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    Summary
    EudraCT Number:2020-003299-42
    Sponsor's Protocol Code Number:PH-L19IL2TNFNMSC-04/19
    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:2021-03-05
    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 number2020-003299-42
    A.3Full title of the trial
    A phase II study of intratumoral administration of L19IL2/L19TNF in non-melanoma skin cancer patients with presence of injectable lesions.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Intratumoral administration of L19IL2/L19TNF in non-melanoma skin cancer patients
    A.3.2Name or abbreviated title of the trial where available
    DUNCAN
    A.4.1Sponsor's protocol code numberPH-L19IL2TNFNMSC-04/19
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04362722
    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 AddressLocalità Bellaria, 35
    B.5.3.2Town/ citySovicille (Siena)
    B.5.3.3Post code53018
    B.5.3.4CountryItaly
    B.5.4Telephone number+39057717816
    B.5.5Fax number+3905771781690
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBifikafusp alfa
    D.3.2Product code L19IL2
    D.3.4Pharmaceutical form Solution for injection
    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 INNbifikafusp alfa
    D.3.9.1CAS number 1957239-90-5
    D.3.9.2Current sponsor codeL19IL2
    D.3.9.3Other descriptive nameDarleukin
    D.3.9.4EV Substance CodeSUB27376
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6500000
    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: 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 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 IMPIntratumoral 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 nameFibromun
    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 number200
    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.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 high-risk, locally advanced (non-metastatic, node negative, single or multifocal), Basal Cell Carcinoma (BCC) or cutaneous Squamous Cell Carcinoma (cSCC) amenable to intratumoral injection, not eligible to surgery or radiation therapy according to the evaluation of a local interdisciplinary tumor board or who refuse surgery or radiation therapy and for whom an histological evaluation is available according to international guidelines
    E.1.1.1Medical condition in easily understood language
    Non melanoma skin cancer
    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 10004146
    E.1.2Term Basal cell carcinoma
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10041834
    E.1.2Term Squamous cell carcinoma of skin
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Efficacy of L19IL2/L19TNF-treated lesions measured as: Confirmed Best Overall Response Rate (BORR) [Complete Response (CR) + Partial Response (PR)] for BCC tumor type measured according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Confirmation of CR requires histopathological analysis of exeresis specimens for lesions removed by surgery or of biopsies in all other cases.
    E.2.2Secondary objectives of the trial
    • Efficacy of L19IL2/L19TNF-treated lesions measured as:
    - Disease Control Rate (DCR) [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)] for each tumor type measured according to RECIST v1.1 criteria.
    - Progression-Free Survival (PFS), assessed separately in patients who are not resected after curative intention and in patients who undergo secondary surgery (neoadjuvant intention), whatever the RECIST response to treatment, taking into account appearance of new lesions and occurrence of metastases, etc.
    - Pathological Response for each tumor type in surgical specimens from tumors which are resected after treatment, or in biopsy for the other types.

    • Safety of intratumoral administration of L19IL2/L19TNF.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients with high-risk, locally advanced (non-metastatic, node negative, single or multifocal), basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC) amenable to intratumoral injection, not eligible to surgery or radiation therapy according to the evaluation of a local interdisciplinary tumor board or who refuse surgery or radiation therapy and for whom a histological evaluation is available according to international guidelines. Eligible patients are those as defined by the European Association of Dermato-Oncology (EADO) operational staging system (stages IIa to IIIb) [1] for BCC and by EADO/EORTC (European Organization for Research and Treatment of Cancer) interdisciplinary guidelines [1] for cSCC.
    2. Patients with injectable and measurable regional cutaneous or subcutaneous in-transit or satellite metastasis but without regional nodal involvement are also eligible.
    3. Male or female patients, age 18 - 100 years.
    4. ECOG Performance Status/WHO Performance Status ≤ 1.
    5. Hemoglobin > 10.0 g/dL.
    6. Platelets > 100 x 109/L.
    7. ALT and AST, GGT and Lipase ≤ 1.5 x the upper limit of normal (ULN).
    8. Serum creatinine < 1.5 x ULN. An age-calibrated definition of CKD has been proposed to distinguish age-related from disease-related changes in eGFR. For patients younger than 40 years, CKD is defined by eGFR below 75 mL/min/1.73m2. For patients with ages between 40 and 65
    years, CKD is defined by 60 mL/min/1.73m2. For subjects older than 65 years without albuminuria or proteinuria, CKD is defined by eGFR
    below 45 mL/min/1.73m2.
    9. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v. 5.0) Grade ≤ 1 unless otherwise specified.
    10. Women of Childbearing Potential (WOCBP) must have negative pregnancy test results at screening. WOCBP must be using, from screening to three 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 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, vasectomised partner.
    11. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
    12. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

