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    Summary
    EudraCT Number:2019-003550-88
    Sponsor's Protocol Code Number:TMV-018-101
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2019-11-27
    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 - PEI
    A.2EudraCT number2019-003550-88
    A.3Full title of the trial
    Full title of the trial: A Phase I/II open-label, dose-escalation, safety, clinical activity, pharmacokinetic and pharmacodynamic study of intra-tumoral application of TMV-018 in combination with 5-Fluorocytosine or anti-PD-1 therapy in patients with tumors.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II dose-escalation trial investigating the oncolytic virus TMV-018 in combination with a chemotherapy precursor (5-Fluorocytosine) or an immunotherapeutic agent (anti-PD-1 therapy) in patients with tumors of the gastrointestinal tract in terms of safety, clinical activity as well as pharmacokinetics and pharmacodynamics.
    A.3.2Name or abbreviated title of the trial where available
    TMV-018-101
    A.4.1Sponsor's protocol code numberTMV-018-101
    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 SponsorThemis Bioscience GmbH
    B.1.3.4CountryAustria
    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 supportThemis Biosience GmbH
    B.4.2CountryAustria
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSSS International Clinical Research GmbH
    B.5.2Functional name of contact pointCRO
    B.5.3 Address:
    B.5.3.1Street AddressLandsberger Str. 23/25
    B.5.3.2Town/ cityGermering
    B.5.3.3Post code82110
    B.5.3.4CountryGermany
    B.5.4Telephone number+49898006500
    B.5.5Fax number+4989800650555
    B.5.6E-mailinfo@cro-sss.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 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 nameTMV-018
    D.3.2Product code TMV-018
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntratumoral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn.a.
    D.3.9.1CAS number n.a.
    D.3.9.2Current sponsor codeTMV-018
    D.3.9.3Other descriptive nameTMV-018
    D.3.10 Strength
    D.3.10.1Concentration unit log10 TCID50 log10 tissue culture infective dose 50
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number7.3
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with histologically confirmed diagnosis of colorectal carcinoma (left-sided or rectal), esophageal carcinoma, or gastric cancer.
    E.1.1.1Medical condition in easily understood language
    Patients with histologically confirmed diagnosis of colorectal carcinoma (left-sided or rectal), esophageal carcinoma, or gastric cancer.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10062240
    E.1.2Term Tumor vaccine therapy
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    ▪ To determine the safety and tolerability of TMV-018 when given alone or in combination
    with the prodrug 5-FC and/or the anti-PD-1 therapy up to day 72 in patients with
    colorectal carcinoma (left-sided or rectal), esophageal carcinoma, or gastric cancer.
    ▪ To determine the maximum tolerated dose (MTD) of TMV-018 in these patients if it is
    at or below 1x108 TCID50.
    • To determine the recommended phase II dose.
    E.2.2Secondary objectives of the trial
    To assess viral replication at injected tumor sites, viremia (distribution of i.t. applied
    TMV-018 into the blood stream), shedding and possible persistence phenomena of
    TMV-018.
    ▪ To quantify rates of T cell infiltration into TMV-018 injected and non-injected tumor
    tissues.
    ▪ To assess the therapeutic efficacy of the TMV-018/5-FC, TMV-018/anti-PD-1, and
    TMV-018/5-FC/anti-PD-1 therapy regime by RECIST version 1.1 criteria, time to
    progression, as well as changes in tumor marker levels (CEA, CA19-9).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed informed consent form must be obtained prior to any research procedures.
    2. At least 18 years of age on the day of signing the informed consent.
    3. Histologically confirmed diagnosis of tumors of the gastrointestinal tract (colo¬rectal cancer (left side or rectal), gastric cancer, esophageal cancer being accessible for endoscope guided injection (without intake of oral laxatives) and sub¬sequent repetitive biopsy taking.
