xml: <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/NCT05968768</url>
    </required_header>
    <id_info>
      <org_study_id>Butterfly</org_study_id>
      <nct_id>NCT05968768</nct_id>
    </id_info>
    <brief_title>To Evaluate the Efficacy and Safety of Naxitamab in Patients With Refractory Ewing's Sarcoma (Butterfly)</brief_title>
    <official_title>To Evaluate the Efficacy and Safety of Naxitamab in Patients With Refractory Ewing's Sarcoma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Anna Raciborska</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Wroclaw Medical University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Institute of Mother and Child, Warsaw, Poland</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>
        Prospective, interventional, open, randomized, national, multicenter, non-commercial trial&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The study includes:&#xD;
  &#xD;
          1. Biology screening: to estimate expression on GD2 on Ewing sarcoma cells from tumor&#xD;
             tissue from archival material. Availability of tumor tissue is required for&#xD;
             pre-screening testing to determine GD2 expression. To be screened for potential&#xD;
             enrollment into the study patients or their legal representatives must have signed the&#xD;
             pre-screening informed consent form (ICF) to consent to using their archival tumor&#xD;
             sample to test the expression of GD2 in their tumor. The expression level of GD2 will be&#xD;
             characterized in tumor tissue by immunohistochemistry (IHC) at a local and a central&#xD;
             diagnostic testing laboratory.&#xD;
  &#xD;
          2. Standard stratifying diagnostic tests (laboratory assessment: morphology, blood&#xD;
             chemistry including ALT, AST, eGFR, creatinine, sodium, potassium, coagulation, urine&#xD;
             analysis including pH, blood, protein, leukocytes, glucose, urobilinogen, bilirubin,&#xD;
             ketones, nitrites, specific gravity, vital signs (body temperature, systolic and&#xD;
             diastolic blood pressure, and pulse rate), ECG, cardiac function test, imaging test:&#xD;
             CT/MRI scan).&#xD;
  &#xD;
          3. Patients with GD2 expression will be randomized in proportions (2:1) to the experimental&#xD;
             (D) and control groups (S). The cohort D will consist of 16 subjects, the cohort S 8&#xD;
             subjects. The exploratory cohort D will receive the experimental regimen in 3-week&#xD;
             cycles consisting of irinotecan given intravenously (iv) 50 mg/m2 after oral&#xD;
             temozolomide 100 mg/m2 on days 1-5 and naxitamab administered iv 2.25 mg/kg/day over 30&#xD;
             - 60 minutes, days 2, 4, 8 and 10 (up to 150 mg/day; total 9 mg/kg per cycle), and&#xD;
             GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Patients randomized to arm S will&#xD;
             receive IT alone. Treatment cycles will be repeated every 21 days summary to 6 cycles or&#xD;
             until disease progression, or subsequent relapsed, or occurrence of intolerable&#xD;
             toxicity, or any event making impossible treatment continuation, or investigator's&#xD;
             judgment, or withdrawal of consent. All activities are presented in Schedule of&#xD;
             Assessments (SoA) at the end of the study synopsis.&#xD;
  &#xD;
          4. Patients will be recalculated according to the intent to treat (ITT) rule.&#xD;
  &#xD;
          5. The study will be conducted in accordance to GCP and after EC approval of the protocol.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 10, 2023</start_date>
    <completion_date type="Anticipated">July 31, 2028</completion_date>
    <primary_completion_date type="Anticipated">May 1, 2027</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Safety assessment of the addition of naxitamab to standard 3-week chemotherapy (CHT) in patients with refractory Ewing's sarcoma (ES)</measure>
      <time_frame>up to 240 days</time_frame>
      <description>Safety will be assessed by number of serious adverse events (SAE), by the number of adverse events (AE), by medical examination with the analysis of recorded vital signs, laboratory abnormalities according to NCI CTCAE v5.0</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Event-Free Survival (EFS )</measure>
      <time_frame>3 years</time_frame>
      <description>Will be measured from randomization to death, disease progression or recurrence, or secondary malignancy, whichever comes first</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression-Free Survival (PFS)</measure>
      <time_frame>1 year</time_frame>
      <description>from randomization to progression of the disease</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall Response Rate (ORR)</measure>
      <time_frame>126 days</time_frame>
      <description>Defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR),</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall Survival (OS)</measure>
      <time_frame>3 years</time_frame>
      <description>Will be measured from randomization to subject's death</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">24</enrollment>
    <condition>Ewing Sarcoma</condition>
    <arm_group>
