<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03779230</url>
  </required_header>
  <id_info>
    <org_study_id>PH-L19TNFGLIO-02/18</org_study_id>
    <nct_id>NCT03779230</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of L19TNF in Patients With Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III / IV Glioma at First Relapse</brief_title>
  <acronym>GLIOMOON</acronym>
  <official_title>A Study to Evaluate the Safety and Efficacy of the Tumor-targeting Human Antibody-cytokine Fusion Protein L19TNF in Patients With Isocitrate Dehydrogenase (IDH) Wildtype WHO Grade III / IV Glioma at First Relapse</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Philogen S.p.A.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Philogen S.p.A.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Open label, non-randomized, mono-center Phase I/II study in subjects with IDH-wildtype WHO&#xD;
      grade III / IV glioma at first relapse.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to explore the safety and efficacy profile of the&#xD;
      antibody-cytokine fusion protein L19TNF in patients with isocitrate dehydrogenase (IDH)&#xD;
      wildtype WHO grade III / IV glioma at first relapse&#xD;
&#xD;
      Phase I:&#xD;
&#xD;
      The primary objective of this phase is to evaluate the safety of L19TNF in patients with&#xD;
      IDH-wildtype WHO grade III / IV glioma at first relapse and to establish and confirm the&#xD;
      recommended dose (RD) for phase II.&#xD;
&#xD;
      Phase II:&#xD;
&#xD;
      The primary objective of this phase is to evaluate antitumor activity of L19TNF in patients&#xD;
      with IDH-wildtype WHO grade III / IV glioma at first relapse.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 31, 2019</start_date>
  <completion_date type="Actual">June 27, 2023</completion_date>
  <primary_completion_date type="Actual">June 27, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Open label, non-randomized, mono-center Phase I/II study in subjects with IDH-wildtype WHO grade III / IV glioma at first relapse.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of Dose Limiting Toxicity (DLT)</measure>
    <time_frame>From the first day of treatment until the end of the DLT window (up to 21 days)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse event (AE), Serious Adverse Events (SAE) and Drug Induced Liver Injury (DILI) assessment based on CTCAE v.5.0</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Standard laboratory (haematology, biochemistry, liver and urine analysis) parameters</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Neurological assessment using the Neurologic assessment in Neuro-Oncology (NANO) scale</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
    <description>Measurement of neurological function in neuro-oncology</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Karnofsky Performance Status</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
    <description>Assessment through a questionnaire of symptom-related restriction of activity, self-sufficiency and self-determination</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Electrocardiogram (ECG) findings. In particular, data about QT/QTc intervals will be collected and analysed for QT/QTc prolongation potentially caused by treatment.</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Echocardiogram (ECHO) findings. In particular, data about QT/QTc intervals will be collected and analysed for QT/QTc prolongation potentially caused by treatment.</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19TNF.</measure>
    <time_frame>Cycle 1 day 1 - First Follow Up visit (up to approximately 9 months)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression-free survival (PFS), according to iRANO (immunotherapy response assessment in neuro-oncology) criteria based on standardized MRI protocol</measure>
    <time_frame>At 6 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 12 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS).</measure>
    <time_frame>From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR, consisting of Complete and partial Response), based on iRANO criteria.</measure>
    <time_frame>At 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Glioma of Brain</condition>
  <arm_group>
    <arm_group_label>L19TNF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be assigned to the following increasing dose levels of L19TNF: 10 and 13 μg/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>L19TNF</intervention_name>
    <description>Patients will be assigned to the following increasing dose levels of L19TNF: 10 and 13 μg/kg.</description>
    <arm_group_label>L19TNF</arm_group_label>
    <other_name>onfekafusp alpha</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female, age 18 or more&#xD;
&#xD;
          2. Patients with histologically confirmed IDH-wildtype WHO grade III / IV glioma at first&#xD;
             relapse&#xD;
&#xD;
          3. Radiographic demonstration of disease progression&#xD;
&#xD;
          4. Presence of at least one lesion of bi-dimensionally measurable disease by MRI of at&#xD;
             least 1 cm (10 mm) in the longest diameter on baseline MRI.&#xD;
&#xD;
          5. Karnofsky Performance Score (KPS) ≥ 70%&#xD;
&#xD;
          6. Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of&#xD;
             HBsAg, anti-HBsAg-Ab and anti-HBcAg-Ab is required. In patients with serology&#xD;
             documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination&#xD;
             and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV&#xD;
