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/NCT06037018</url>
    </required_header>
    <id_info>
      <org_study_id>CC312-001(C)</org_study_id>
      <nct_id>NCT06037018</nct_id>
    </id_info>
    <brief_title>Safety Study of CC312 in Adult Patients With Relapsed/Refractory CD19 Positive B-cell Hematologic Malignancies</brief_title>
    <official_title>A Phase 1 Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Efficacy of CC312 in Adult Patients With Relapsed/Refractory CD19 Positive B-cell Hematologic Malignancies</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>CytoCares Inc</agency>
        <agency_class>Industry</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>CytoCares Inc</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>
        This is a Phase 1, open-label, dose-escalation study to evaluate the safety, PK, PD and&#xD;
        immunogenicity of CC312 following intravenous doses of CC312 in patients with relapsed and&#xD;
        refractory (r/r) CD19 expressing B-cell non-Hodgkin lymphoma and B-cell lymphocytic leukemia.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This study is an accelerated dose titration design divided into 2 parts.&#xD;
  &#xD;
        Part 1 of the study is an accelerated dose-escalation design involving 5 dose levels: 0.3,&#xD;
        0.6, 1.2, 2.4 and 4.8 mcg given intravenously (IV) with cohorts of one patient per dose&#xD;
        level. Patients in this part will receive 1 priming dose (D-7) and 1 intermediate dose of&#xD;
        CC312 (D-3) on the first week, followed by twice weekly dosing of escalated dose for three&#xD;
        weeks beginning on the second week. The dose limiting toxicity (DLT) observation period will&#xD;
        be 28 days. The optimal priming dose and intermediate dose level will be determined in this&#xD;
        part.&#xD;
  &#xD;
        Part 2-A will follow a standard 3 + 3 dose escalation design using five dose levels: 9.6, 16,&#xD;
        24, 34 and 45 μg to obtain data on the safety and tolerability of CC312. Patients in this&#xD;
        part will receive priming dose and intermediate dose of CC312 established in Part 1 before&#xD;
        given the treatment dose. MTD or RP2D will be determined in Part 2-A and tested in expanded&#xD;
        population(Part 2-B).&#xD;
  &#xD;
        Part 2-B is planned for cohorts of 6-10 patients with B-cell non-Hodgkin lymphoma or B-cell&#xD;
        lymphocytic leukemia receiving priming/ treatment dose levels as defined in the Part 1 and&#xD;
        Part 2-A study.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 7, 2023</start_date>
    <completion_date type="Anticipated">March 2026</completion_date>
    <primary_completion_date type="Anticipated">March 2025</primary_completion_date>
    <phase>Phase 1</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>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Dose limiting toxicities (DLTs)</measure>
      <time_frame>From the first infusion of CC312 till the end of the 28 days DLT（Dose Limiting Toxicity）observation period.</time_frame>
      <description>Toxicity will be evaluated according to the NCI CTCAE, Version 5.0, except CRS which will be graded according to ASTCT Consensus Grading for CRS.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Incidence and severity of adverse event (AE)</measure>
      <time_frame>From the first infusion of CC312 until 28 days following the end of treatment.</time_frame>
      <description>Overall numbers of participants with any AE, including any laboratory abnormality, treatment-emergent adverse event (TEAE), and serious adverse events (SAE). Severity (toxicity grade) for each AE will be determined using the NCI CTCAE, version 5.0; except cytokine release syndrom (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which will be graded according to ASTCT Consensus Grading.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Pharmacokinetics (PK): serum concentration</measure>
      <time_frame>Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose and multiple-timepoints-post-dose; Cycle 2 and subsequent cycle: 1 hour-pre-dose; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.</time_frame>
      <description>Blood samples will be collected to analysis serum concentration of CC312. Derived PK parameters will be calculated using the non-compartmental model.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacodynamics (PD): cytokine analysis</measure>
      <time_frame>Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose and multiple-timepoints-post-dose; Cycle 2 and subsequent cycle: 1 hour-pre-dose; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.</time_frame>
      <description>Peripheral blood will be collected for CRS-related cytokine analysis in all dose escalation cohorts.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Pharmacodynamics (PD): immunophenotyping</measure>
      <time_frame>Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose and multiple-timepoints-post-dose; Cycle 2 and subsequent cycle: 1 hour-pre-dose; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.</time_frame>
      <description>Peripheral blood will be collected for immunophenotyping (including the activation of CD4+ and CD8+ T cells, and depletion of B cells) in all dose escalation cohorts.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Immunogenicity: anti-CC312 antibody</measure>
      <time_frame>Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose on Day-7/Day 8. Cycle 2 and subsequent cycle: within 1 hour before infusion on Day 1/Day 15; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.</time_frame>
      <description>The proportions of participants with positive anti-drug antibody (ADA) status and those with positive neutralizing anti-drug antibody (NAb) status will be presented by descriptive statistics.</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Tumor response to CC312</measure>
      <time_frame>From the first infusion of CC312 until 28 days following the end of treatment.</time_frame>
