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    Summary
    EudraCT Number:2018-004104-19
    Sponsor's Protocol Code Number:PH-L19TNFSARC-03/18
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-07-27
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-004104-19
    A.3Full title of the trial
    A randomized study to investigate the efficacy and safety of the tumor-targeting human antibody-cytokine fusion protein L19TNF in previously treated patients with advanced stage or metastatic soft-tissue sarcoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the efficacy and safety of L19TNF in previously treated patients with advanced stage or metastatic soft-tissue sarcoma
    A.3.2Name or abbreviated title of the trial where available
    FLASH
    A.4.1Sponsor's protocol code numberPH-L19TNFSARC-03/18
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04733183
    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 SponsorPhilogen S.p.A.
    B.1.3.4CountryItaly
    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 supportPhilogen S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSofpromed Investigación Clínica, SLU
    B.5.2Functional name of contact pointHead of Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressC/ Gran Vía Asima 20 - 3rd Floor - Office 23
    B.5.3.2Town/ cityPalma
    B.5.3.3Post code07009
    B.5.3.4CountrySpain
    B.5.4Telephone number0034607939266
    B.5.6E-mailpledesma@sofpromed.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1739
    D.3 Description of the IMP
    D.3.1Product nameOnfekafusp alfa
    D.3.2Product code L19TNF
    D.3.4Pharmaceutical form Solution 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 INNOnfekafusp alfa
    D.3.9.1CAS number 1957239-88-1
    D.3.9.2Current sponsor codeL19TNF
    D.3.9.3Other descriptive nameL19TNFALFA
    D.3.9.4EV Substance CodeSUB29010
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number400
    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 Yes
    D.3.11.13.1Other medicinal product typeL19TNF is a new agent with potential antitumor activity, similar to another antitumoral drug already available called Tasonermin, Beromun (TNFalpha).
    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
    Unresectable and/or metastatic soft-tissue sarcoma after failure of at least two prior systemic therapy regimens
    E.1.1.1Medical condition in easily understood language
    Soft-tissue sarcoma after failure of at least two prior systemic therapy regimens
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10075333
    E.1.2Term Soft tissue sarcoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the trial is to evaluate whether L19TNF in combination with dacarbazine (DTIC) given for unresectable or metastatic soft-tissue sarcoma prolongs progression free survival after at least two lines of systemic therapy, as compared to dacarbazine (DTIC) alone.
    E.2.2Secondary objectives of the trial
    The key secondary objective of the study is to demonstrate with statistical superiority that L19TNF in combination with DTIC, given for unresectable or metastatic soft-tissue sarcoma, prolongs OS after at least two lines of systemic therapy for advanced or metastatic disease, as compared to DTIC alone.


    The other secondary objectives of the study are as follows:
    - Efficacy of L19TNF in combination with DTIC compared to DTIC alone
    - Safety of L19TNF in combination with DTIC
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female, 18 to 80 years of age.
    2. Histologically or cytologically confirmed advanced unresectable or metastatic soft tissue sarcoma (STS), Grade 2 - 3 according to the FNCLCC grading system. Participants with bone sarcomas including Ewing sarcoma, Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded.
    3. Subjects who received at least two prior systemic therapies (e.g., anthracyclines, taxanes, ifosfamide, gemcitabine, trabectedin, pazopanib, eribulin) for advanced or metastatic disease including at least one prior therapy based on anthracyclines as monotherapy or in combination. Neoadjuvant and adjuvant therapies can be considered as a prior line of treatment if the time to recurrence from completion of treatment was ≤ 12 months. Previous therapy with anthracyclines is not compulsory in situations of contraindications to this class of drugs. All previous therapies must have completed ≥ 3 weeks (21 days) prior to study treatment start.
    4. Evidence of disease progression after prior line of therapy for advanced or metastatic disease.
    5. Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria v.1.1. If only one lesion is present at screening this lesion should not have been irradiated during previous treatments.
    6. Life expectancy of at least 3 months in the judgment of the investigator.
    7. ECOG ≤ 2.
    8. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible.