    4. Before enrolment (i.e., at least 4 weeks before study treatment): Prior chemotherapy, targeted therapy (e.g., bevacizumab), radiotherapy, to treat cancer or major surgery have to be stopped at least 4 weeks prior to enrolment.
    5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and life expectancy ≥ 3 months as assessed during screening period.
    6. All female participants of childbearing potential, defined as all woman physiologically capable of becoming pregnant, must have a negative pregnancy test at screening.
    7. Willingness not to become pregnant or to father a child during study participation by practicing reliable methods of contraception.
    8. In case of gastric or esophageal cancer, subjects must have under¬gone at least one line of anti-tumoral therapy. Patients with colorectal cancer (left side or rectal) must have undergone at least two lines of anti-tumoral therapy.
    9. Adequate organ function (hematological, renal, hepatic, coagulation within 2 weeks prior to enrollment defined as follows:
    • ANC ≥ 1500/mm3 (1.5 x 109/L)
    • Platelet count ≥ 100 000/mm3 (100 x 109/L)
    • Hemoglobin ≥ 9 g/dL (90 g/L)
    • Serum creatinin ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min for subjects with creatinine levels > 1.5 x ULN
    • Serum total bilirubin ≤ 1.5 x ULN
    • AST ≤ 2.5 x ULN
    • ALT ≤ 2.5 x ULN
    • Prothrombin time (PT) or INR ≤ 1.5 x ULN partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN
    E.4Principal exclusion criteria
    1. The participant may not be enrolled in the study if any of the following applies: Patients who participated in other studies of anti-tumor therapy within 2 weeks before enrolment.
    2. Patients with brain metastases.
    3. Patients with poorly controlled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg), or cardiovascular and cerebrovascular diseases with clinical significance, such as cerebrovascular accident (within 6 months before signing informed consent), myocardial infarction (within 6 months before signing
    informed consent), unstable angina pectoris, congestive heart failure (New York Heart Association Class II or above), or severe arrhythmia, which cannot be controlled with drugs or have potential impact on treatment.
    4. Patients with other serious organic diseases or mental disorders.
    5. Patients with active infections, which cannot be controlled with drugs or have potential impact on treatment.
    6. Patients with known history of human immunodeficiency virus (HIV).
    7. Patients who have received an organ transplant and who are under continuous immunosuppression.
    8. Use of immunosuppressive drugs like corticosteroids (excluding topical preparations)
    within 30 days prior to the first TMV-018 injection or anticipated use before completion of study visit 6 (day 182).
    9. Pregnancy (positive pregnancy test at screening or before end of study participation) or
    lactation at screening or planning to become pregnant before completion of study
    participation.
    10. reliable contraception methods.
    11. Patients with an impaired renal function (creatinine clearance ≤ 40 mL/min).
    12. Patients currently or recently (< 2 months) taking fluconazole, clotrimazole troches, itraconazole, amphotericin or other oral anti-fungal medications.
    13. Known hypersensitivity to 5-FC or its excipients.
    14. Known hypersensitivity to pembrolizumab, its excipients, or other monoclonal antibody.TMV-018-101 EudraCT 2019-003550-88 Protocol Final Version 1.3, 21-Nov-2019 Page 48/93
    15. Severe immune-related adverse reactions from treatment with ipilimumab, defined as any grade 4 toxicity or grade3 toxicity requiring corticosteroid treatment (> 10 mg/day prednisone or equivalent) for greater than 12 weeks.
    16. Patients with active autoimmune disease.
    17. Other medical condition or laboratory abnormality that in the judgment of the Investigator may increase the risk associated with study participation or may interfere with
    interpretation of study results.
    18. History of severe systemic reaction or side-effect after a measles vaccination.
    19. Known deficiency in dihydropyrimidine dehydrogenase (DPD) or total DPD deficiency
    diagnosed at baseline in those patients not previously treated with 5-FU-related
    compounds.
    20. Subjects who continue to experience > grade 1 Common Terminology Criteria for Adverse Events (CTCAE) toxicity due to cancer therapy within 4 weeks prior to enrollment will not be eligible.
