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    Summary
    EudraCT Number:2012-004495-19
    Sponsor's Protocol Code Number:PH-L19IL2DTIC-04/12
    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:2012-11-15
    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 number2012-004495-19
    A.3Full title of the trial
    A Phase I/II Dose Escalation study of the tumor-targeting human L19-IL2 monoclonal antibody-cytokine fusion protein in combination with Dacarbazine for patients with metastatic melanoma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase I/II Dose Escalation study of the tumor-targeting L19-IL2 antibody-cytokine in combination with Dacarbazine for patients with metastatic melanoma.
    A.4.1Sponsor's protocol code numberPH-L19IL2DTIC-04/12
    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 Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLocalità Bellaria n. 35
    B.5.3.2Town/ citySovicille
    B.5.3.3Post code53018
    B.5.3.4CountryItaly
    B.5.4Telephone number0039057717816
    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 Yes
    D.2.1.1.1Trade name Dacarbazin
    D.2.1.1.2Name of the Marketing Authorisation holderMedac
    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 nameDacarbazin
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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.3.2Product code L19IL2
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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 typemonoclonal antibody-cytokine fusion protein
    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
    Metastatic Melanoma stage IV
    E.1.1.1Medical condition in easily understood language
    Metastatic Melanoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10027481
    E.1.2Term Metastatic melanoma
    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
    Phase I:
    Maximum tolerated dose (MTD) and the recommended dose (RD) of L19IL2 for phase II when administered in combination with a fixed dose of DTIC.

    Phase II: Antitumor activity in terms of best objective response rate (BORR) in patients treated with L19-IL2 at RD in combination with DTIC versus patients treated with DTIC monotherapy.
    E.2.2Secondary objectives of the trial
    For Phase I:
    •Antitumor activity in terms of confirmed best objective response rate (BORR), duration of overall response, disease control rate, progression free survival (PFS) and overall survival (OS).

    For Phase II:
    •Safety and Tolerability of L19-IL2 in combination with DTIC vs DTIC alone.
    •Duration of overall response, as well as disease control rate, progression free survival (PFS) and overall survival (OS).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 18-70 years of age, inclusive
    2. Must have histologically or cytologically confirmed cutaneous metastatic melanoma (Stage IV). For the Phase II part only patients with Stage IV M1a or M1b will be enrolled.
    3. Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as identified by CT or MRI scan within 28 days before the first study drug administration.
    4. Baseline LDH within normal range.
    5. Maximal 1 line of previous systemic treatment for metastatic disease (prior adjuvant melanoma therapy, e.g., IFNa, is permitted.
    6. For women of childbearing potential, a negative pregnancy test within 72 hours prior to the first dose of study treatment.
    7. Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
    8. Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
    9. Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
    10. Life expectancy of at least three months.
    11. Adequate organ function: serum creatinine ≤ 1.5 x ULN, total bilirubin ≤ 30 mM/L (or mg/dL, ≤ 2.0 mg/dL), hepatic transaminases ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN.
    12. ANC count ≥ 1.5 x 10^9/L, platelet count ≥ 100 x 10
    ^9/L, hemoglobin > 9 g/dL.
    13. Normal 12-lead ECG and normal bidimensional echocardiogram or MUGA.
    14. All toxic effects of prior therapy must have resolved to grade ≤1 unless otherwise specified above.
    15. Willing and able to give written informed consent
    E.4Principal exclusion criteria
    1. Pregnant or breastfeeding female
    2. Primary ocular melanoma
    3. Primary mucosal melanoma
    4. Use of any investigational or other anti-cancer drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of DTIC and L19-IL2.
    5. Prior radiation to a target lesion, unless there has been clear progression of the lesion since radiotherapy.
    6. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection.
    7. History or clinical evidence of brain metastases or leptomeningeal disease.
    8. Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix.
    9. Treatment with DTIC within 6 months before start of study.
    10. Treatment with Ipilimumab within 6 months before start of study.
    11. Hypersensitivity to DTIC
    12. Concomitant use of drugs known to alter cardiac conduction
    13. Chronic use of corticosteroids used in the management of cancer or non-cancer-related illness.
    14. Unstable or serious concurrent uncontrolled medical conditions.
    15. Inadequately controlled cardiac arrhythmias including atrial fibrillation.
    16. History of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
    17. Heart insufficiency > grade II NYHA criteria.
    18. Uncontrolled hypertension
    19. Ischemic peripheral vascular disease.
    20. Active infection or incomplete wound healing.
    21. History or evidence of active autoimmune disease.
    22. Known history of allergy to intravenously administered proteins/peptides/antibodies.
    23. History of organ allograft.
    24. Major trauma including surgery within 4 weeks prior to entering the study.
    25. Any underlying medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results (e.g., AE).
    E.5 End points
    E.5.1Primary end point(s)
    Phase I
    • Safety evaluation performed on days 1 through 21 including AEs, SAE and standard laboratory assessment will be used for determination of dose limiting toxicity (DLT).

    Phase II for both arms
    • Best objective response rate (BORR), which is defined as the rate of patients with Complete Response (CR) or Partial Response (PR) (defined according to RECIST 1.1 ) from the start of the study treatment until the end of the study.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I: day 1-21
    Phase II: from the start of the study treatment until the end of the study.
    E.5.2Secondary end point(s)
    Phase I
    1) Confirmed best objective response rate (BORR), which is defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) as per RECIST 1.1 criteria in patients treated with L19-IL2 in combination with DTIC
    2) Duration of overall response according to RECIST 1.1
    3) Disease control rate (CR + PR + SD) at 24 weeks
    4) Median progression free survival (mPFS) defined as the time elapsed between treatment initiation and tumor progression or death from any cause, with censoring of patients who are lost to follow-up.
    5) Median overall survival and Overall Survival rate at 1 year from treatment initiation until death due to any cause

    Phase II for both arms:
    1) Safety evaluation including AEs, SAE and standard laboratory assessment
    2) Duration of overall response according to RECIST 1.1
    3) Disease control rate (CR + PR + SD) at 24 weeks
    4) Median progression free survival (mPFS) defined as the time elapsed between treatment initiation and tumor progression or death from any cause, with censoring of patients who are lost to follow-up.
    5) Median Overall survival and overall survival rate at 1 year from treatment initiation until death due to any cause
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase I:
    1) from the start to the end of the study
    2) from the start to the end of the study
    3) at 24 weeks
    4) from the start to the end of the study
    5) at 1 year from treatment initiation

    Phase II:
    1) from the start to the end of the study
    2) from the start to the end of the study
    3) at 24 weeks
    4) from the start to the end of the study
    5) at 1 year from treatment initiation
    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 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
    Human pharmacology Phase I non first administration in human
    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 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 trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 No
    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 years3
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 26
    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 Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 96
    F.4.2.2In the whole clinical trial 96
    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
    Keine
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-04-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-04-03
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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