      <arm_group_label>Experimental - Naxitamab Arm</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Treatment with naxitamab will be continued no longer than 6 cycles a year or until disease progression, patient consent, unacceptable toxicities, or study closure</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control Group - standard treatment</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>The control group - will receive only standard treatment.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Naxitamab</intervention_name>
      <description>Naxitamab will be used only in a hospital setting and must be administered under the supervision of a doctor with experience in the use of oncological therapies. The medicinal product must be administered by a healthcare professional prepared to deal appropriately with severe allergic reactions, including anaphylaxis, in an environment that provides immediate, full access to resuscitation. The patient should have 2 well-functioning IV accesses before any naxitamab treatment is initiated. The solution should be administered through a peripheral or central intravenous catheter. Other concomitant intravenous medicinal products should be administered through separate intravenous access. Before the start of each infusion, premedication will be carried out.</description>
      <arm_group_label>Experimental - Naxitamab Arm</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Histologically proven Ewing sarcoma of the bone or soft tissues.&#xD;
  &#xD;
            2. Subject's archival tumour sample (formalin-fixed, paraffin-embedded; FFPE) available&#xD;
               for evaluation of GD2 expression.&#xD;
  &#xD;
            3. Documented disease progression (during or after completion of at least one line&#xD;
               treatment) or any subsequent recurrence.&#xD;
  &#xD;
            4. GD2 positive tumor assessed by IHC.&#xD;
  &#xD;
            5. Age ≥ 2 years and ≤ 21 years.&#xD;
  &#xD;
            6. Life expectancy of at least 12 weeks from the time informed consent was signed.&#xD;
  &#xD;
            7. Previous systemic anticancer treatment completed ≥ 3 weeks, major surgery ≥ 2 weeks,&#xD;
               and radiation therapy ≥ 4 weeks prior to study enrollment.&#xD;
  &#xD;
            8. Recovered from adverse effects of prior surgery, radiotherapy, or Clinical trial&#xD;
               protocol BUTTERFLY version 1.0 of 30.09.2022 r.anti-neoplastic therapy at the&#xD;
               discretion of the investigator.&#xD;
  &#xD;
            9. Signing of informed consent for trial participation (including for naxitamab&#xD;
               treatment) according with current legal regulations.&#xD;
  &#xD;
           10. Consent to the use of effective contraception throughout the period of the study and a&#xD;
               minimum of 1 year after discontinuation of study treatment in patients at puberty and&#xD;
               sexual maturity&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Failure to meet any of the inclusion criteria.&#xD;
  &#xD;
            2. Not eligible to IT.&#xD;
  &#xD;
            3. Previous treatment with an anti-GD2 antibody.&#xD;
  &#xD;
            4. Hypersensitivity to the study drugs or any of their ingredients (covers IT and&#xD;
               naxitamab).&#xD;
  &#xD;
            5. Simultaneous treatment with other drugs which might interact with naxitamab or IT&#xD;
               regimen.&#xD;
  &#xD;
            6. Persistent toxicity related to prior therapy, making it impossible to treat with&#xD;
               naxitamab.&#xD;
  &#xD;
            7. Significant cardiac conduction abnormalities, including known familial prolonged QT&#xD;
               syndrome, or screening corrected QT interval (QTc) &gt;480 msec.&#xD;
  &#xD;
            8. Symptoms of congestive heart failure or left ventricular ejection fraction &lt;50%.&#xD;
  &#xD;
            9. Inadequate pulmonary function defined as evidence of dyspnea at rest, exercise&#xD;
               intolerance, and/or chronic oxygen requirement. In addition, room air pulse oximetry &lt;&#xD;
               94% and/or abnormal pulmonary function tests if these assessments are clinically&#xD;
               indicated.&#xD;
  &#xD;
           10. Requirement, or likely requirement, for corticosteroids at doses &gt;10 mg prednisolone&#xD;
               (or equivalent) per day or other immunosuppressive agents.&#xD;
  &#xD;
           11. Diagnosis of other malignancies before study inclusion.&#xD;
  &#xD;
           12. Planning to become pregnant (while being treated with IT or naxitamab), pregnancy or&#xD;
               breastfeeding.&#xD;
  &#xD;
           13. Other acute or persistent disorders, behaviors or abnormal laboratory test results,&#xD;
               which might increase the risk related to the participation in this clinical trial or&#xD;
               to taking the study drug, or which might influence the interpretation of the study&#xD;
               results, or which, in the investigator's opinion, disqualify a patient from&#xD;
               participating in the tri&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>2 Years</minimum_age>
      <maximum_age>21 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Mother and Child Institute</name>
        <address>
          <city>Warsaw</city>
          <state>Mazowian</state>
          <zip>01-211</zip>
          <country>Poland</country>
        </address>
      </facility>
      <contact>
        <last_name>Katarzyna Maleszewska</last_name>
        <phone>+48 22 32 77 205</phone>
        <email>klinika.onkologii@imid.med.pl</email>
      </contact>
      <investigator>
        <last_name>Anna Raciborska, Prof</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Poland</country>
    </location_countries>