             antibody test. Subjects with a positive test for HCV antibody but no detection of&#xD;
             HCV-RNA indicating no current infection are eligible.&#xD;
&#xD;
          7. Female patients: negative pregnancy test for women of childbearing potential (WOCBP)*&#xD;
             within 14 days of starting treatment. WOCBP must agree to use, from the screening to&#xD;
             six months following the last study drug administration, highly effective&#xD;
             contraception methods, as defined by the &quot;Recommendations for contraception and&#xD;
             pregnancy testing in clinical trials&quot; issued by the Head of Medicine Agencies'&#xD;
             Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for&#xD;
             instance, progesteron-only or combined (estrogen- and progesteron-containing) hormonal&#xD;
             contraception associated with inhibition of ovulation, intrauterine devices,&#xD;
             intrauterine hormone-releasing systems, bilateral tubal occlusion or vasectomized&#xD;
             partner.&#xD;
&#xD;
             Male patients: Male subjects able to father children must agree to use two acceptable&#xD;
             methods of contraception throughout the study (e.g. condom with spermicidal gel).&#xD;
             Double-barrier contraception is required.&#xD;
&#xD;
          8. Negative TB test (e.g. Mantoux or Quantiferon assay).&#xD;
&#xD;
          9. Evidence of a personally signed and dated informed consent document indicating that&#xD;
             the subject has been informed of all pertinent aspects of the study.&#xD;
&#xD;
         10. Willingness and ability to comply with the scheduled visits, treatment plan,&#xD;
             laboratory tests and other study procedures *Women of childbearing potential are&#xD;
             defined as females who have experienced menarche, are not postmenopausal (12 months&#xD;
             with no menses without an alternative medical cause) and are not permanently&#xD;
             sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral&#xD;
             salpingectomy)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Second or later glioma progression.&#xD;
&#xD;
          2. Surgical resection or biopsy of glioma within 4 weeks of the start of study treatment.&#xD;
&#xD;
          3. Subjects who participated in an investigational drug or device study within 4 weeks&#xD;
             prior to study treatment start.&#xD;
&#xD;
          4. Treatment with tumor-treating fields&#xD;
&#xD;
          5. Radiotherapy within 6 weeks prior to study treatment start.&#xD;
&#xD;
          6. Patients unable to undergo contrast-enhanced MRI.&#xD;
&#xD;
          7. Patient taking herbal medications within 7 days prior to first dose of the study drug.&#xD;
&#xD;
          8. Known history of allergy to TNF, excipient in study medication or any other&#xD;
             intravenously administered human proteins/peptides/antibodies.&#xD;
&#xD;
          9. Absolute neutrophil count (ANC) &lt; 1.5 x 10^9/L, platelets &lt; 100 x 10^9/L or&#xD;
             haemoglobin (Hb) &lt; 9.0 g/dl.&#xD;
&#xD;
         10. Chronically impaired renal function as indicated by creatinine clearance &lt; 60 mL/min.&#xD;
&#xD;
         11. Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN)&#xD;
&#xD;
         12. Any severe concomitant condition which makes it undesirable for the patient to&#xD;
             participate in the study or which could jeopardize compliance with the protocol, in&#xD;
             the opinion of the investigator.&#xD;
&#xD;
         13. History within the last year of cerebrovascular disease and/or acute or subacute&#xD;
             coronary syndromes including myocardial infarction, unstable or severe stable angina&#xD;
             pectoris.&#xD;
&#xD;
         14. Heart insufficiency (&gt; Grade II, New York Heart Association (NYHA) criteria).&#xD;
&#xD;
         15. Clinically significant cardiac arrhythmias or requiring permanent medication.&#xD;
&#xD;
         16. Abnormal LVEF or any other abnormalities observed during baseline ECG and&#xD;
             echocardiogram investigations that are considered as clinically significant by the&#xD;
             investigator.&#xD;
&#xD;
         17. Uncontrolled hypertension.&#xD;
&#xD;
         18. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine&#xD;
             classification).&#xD;
&#xD;
         19. Medically documented history of or active major depressive episode, bipolar disorder&#xD;
             (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt&#xD;
             or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or&#xD;
             patients with active severe personality disorders.&#xD;
&#xD;
         20. Anxiety ≥ CTCAE grade 3&#xD;
&#xD;
         21. Severe diabetic retinopathy such as severe non-proliferative retinopathy and&#xD;
             proliferative retinopathy.&#xD;
&#xD;
         22. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery)&#xD;
             within 4 weeks of administration of study treatment.&#xD;
&#xD;
         23. Pregnancy or breast-feeding.&#xD;
&#xD;
         24. Requirement of chronic administration of high dose corticosteroids or other&#xD;
             immunosuppressant drugs. Subjects must have been either off corticosteroids, or on a&#xD;
             stable or decreasing dose ≤ 10 mg daily prednisone (or equivalent) for at least 2&#xD;
             weeks prior to study treatment start. Limited or occasional use of corticosteroids to&#xD;
             treat or prevent acute adverse reactions is not considered an exclusion criterion.&#xD;
&#xD;