    E.4Principal exclusion criteria
    • Previous or concurrent cancer type that is distinct from the cancers being evaluated in this study, except any cancer curatively treated more than 2 years prior to study entry.
    • Topical or systemic chemotherapy, immunotherapy or radiation therapy on the tumor sites in the 4 weeks prior to study drug administration.
    • Patients with node positive BCC/cSCC who are candidate to SHH inhibitor or checkpoint inhibitor therapy.
    • Presence of active severe bacterial or viral 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. In particular a documented test for HIV, HBV and HCV excluding active infection is needed.
    • History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris, inadequately treated cardiac arrhythmias and heart insufficiency (any grade, New York Heart Association (NYHA) criteria).
    • Any abnormalities observed during baseline ECG investigations that are considered as clinically significant by the investigator.
    • Known arterial aneurysms.
    • INR > 3.
    • Uncontrolled hypertension.
    • Known uncontrolled coagulopathy or bleeding disorder.
    • Known hepatic cirrhosis or severe pre-existing hepatic impairment.
    • Moderate to severe respiratory failure.
    • Active autoimmune disease.
    • Patient requires or is taking systemic corticosteroids (>5 mg/day) or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions and asthma/COPD is not considered an exclusion criterion.
    • Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies.
    • Pregnancy or breast-feeding.
    • Ischemic peripheral vascular disease (Grade IIb-IV).
    • Severe diabetic retinopathy.
    • Recovery from major trauma including surgery within 4 weeks prior to enrollment.
    • Solid organ transplant recipient or patient with iatrogenic or pathologic severe immune suppression.
    • Any conditions that in the opinion of the investigator could hamper compliance with the study protocol
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed Best Overall Response Rate (BORR) [Complete Response (CR) + Partial Response (PR)] for BCC tumor type measured according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Confirmation of CR requires histopathological analysis of exeresis specimens for lesions removed by surgery or of biopsies in all other cases.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy is evaluated as Confirmed Best Overall Response Rate (BORR) which consists of CR and PR over a period of 1 year from beginning of treatment.
    E.5.2Secondary end point(s)
    • Efficacy of L19IL2/L19TNF measured as:

    o Disease Control Rate (DCR) [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)] for each tumor type measured according to RECIST v1.1 criteria.
    o Progression-Free Survival (PFS), assessed separately in patients who are not resected after curative intention and in patients who undergo secondary surgery (neoadjuvant intention), whatever the RECIST response to treatment, taking into account appearance of new lesions and occurrence of metastases, etc.
    o Pathological Response for each tumor type in surgical specimens from tumors which are resected after treatment, or in biopsy for the other types.

    • Safety of intratumoral administration of L19IL2/L19TNF.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Disease Control Rate (DCR) [Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)] for each tumor type measured according to RECIST v1.1 criteria.
    - Progression-Free Survival (PFS), assessed separately in patients who are not resected after curative intention and in patients who undergo secondary surgery (neoadjuvant intention), whatever the RECIST response to treatment, taking into account appearance of new lesions and occurrence of metastases, etc
    - Pathological Response for each tumor type in surgical specimens from tumors which are resected after treatment, or in biopsy for the other types.
    - Safety of intratumoral administration of L19IL2/L19TNF at every administration and 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 No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    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.8.3 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    Germany
    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
    LPLV
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 46
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 46
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 32
    F.4.2.2In the whole clinical trial 92
    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)
    Nothing planned.
    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 Decision2021-06-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-13
    P. End of Trial
    P.End of Trial StatusOngoing
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