Bauchspeicheldrüsenkrebs
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10033604
    E.1.2Term Pancreatic cancer
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10051971
    E.1.2Term Pancreatic adenocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10033599
    E.1.2Term Pancreatic adenocarcinoma metastatic
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10033605
    E.1.2Term Pancreatic cancer metastatic
    E.1.2System Organ Class 100000004864
    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 study, including the dose escalating part (Part 1a), the dose expansion part (Part 1b) as well as the consolidation part (Part 2), is to determine the safety and tolerability of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine, followed by sequential immune targeting with PD-L1 blockade in combination with low-dose Lenalidomide in patients with advanced PDAC (Part 1 and 2).
    Moreover, in the dose escalating part of the study (Part 1a), the recommended dose for expansion and dose-limiting toxicity of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine will be identified.
    E.2.2Secondary objectives of the trial
    - to assess overall response rate (ORR) , CA 19-9 response and disease control rate (=1st DCR after 3 cycles), progression free survival and overall survival in patients treated at the recommended dose and regimen of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine (Part 1a and Part 1b)
    - to show a promising clinical activity of the selected epigenetic and chemotherapeutic targeting approach from Part 1a with regard to the disease control rate (Part 1b)
    - to assess 2nd ORR, 2nd CA 19-9 response and 2nd DCR (after start of Part 2), PFS and OS in patients treated with Durvalumab and Lenalidomide as consolidation treatment (Part 2)
    - to assess overall survival (OS) in all patients treated at the recommended dose and regimen
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - Exploratory analyses on tumor biopsy samples may include but will not be limited to: Genetic, epigenetic and expression profiling of tumor cells and immune phenotyping before and after therapy initiation including next generation sequencing (NGS)-based DNA/RNA-seq, genome-wide methylation profiling, immune cells infiltrate characterization (e.g. CD8, CD4, Treg, Macrophages and DC), immune phenotyping (e.g. interferon-stimulating genes such as IFI16, IFI27, IFI44, IFI44L, MX1 and OASL; induction of endogenous retroviral sequences (=ERVs) such as Syncytin-1-3, ERV-3, env-K, env-H and env-Fc1-2) by epigenetic treatment.
    - An exploratory objective of this study is to evaluate biomarkers in liquid biopsies, including but not limited to tracking oncogenic mutations such as KRAS in cell free DNA (ctDNA analysis), cytokines, chemokines, circulating receptors or ligands, other immune-related biomarkers (e.g. interleukin 2, interferon-γ) and immuno-phenotyping (e.g. CD8, CD4, Treg, Macrophages).

    E.3Principal inclusion criteria
    1. Patients must have histologically confirmed PDAC
    2. Patients must have metastatic disease (stage IV) and not received prior chemotherapy for stage IV disease (adjuvant/additive chemotherapy is allowed if completed at least 6 months prior to study inclusion)
    3. Patients must not have received the following drugs before: Azacitidine, Romidepsin, any checkpoint-inhibitor or immunomodulating agents such as IMiDs (Lenalidomide)
    4. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v. 1.1
    5. Male or female, age ≥ 18 years
    6. Body weight > 30 kg for inclusion into Part 2 (according to Durvalumab treatment)
    7. ECOG performance status 0 or 1
    8. Patients must have normal organ and marrow function as defined below
    • Leukocytes ≥ 2,5*10^9/L
    • Absolute neutrophil count ≥ 1,5*10^9/L
    • Platelets ≥ 100*10^9/L
    • Haemoglobin ≥ 9 g/dL
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) This will not apply to patients with confirmed Gilbert’s syndrome (persistent or
    recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be
    allowed only in consultation with their physician
    • Asparate aminotransferase/alanine aminotransferase (AST/ALT) (SGOT/SGPT) ≤ 2.5 x ULN and ≤ 5 in the case of liver metastasis
    • Measured creatinine clearance (CL) >60 mL/min or Calculated creatinine CL>60 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault
    1976) or by 24-hour urine collection for determination of creatinine clearance
    9. Patients must be recovered from the effects of any prior surgery
    10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
    11. All subjects must agree to refrain from donating blood while on study drug and for 90 days after discontinuation from this study treatment
    12. All subjects must have a life expectancy of at least 12 weeks
    13. All subjects must agree not to share medication.
    14. Females of childbearing potential (FCBP) must
    • Understand the potential teratogenic risk to the unborn child
    • Understand the need and agree to utilize two reliable forms of contraception simultaneously without interruption for at least 28 days before starting study drug, while participating in the study (including dose interruptions), and for at least 90 days after study treatment discontinuation
    • Understand and agree to inform the investigator if a change or stop of method of contraception is needed
    • Be capable of complying with effective contraceptive measures
    • Be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
    • Understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test
    • Understand the need and accept to undergo pregnancy testing based on the frequency outlined in this protocol
    • Acknowledges that she understands the hazards Lenalidomide can cause to an unborn fetus and the necessary precautions associated with the use of Lenalidomide
    • Females must agree to abstain from breastfeeding during study participation and for at least 90 days after study drug discontinuation
    15. Males must
    • Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female or a FCBP
    • Agree to use a latex condom during any sexual contact with FCBP or a pregnant female while participating in the study and for 90 days following discontinuation from this study, even if he has undergone a successful vasectomy. For treatment with Gemcitabine and nab-Paclitaxel men must avoid fathering a child/ use a condom up to 6 months after their last dose. Depending on duration of Lenalidomide/Durvalumab treatment this period can be longer than 90 days after study discontinuation
    • Agree to refrain from donating semen or sperm while on the study drugs and for 90 days after discontinuation from this study treatment. For treatment with nab-Paclitaxel and Gemcitabine male subjects must agree not to father a child or donate semen for at least 6 month afterlast intake of medication
    • Agree not to father a child during the course of the trial and for at least 90 days after last administration of study drugs. For Gemcitabine and nab-Paclitaxel treatment up to 6 month after last drug intake.