    9. Female patients: negative serum pregnancy test at screening for women of childbearing potential (WOCBP)*. WOCBP must agree to use, from the screening to six months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Male patients: Male subjects able to father children must agree to use two acceptable methods of contraception throughout the study (e.g. condom with spermicidal gel). Double-barrier contraception is required.
    10. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
    11. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
    E.4Principal exclusion criteria
    1. Anti-cancer treatment with radiation therapy (with the exception of radiation of single lesions for palliative reasons, e.g. pain management which then are not taken as indicator lesions for iRECIST response), chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 3 weeks prior to study treatment start.
    2. Subjects who participated in an investigational drug or device study within 3 weeks prior to study treatment start.
    3. Previous treatment with TNF or L19TNF or DTIC.
    4. Known history of allergy to intravenously administered human proteins/peptides/antibodies and any other constituent of the product.
    5. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and hemoglobin (Hb) < 9.0 g/dl, with the exception of values lower than these due to cytologically or histologically proven marrow metastasis, which will not constitute exclusion criteria.
    6. Chronically impaired renal function as expressed by creatinine clearance < 60 mL/min or serum creatinine > 1.5 ULN.6. Chronically impaired renal function as expressed by creatinine clearance < 60 mL/min or serum creatinine > 1.5 ULN.
    7. Inadequate liver function (ALT or AST ≥ 3 x ULN or ALP or GGT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN). For patients with metastatic lesions in the liver ALT, AST, GGT or ALP ≥ 5 x ULN.
    8. Any severe concomitant condition which in the opinion of investigators makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
    9. History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
    10. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
    11. Clinically significant cardiac arrhythmias.
    12. Abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator.
    13. Uncontrolled hypertension.
    14. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
    15. Severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy.
    16. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 4 weeks of administration of study treatment.
    17. Pregnancy or breast-feeding.
    18. Requirement of chronic administration of corticosteroids or other immunosuppressant drugs. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
    19. Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
    20. Known active or latent tuberculosis (TB).
    21. Concurrent malignancies other than soft-tissue sarcoma, unless the patient has been disease-free for at least 2 years.
    22. Serious, non-healing wound, ulcer or bone fracture.
    23. Allergy to study medication or excipients in study medication.
    24. Concurrent therapy with anticoagulants at full therapeutic dose.
    25. Concurrent use of other anti-cancer treatments or agents other than study medication.
    E.5 End points
    E.5.1Primary end point(s)
    The following primary efficacy endpoint will be considered:
    - Progression-free survival (PFS) according to RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    PFS will be assessed throughout the study
    E.5.2Secondary end point(s)
    Key secondary efficacy endpoint:
    - Overall survival (OS)

    Other secondary endpoints:
    Efficacy
    - Objective response rate (ORR, consisting of CR and PR; only the non-irradiated lesions are measured) according to RECIST v1.1 between arms.
    - Objective response rate (ORR, consisting of iCR and iPR; only the non-irradiated lesions are measured) according to iRECIST in arm 1.
    - Progression-free survival (PFS) rate at 3, 6, 9 and 12 months according to RECIST v1.1 between arms.
    - Progression-free survival (iPFS) rate at 3, 6, 9 and 12 months according to iRECIST in arm 1.
    - Overall survival (OS) rate at 12, 24 and 36 months between arms.
    Safety:
    - Adverse Events (AEs), Serious Adverse Events (SAE) and Drug Induced Liver Injury (DILI) assessment based on CTCAE v.5.0.
    - Standard laboratory (hematology, biochemistry and urinalysis) parameters.
    - Physical examination findings including assessment of vital signs and physical measurements.
    - Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19TNF.
    - Characterization of pharmacokinetics (PK) of L19TNF, DTIC and AIC
    E.5.2.1Timepoint(s) of evaluation of this end point
    Multiple timepoints throughout and after the end of the study, depending on the specific endpoint (see section E.5.2 for details)
    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 No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero 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: 74
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 No
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 58
    F.4.2.2In the whole clinical trial 98
    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 Decision2022-09-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-10-25
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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