    <results_reference>
      <citation>Nakajima M, Guo HF, Hoseini SS, Suzuki M, Xu H, Cheung NV. Potent antitumor effect of T cells armed with anti-GD2 bispecific antibody. Pediatr Blood Cancer. 2021 Jul;68(7):e28971. doi: 10.1002/pbc.28971. Epub 2021 Apr 12.</citation>
      <PMID>33844437</PMID>
    </results_reference>
    <results_reference>
      <citation>Chan GC, Chan CM. Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma. Biomolecules. 2022 Feb 24;12(3):358. doi: 10.3390/biom12030358.</citation>
      <PMID>35327550</PMID>
    </results_reference>
    <results_reference>
      <citation>Musumeci F, Cianciusi A, D'Agostino I, Grossi G, Carbone A, Schenone S. Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma. Molecules. 2021 Nov 23;26(23):7069. doi: 10.3390/molecules26237069.</citation>
      <PMID>34885651</PMID>
    </results_reference>
    <results_reference>
      <citation>Wingerter A, El Malki K, Sandhoff R, Seidmann L, Wagner DC, Lehmann N, Vewinger N, Frauenknecht KBM, Sommer CJ, Traub F, Kindler T, Russo A, Otto H, Lollert A, Staatz G, Roth L, Paret C, Faber J. Exploiting Gangliosides for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline Glioma. Cancers (Basel). 2021 Jan 29;13(3):520. doi: 10.3390/cancers13030520.</citation>
      <PMID>33572900</PMID>
    </results_reference>
    <results_reference>
      <citation>Nazha B, Inal C, Owonikoko TK. Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy. Front Oncol. 2020 Jul 7;10:1000. doi: 10.3389/fonc.2020.01000. eCollection 2020.</citation>
      <PMID>32733795</PMID>
    </results_reference>
    <results_reference>
      <citation>Hensel J, Metts J, Gupta A, Ladle BH, Pilon-Thomas S, Mullinax J. Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy. Cancer J. 2022 Jul-Aug 01;28(4):322-327. doi: 10.1097/PPO.0000000000000603.</citation>
      <PMID>35880942</PMID>
    </results_reference>
    <results_reference>
      <citation>Mora J. Autologous Stem-Cell Transplantation for High-Risk Neuroblastoma: Historical and Critical Review. Cancers (Basel). 2022 May 24;14(11):2572. doi: 10.3390/cancers14112572.</citation>
      <PMID>35681553</PMID>
    </results_reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 13, 2023</study_first_submitted>
    <study_first_submitted_qc>July 28, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 1, 2023</study_first_posted>
    <last_update_submitted>July 28, 2023</last_update_submitted>
    <last_update_submitted_qc>July 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 1, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>Institute of Mother and Child, Warsaw, Poland</investigator_affiliation>
      <investigator_full_name>Anna Raciborska</investigator_full_name>
      <investigator_title>Prof Ass</investigator_title>
    </responsible_party>
    <keyword>Ewing Sarcoma</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sarcoma</mesh_term>
      <mesh_term>Sarcoma, Ewing</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05968768
  org study id: Butterfly
  nct id: NCT05968768
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Prospective, interventional, open, randomized, national, multicenter, non-commercial trial
  The study includes:
  
          1. Biology screening: to estimate expression on GD2 on Ewing sarcoma cells from tumor
             tissue from archival material. Availability of tumor tissue is required for
             pre-screening testing to determine GD2 expression. To be screened for potential
             enrollment into the study patients or their legal representatives must have signed the
             pre-screening informed consent form (ICF) to consent to using their archival tumor
             sample to test the expression of GD2 in their tumor. The expression level of GD2 will be
             characterized in tumor tissue by immunohistochemistry (IHC) at a local and a central
             diagnostic testing laboratory.
  
          2. Standard stratifying diagnostic tests (laboratory assessment: morphology, blood
             chemistry including ALT, AST, eGFR, creatinine, sodium, potassium, coagulation, urine
             analysis including pH, blood, protein, leukocytes, glucose, urobilinogen, bilirubin,
             ketones, nitrites, specific gravity, vital signs (body temperature, systolic and
             diastolic blood pressure, and pulse rate), ECG, cardiac function test, imaging test:
             CT/MRI scan).
  
          3. Patients with GD2 expression will be randomized in proportions (2:1) to the experimental
             (D) and control groups (S). The cohort D will consist of 16 subjects, the cohort S 8
             subjects. The exploratory cohort D will receive the experimental regimen in 3-week
             cycles consisting of irinotecan given intravenously (iv) 50 mg/m2 after oral
             temozolomide 100 mg/m2 on days 1-5 and naxitamab administered iv 2.25 mg/kg/day over 30
             - 60 minutes, days 2, 4, 8 and 10 (up to 150 mg/day; total 9 mg/kg per cycle), and
             GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Patients randomized to arm S will
             receive IT alone. Treatment cycles will be repeated every 21 days summary to 6 cycles or
             until disease progression, or subsequent relapsed, or occurrence of intolerable
             toxicity, or any event making impossible treatment continuation, or investigator's
             judgment, or withdrawal of consent. All activities are presented in Schedule of
             Assessments (SoA) at the end of the study synopsis.