    Note: Subjects with ≤ grade 2 neuropathy and alopecia are an exception to this criterion.
    21. Use of anti-cancer treatments within 4 weeks of TMV-018 treatment start:
    • Chemotherapy (at least 4 weeks for e.g. 5-FU containing chemotherapies, oxaliplatin,
    cisplatin, and taxanes).
    • Agents targeting the vascular endothelial growth factor (VEGF) pathway (e.g., bevacizumab, ramucirumab, aflibercept, etc.), EGFR (e.g. cetuximab and panitumumab), Her2neu (e.g. trastuzumab).
    • Other signal transduction inhibitors and monoclonal antibodies.
    • Immunotherapy or biological response modifiers.
    • Systemic hormonal anti-cancer therapy.
    • Any experimental therapy.
    E.5 End points
    E.5.1Primary end point(s)
    • Determination of the MTD: If one patient experiences a DLT, up to six patients will be treated at the same dose level. If a DLT is observed
    in only one of six patients treated at 1x108 TCID50, the remaining patients will also be treated with 1x108 TCID50. In case a DLT is observed in two of six patients, the remaining patients will be treated with 1x107 TCID50. Furthermore, if the same specific NTE occurs in 2 or more patients after the first administration of the same or higher dose level, the trial will also be continued using a classic 3 + 3 dose escalation design.
    • Recommended phase II dose: The recommended phase II dose will be evaluated based on toxicity data, pharmacokinetic and pharmacodynamic behavior, as well as anti-tumor responses.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Study Visits 1-11 (SFU)
    E.5.2Secondary end point(s)
    Viral replication at injected tumor sites, viremia (distribution of i.t. applied TMV-018 into
    the blood stream), and shedding will be analyzed using TCID50 assays using samples
    obtained from tumor, blood, urine, saliva, sputum, as well as feces at different times
    post TMV-018 treatment initiation
    ▪ T cell infiltration into tumor tissue will be analyzed using immunohistochemical assays.
    ▪ Number of Responses (Complete and Partial, Stable and Progressive Disease) [Time
    Frame: up to 24 months after SFU]. Responses will be summarized for TMV-018 by
    simple descriptive summary statistics delineating Complete and Partial Responses as
    well as Stable and Progressive Disease. RECIST (version 1.1) criteria will be used. For
    target lesions: Complete Response (CR), disappearance of all target lesions; Partial
    Response (PR), ≥ 30% decrease in the sum of the longest diameter (LD) of target
    lesions; Progressive disease (PD), at least a 20% increase in the sum of LD of target
    lesions taking as reference the smallest sum LD recorded since the treatment started
    or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient
    shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references
    the smallest sum LD. Tumor marker levels (CEA and CA19-9) and time to progression
    target lesions: Complete Response (CR), disappearance of all target lesions; Partial
    Response (PR), ≥ 30% decrease in the sum of the longest diameter (LD) of target
    lesions; Progressive disease (PD), at least a 20% increase in the sum of LD of target
    lesions taking as reference the smallest sum LD recorded since the treatment started
    or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient
    shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references
    the smallest sum LD. Tumor marker levels (CEA and CA19-9) and time to Progression.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At study Visits 2-10 and SFU.
    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 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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    open-label, multicenter, dose-escalation phase I/II trial
    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 Yes
    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
    open-label, multicenter, dose-escalation phase I/II trial
    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 trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States 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
    Last Patient Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state39
    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)
    All patients who continue to demonstrate clinical benefit and/or a CR, PR or SD status are eligible to receive the trial medication from the Sponsor at a schedule discussed between Sponsor and Investigator. Patients who show confirmed progressive disease (see PD definition in iRECIST criteria) are considered non-responders and should receive alternative treatments according to the investigator’s discretion (not related to the clinical study).
    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 Decision2020-07-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-03-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-11-13
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