    16. Females of non-childbearing potential:
    • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhea for at least 24 consecutive months without an alternative medical cause
    E.4Principal exclusion criteria
    1. Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events from agents administered more than 4 weeks earlier
    2. Patients receiving any other investigational agents
    3. Patients who have previously received Romidepsin, Azacitidine, Lenalidomide or Durvalumab or any PD1 or PD-L1 inhibitor or participate currently on an other clinical trial, unless it is an observational clinical study or during the follow-up period of an interventional study
    4. Patients with untreated or uncontrolled brain metastases or leptomeningeal disease
    5. Presence of other active illnesses
    6. Any known cardiac abnormalities such as:
    • Congenital long QT syndrome
    • QTc interval ≥ 470 milliseconds. Calculated from 3 ECGs using Fridericias Correction
    7. Myocardial infarction within 6 months of C1D1
    8. Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia
    9. Symptomatic coronary artery disease, e.g., angina Canadian Class II-IV
    10. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or known ejection fraction <40% by MUGA or <50% by echocardiogram and/or MRI
    11. A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD)
    12. Concomitant use of any drug known to prolong QT interval
    13. Concomitant use of strong CYP3A4 inhibitors
    14. Lactating, pregnant or breast feeding
    15. Patients with any other medical or psychological condition deemed by the investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
    16. Diagnosis of immunodeficiency or any condition that requires systemic steroid therapy or other forms of immunosuppressive therapy
    17. Prior thromboembolic events
    18. History of other malignancies, except:
    • Malignancy treated with curative intent and with no known active disease present for ≥ 5 years before the first dose of study drug and felt to be at low risk for recurrence by investigator.
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated carcinoma in situ without current evidence of disease
    19. Any uncontrolled active systemic infection
    20. Major surgery within 4 weeks of first dose of study drug
    21. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk.
    22. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
    23. History of interstitial lung disease, idiopathic pulmonary fibrosis, or pulmonary hypersensitivity pneumonitis
    24. Unable to swallow oral medication or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
    25. Concomitant use of warfarin or other Vitamin K antagonists
    26. Known allergy or hypersensitivity to any study drug or any of the study drug excipients
    27. Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information
    28. Current or prior use of immunosuppressive medication within 14 days (use 28 days if combining Durvalumab with a novel agent) before the first dose of Durvalumab
    29. Active or prior documented autoimmune or inflammatory disorders
    30. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria .
    • Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
    • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab may be included only after consultation with the Study Physician.
    31. History of allogenic organ transplantation
    32. Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus
    33. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP
    34. Subject is an employee of GWT-TUD GmbH
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the safety and tolerability of Azacitidineand/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine, followed by sequential immune targeting with programmed death-ligand (PD-L)1 blockade in combination with low-dose Lenalidomide in patients with advanced PDAC (Part 1 and 2).
    Safety and tolerability will be determined by the following parameters:
    • Clinical laboratory (clinical chemistry, hematology, urinalysis)
    • Performance status according to Eastern Cooperation Oncology Group (ECOG)
    • Recording of AEs and concomitant medication
    • Physical examination
    • ECG
    • ECHO (Echocardiography) or MUGA (Multiple-Gated-Acquisition-(MUGA)-Radionuclide-Imaging)
    • Vital signs (pulse, blood pressure, body temparature)
    Moreover, in the dose escalating part of the study (Part 1a/Phase I), the recommended dose for expansion (RDE) and dose limiting toxicity (DLT) of Azacitidine and/or Romidepsin in combination with nab-Paclitaxel/Gemcitabine will be identified after completion of 3 treatment cycles.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after completion of 3 treatment cycles
    E.5.2Secondary end point(s)
    The secondary endpoints (after completion of 3 treatment cycles) are defined as:
    Part 1:
    • Overall response rate (ORR) according to RECIST version 1.1 (stable disease [SD] and complete response [CR] and partial response [PR]) after respective treatment)
    • CA19-9 Response: CA19 -9 change after treatment compared to baseline level
    • Disease-control rate (DCR) at 3-month according to RECIST version 1.1 (CR and PR and stable disease [SD] after respective treatment)
    • Overall survival (OS)
    • Progression free survival (PFS)
    Part 2:
    • Overall response rate (ORR) according to irRECIST1.1 (Wolchok, 2009) (CR and PR and SD) after/during treatment with Lenalidomide and Durvalumab
    • 2nd CA19-9 Response: CA19 -9 change after treatment compared to last level determined in Part 1
    • 2nd DCR at 3-month and 6-month according to irRECIST1.1 (CR and PR and stable disease [SD] after respective treatment)
    • Overall survival (OS)
    • Progression free survival (PFS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    after completion of 3 treatment cycles
    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 Yes
    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) 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
    combined epigenetic and chemotherapeutic targeting
    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 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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    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 concerned8
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 30
    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 state75
    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)
    12 month active follow up period will performed followed by a 2 years reporting period for second primary malignancies (SPMs). At the active follow up phase patients well-being, life expectancy and occurred AEs will be recorded. Furthermore, blood samples will be taken every 3 month. The observation phase for SPMs will end 3 years after last intake of study drug. After conclusion of the clinical study, patients will receive further standard medical care as usual for this kind of disease.
    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 Decision2019-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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