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    Summary
    EudraCT Number:2016-003239-38
    Sponsor's Protocol Code Number:PH-L19TNFDOX2-03/16
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-08-16
    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 - PEI
    A.2EudraCT number2016-003239-38
    A.3Full title of the trial
    A Phase III study comparing the efficacy of the combination of doxorubicin and the tumor-targeting human antibody-cytokine fusion protein L19TNF to doxorubicin alone as first-line therapy in patients with advanced or metastatic soft tissue sarcoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study comparing the efficacy of the combination of doxorubicin and L19TNF to doxorubicin alone a in patients with advanced or metastatic soft tissue sarcoma
    A.3.2Name or abbreviated title of the trial where available
    FIBROSARC
    A.4.1Sponsor's protocol code numberPH-L19TNFDOX2-03/16
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04650984
    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 organisationPhilogen S.p.A.
    B.5.2Functional name of contact pointRegulatory Department
    B.5.3 Address:
    B.5.3.1Street AddressLoc. Bellaria, 35
    B.5.3.2Town/ citySovicille (Siena)
    B.5.3.3Post code53018
    B.5.3.4CountryItaly
    B.5.4Telephone number0039057717816
    B.5.5Fax number003905771781690
    B.5.6E-mailregulatory@philogen.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.3.9.3Other descriptive nameL19TNF
    D.3.9.4EV Substance CodeSUB29010
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number13
    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 or metastatic soft tissue sarcoma
    E.1.1.1Medical condition in easily understood language
    Soft tissue sarcoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level HLGT
    E.1.2Classification code 10041299
    E.1.2Term Soft tissue sarcomas
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 doxorubicin given for advanced or metastatic soft tissue sarcoma prolongs progression free survival, as compared to doxorubicin alone.

    The following efficacy endpoint will be considered:
    - Progression-free survival (PFS)
    E.2.2Secondary objectives of the trial
    To assess the efficacy, the following measurements will be considered:

    - Overall survival (OS)
    - Median Progression Free Survival (mPFS)
    - Median Overall Survival (mOS).
    - Overall Response Rate (ORR, consisting of CR and PR) and Best Overall Response Rate (BORR)

    To assess the safety profile of L19TNF combined with doxorubicin. The following safety endpoints will be considered:
    - Adverse Events (AEs) assessment based on CTCAE v.4.03.
    - Standard laboratory (haematology, biochemistry and urinalysis) parameters.
    - Physical examination findings including assessment of vital signs and physical measurements.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 - 75 years.
    2. Patients must have histological evidence of advanced unresectable and/or metastatic high-grade soft tissue sarcoma (grade 2 – 3 according to the FNCLCC grading system) not amenable to curative treatment with surgery or radiotherapy and for which doxorubicin treatment is considered appropriate. Participants with Osteosarcoma, Chondrosarcoma, Ewing Sarcoma/ Primitive Neuroectodermal Tumor (PNET), Kaposi’s Sarcoma, Dermatofibrosarcoma protuberans, and Gastrointestinal Stromal Tumors (GIST) will be excluded.
    3. Patients must have at least one unidimensionally measurable lesion by computed tomography as defined by RECIST criteria 1.1. This lesion should not have been irradiated during previous treatments.
    4. Life expectancy of at least 3 months.
    5. ECOG ≤ 2.
    6. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV, 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.
    7. 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 administration of L19TNF and/or Doxorubicin, 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 from the screening to four months following the last administration of L19TNF and/or Doxorubicin (e.g. condom with spermicidal gel). Double-barrier contraception is required.
    8. Informed consent signed and dated to participate in the study.
    9. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
    *
    Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy)
    E.4Principal exclusion criteria
    1. Prior therapy (except surgery and radiation) for unresectable or metastatic malignant soft tissue sarcoma.
    2. Previous treatment with anthracycline-containing chemotherapy.
    3. Radiotherapy within 4 weeks prior to therapy.
    4. Known history of allergy to TNFα, anthracyclines or other intravenously administered human proteins/peptides/antibodies.
    5. Previous therapy with recombinant TNF.
    6. Absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L and haemoglobin (Hb) < 9.0 g/dl.
    7. Chronically impaired renal function as expressed by creatinine ≥ 2.0 x ULN.
    8. Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN).
    9. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol.
    10. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
    11. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
    12. Clinically significant cardiac arrhythmias or requiring permanent medication.
    13. Uncontrolled hypertension, despite optimal therapy.
    14. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification).
    15. Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative 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. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment.
    23. Serious, non-healing wound, ulcer or bone fracture.
    24. Allergy to study medication or excipients in study medication.
    25. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months.
    26. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin).
    27. Concurrent use of other anti-cancer treatments or agents other than study medication.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of the trial is to evaluate whether L19TNF in combination with doxorubicin given for advanced or metastatic soft tissue sarcoma prolongs progression free survival, as compared to doxorubicin alone.

    The following efficacy endpoint will be considered:
    - Progression-free survival (PFS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of study
    E.5.2Secondary end point(s)
    To assess the efficacy, the following measurements will be considered:
    - Overall survival (OS)
    - Median Progression Free Survival (mPFS)
    - Median Overall Survival (mOS).
    - Overall Response Rate (ORR, consisting of CR and PR) and Best Overall Response Rate (BORR)

    To assess the safety profile of L19TNF combined with doxorubicin. The following safety endpoints will be considered:
    - Adverse Events (AEs) assessment based on CTCAE v.4.03.
    - Standard laboratory (haematology, biochemistry and urinalysis) parameters.
    - Physical examination findings including assessment of vital signs and physical measurements.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Median Overall survival (mOS).
    - Overall response rate (ORR, consisting of CR and PR).
    - Progression-free survival (PFS) rate at 3, 6, 9, 12 and 18 months.
    - Overall survival (OS) rate at 12 and 18 months.

    Safety profile of L19TNF combined with doxorubicin: throughout the study
    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 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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.2.3.1Comparator description
    Doxorubicin
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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 years7
    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 years7
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    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 state59
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 59
    F.4.2.2In the whole clinical trial 118
    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)
    Patients with partial response or stable disease after the maximum of 6 cylces of treatment will receive maintenance therapy with infusions of L19TNF every 3 weeks for up to 18 months, toxicity or until progression occurs.
    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 Decision2017-01-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-28
    P. End of Trial
    P.End of Trial StatusOngoing
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