         25. Presence of active and uncontrolled infections or other severe concurrent disease,&#xD;
             which, in the opinion of the investigator, would place the patient at undue risk or&#xD;
             interfere with the study.&#xD;
&#xD;
         26. Concurrent malignancies, unless the patient has been disease-free for at least 2&#xD;
             years.&#xD;
&#xD;
         27. Growth factors or immunomodulatory agents within 7 days prior to the administration of&#xD;
             study treatment.&#xD;
&#xD;
         28. Serious, non-healing wound, ulcer or bone fracture.&#xD;
&#xD;
         29. Requirement of concurrent therapy with anticoagulants at therapeutic doses.&#xD;
&#xD;
         30. Requirement of concurrent use of other anti-cancer treatments or agents other than&#xD;
             study medication.&#xD;
&#xD;
         31. Any recent live vaccination within 4 weeks prior to treatment or plan to receive&#xD;
             vaccination during the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tobias Weiss, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsspital Zürich</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Inselspital Bern</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHUV Départment d'Oncologie</name>
      <address>
        <city>Lausanne</city>
        <zip>CH-1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitatspital Zurich - Klinik fur Neurologie &amp; Hirntumorzentrum</name>
      <address>
        <city>Zürich</city>
        <zip>CH-8091</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>June 27, 2023</last_update_submitted>
  <last_update_submitted_qc>June 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 29, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03779230
org study id: PH-L19TNFGLIO-02/18
nct id: NCT03779230
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Open label, non-randomized, mono-center Phase I/II study in subjects with IDH-wildtype WHO
      grade III / IV glioma at first relapse.
The purpose of this study is to explore the safety and efficacy profile of the
      antibody-cytokine fusion protein L19TNF in patients with isocitrate dehydrogenase (IDH)
      wildtype WHO grade III / IV glioma at first relapse

      Phase I:

      The primary objective of this phase is to evaluate the safety of L19TNF in patients with
      IDH-wildtype WHO grade III / IV glioma at first relapse and to establish and confirm the
      recommended dose (RD) for phase II.

      Phase II:

      The primary objective of this phase is to evaluate antitumor activity of L19TNF in patients
      with IDH-wildtype WHO grade III / IV glioma at first relapse.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open label, non-randomized, mono-center Phase I/II study in subjects with IDH-wildtype WHO grade III / IV glioma at first relapse.
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of Dose Limiting Toxicity (DLT)
time frame: From the first day of treatment until the end of the DLT window (up to 21 days)
measure: Adverse event (AE), Serious Adverse Events (SAE) and Drug Induced Liver Injury (DILI) assessment based on CTCAE v.5.0
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
measure: Standard laboratory (haematology, biochemistry, liver and urine analysis) parameters
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
measure: Neurological assessment using the Neurologic assessment in Neuro-Oncology (NANO) scale
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
description: Measurement of neurological function in neuro-oncology
measure: Karnofsky Performance Status
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
description: Assessment through a questionnaire of symptom-related restriction of activity, self-sufficiency and self-determination
measure: Electrocardiogram (ECG) findings. In particular, data about QT/QTc intervals will be collected and analysed for QT/QTc prolongation potentially caused by treatment.
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
measure: Echocardiogram (ECHO) findings. In particular, data about QT/QTc intervals will be collected and analysed for QT/QTc prolongation potentially caused by treatment.
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
measure: Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19TNF.
time frame: Cycle 1 day 1 - First Follow Up visit (up to approximately 9 months)
measure: Progression-free survival (PFS), according to iRANO (immunotherapy response assessment in neuro-oncology) criteria based on standardized MRI protocol
time frame: At 6 months
measure: Progression free survival (PFS)
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 12 months)
measure: Overall survival (OS).
time frame: From the inclusion in the study (signature of the informed consent form - ICF) until the end of follow-up (up to approximately 36 months)
measure: Overall Response Rate (ORR, consisting of Complete and partial Response), based on iRANO criteria.
time frame: At 12 weeks, 18 weeks, 24 weeks, 36 weeks, 48 weeks
arm group label: L19TNF
arm group type: Experimental
description: Patients will be assigned to the following increasing dose levels of L19TNF: 10 and 13 μg/kg.
intervention type: Drug
intervention name: L19TNF
description: Patients will be assigned to the following increasing dose levels of L19TNF: 10 and 13 μg/kg.
arm group label: L19TNF
other name: onfekafusp alpha
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Tobias Weiss, MD
role: Principal Investigator
affiliation: Universitätsspital Zürich
facility: 
facility: 
facility: 
country: Switzerland
responsible party type: Sponsor
mesh term: Glioma
sharing ipd: No