  
          4. Patients will be recalculated according to the intent to treat (ITT) rule.
  
          5. The study will be conducted in accordance to GCP and after EC approval of the protocol.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Safety assessment of the addition of naxitamab to standard 3-week chemotherapy (CHT) in patients with refractory Ewing's sarcoma (ES)
  time frame: up to 240 days
  description: Safety will be assessed by number of serious adverse events (SAE), by the number of adverse events (AE), by medical examination with the analysis of recorded vital signs, laboratory abnormalities according to NCI CTCAE v5.0
  measure: Event-Free Survival (EFS )
  time frame: 3 years
  description: Will be measured from randomization to death, disease progression or recurrence, or secondary malignancy, whichever comes first
  measure: Progression-Free Survival (PFS)
  time frame: 1 year
  description: from randomization to progression of the disease
  measure: Overall Response Rate (ORR)
  time frame: 126 days
  description: Defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR),
  measure: Overall Survival (OS)
  time frame: 3 years
  description: Will be measured from randomization to subject's death
  arm group label: Experimental - Naxitamab Arm
  arm group type: Experimental
  description: Treatment with naxitamab will be continued no longer than 6 cycles a year or until disease progression, patient consent, unacceptable toxicities, or study closure
  arm group label: Control Group - standard treatment
  arm group type: No Intervention
  description: The control group - will receive only standard treatment.
  intervention type: Drug
  intervention name: Naxitamab
  description: Naxitamab will be used only in a hospital setting and must be administered under the supervision of a doctor with experience in the use of oncological therapies. The medicinal product must be administered by a healthcare professional prepared to deal appropriately with severe allergic reactions, including anaphylaxis, in an environment that provides immediate, full access to resuscitation. The patient should have 2 well-functioning IV accesses before any naxitamab treatment is initiated. The solution should be administered through a peripheral or central intravenous catheter. Other concomitant intravenous medicinal products should be administered through separate intravenous access. Before the start of each infusion, premedication will be carried out.
  arm group label: Experimental - Naxitamab Arm
  criteria: 
  gender: All
  minimum age: 2 Years
  maximum age: 21 Years
  healthy volunteers: No
  facility: 
  contact: 
  investigator: 
  country: Poland
  citation: Nakajima M, Guo HF, Hoseini SS, Suzuki M, Xu H, Cheung NV. Potent antitumor effect of T cells armed with anti-GD2 bispecific antibody. Pediatr Blood Cancer. 2021 Jul;68(7):e28971. doi: 10.1002/pbc.28971. Epub 2021 Apr 12.
  PMID: 33844437
  citation: Chan GC, Chan CM. Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma. Biomolecules. 2022 Feb 24;12(3):358. doi: 10.3390/biom12030358.
  PMID: 35327550
  citation: Musumeci F, Cianciusi A, D'Agostino I, Grossi G, Carbone A, Schenone S. Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma. Molecules. 2021 Nov 23;26(23):7069. doi: 10.3390/molecules26237069.
  PMID: 34885651
  citation: Wingerter A, El Malki K, Sandhoff R, Seidmann L, Wagner DC, Lehmann N, Vewinger N, Frauenknecht KBM, Sommer CJ, Traub F, Kindler T, Russo A, Otto H, Lollert A, Staatz G, Roth L, Paret C, Faber J. Exploiting Gangliosides for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline Glioma. Cancers (Basel). 2021 Jan 29;13(3):520. doi: 10.3390/cancers13030520.
  PMID: 33572900
  citation: Nazha B, Inal C, Owonikoko TK. Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy. Front Oncol. 2020 Jul 7;10:1000. doi: 10.3389/fonc.2020.01000. eCollection 2020.
  PMID: 32733795
  citation: Hensel J, Metts J, Gupta A, Ladle BH, Pilon-Thomas S, Mullinax J. Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy. Cancer J. 2022 Jul-Aug 01;28(4):322-327. doi: 10.1097/PPO.0000000000000603.
  PMID: 35880942
  citation: Mora J. Autologous Stem-Cell Transplantation for High-Risk Neuroblastoma: Historical and Critical Review. Cancers (Basel). 2022 May 24;14(11):2572. doi: 10.3390/cancers14112572.
  PMID: 35681553
  responsible party type: Sponsor-Investigator
  investigator affiliation: Institute of Mother and Child, Warsaw, Poland
  investigator full name: Anna Raciborska
  investigator title: Prof Ass
  mesh term: Sarcoma
  mesh term: Sarcoma, Ewing