      <description>B-NHL, B-ALL and CLL will be evaluated by Lugano criteria, NCCN Guidelines 2021, and iwCLL guidelines 2008, respectively. Therapeutic endpoints includes: overall response rate [ORR] (including complete remission [CR] and partial remission [PR]), duration of overall response [DOR], disease control rate [DCR], and relapse-free survival [RFS] in participants.</description>
    </other_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">44</enrollment>
    <condition>Non-hodgkin Lymphoma</condition>
    <condition>Acute Lymphoblastic Leukaemia</condition>
    <condition>Chronic Lymphocytic Leukemia</condition>
    <arm_group>
      <arm_group_label>CC312</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>CC312</intervention_name>
      <description>Doses from 0.3 to 45 µg/dose by intravenous infusion</description>
      <arm_group_label>CC312</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. CD19 positive B-cell malignancies confirmed as one of the following: aggressive or&#xD;
               indolent B-cell NHL, philadelphia chromosome-positive or -negative B-cell ALL, or&#xD;
               B-cell CLL; patient must meet the definition of relapse/refractory before enrollment.&#xD;
  &#xD;
            2. ECOG (Eastern Cooperative Oncology Group) performance status 0-2, life expectancy &gt;3&#xD;
               months；&#xD;
  &#xD;
            3. Clinical laboratory values as specified below during the Screening period.&#xD;
  &#xD;
                 -  Total bilirubin &lt;1.5 ULN, may be elevated up to 3 x ULN if the elevation can be&#xD;
                    reasonably ascribed to the presence of metastatic disease in the liver or in&#xD;
                    patients with documented Gilbert's Syndrome;&#xD;
  &#xD;
                 -  ALT or AST &lt;3ULN, may be elevated up to 5 x ULN if the elevation can be&#xD;
                    reasonably ascribed to the presence of metastatic disease in liver;&#xD;
  &#xD;
                 -  Calculated creatinine clearance &gt; 50 mL/min (The Cockcroft-Gault formula);&#xD;
  &#xD;
                 -  Hemoglobin ≥ 7 g/dL;&#xD;
  &#xD;
                 -  Neutrophil count &gt; 1,000/mm3 for B-cell NHL patient;&#xD;
  &#xD;
                 -  Platelet count &gt; 75,000/mm3 for B-cell NHL patient;&#xD;
  &#xD;
                 -  B-ALL patients must have peripheral blast count ≤ 30,000/ mm3 prior to first dose&#xD;
                    of CC312.&#xD;
  &#xD;
                 -  Prothrombin time-international normalized ratio (PT-INR) ≤ 1.5ULN.&#xD;
  &#xD;
            4. Female patients of childbearing potential or male patients with a partner of&#xD;
               childbearing potential must use one or more contraception methods from screening and&#xD;
               continued during study treatment until 3 months after the last dose;&#xD;
  &#xD;
            5. Ability to understand and willingness to provide written informed consent and to&#xD;
               comply with scheduled visits and study procedures.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Systemic anticancer therapy within 5 half-lives of the agent or attending clinical&#xD;
               trials 4 weeks prior to beginning CC312;&#xD;
  &#xD;
            2. Treatment with radiotherapy within 2 weeks before the study entry;&#xD;
  &#xD;
            3. Treatment with CAR-T within 3 months before the study entry;&#xD;
  &#xD;
            4. Active serious infection requiring antibiotics within 14 days before study entry;&#xD;
  &#xD;
            5. Patients with prior treatment with anti-CD19 directed therapies are eligible only if&#xD;
               their tumor cells have been shown to express CD19 after completing the CD19-directed&#xD;
               therapy;&#xD;
  &#xD;
            6. Patients with brain metastases or other significant neurological conditions, except&#xD;
               for brain metastases which are asymptomatic and radiologically stable without need for&#xD;
               steroids for 2 weeks before the first dose of CC312;&#xD;
  &#xD;
            7. Treatment with corticosteroids (&gt;10mg daily prednisone or equivalent) or&#xD;
               immunosuppressive medication ≤ 7 days before the first dose of CC312, with the&#xD;
               following exceptions:&#xD;
  &#xD;
                 -  Topical, ocular, intra-articular, intranasal, or inhalational corticosteroids;&#xD;
  &#xD;
                 -  Use of dexamethasone to reduce peripheral blast counts in ALL;&#xD;
  &#xD;
            8. Vaccination with a live virus vaccine within 4 weeks prior to the study enrollment;&#xD;
  &#xD;
            9. Current autoimmune disease or history of autoimmune disease with potential CNS&#xD;
               involvement;&#xD;
  &#xD;
           10. Known to be allergic to protein drugs or recombinant proteins or excipients in the&#xD;
               CC312 drug formulation. Patients who experienced Grade 3 reactions that lasted &lt; 24h&#xD;
               may be eligible after discussion with investigator；&#xD;
  &#xD;
           11. Except for the tolerable events determined by the investigator, any toxic effects of&#xD;
               the prior therapy which have not resolved to Grade 1 (CTCAE v5.0);&#xD;
  &#xD;
           12. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse;&#xD;
  &#xD;
           13. Cerebrovascular accident (CVA), Transient ischemic attack (TIA), myocardial infarction&#xD;
               (MI), unstable angina, or New York Heart Association (NYHA) class III or IV heart&#xD;
               failure occurring within &lt;6 months of study entry; uncontrolled arrhythmia within &lt; 3&#xD;
               months of study entry. Patients with rate-controlled arrhythmias may be eligible for&#xD;
               study entry at discretion of the Investigator.;&#xD;
  &#xD;
           14. Major surgery &lt; 4 weeks or minor surgery &lt; 2 weeks prior to screening; wound must be&#xD;
               fully healed (minor surgical procedures such as catheter placement are not&#xD;
               exclusionary criteria);&#xD;
  &#xD;
           15. Existence of congenital long QT syndrome, QTcF &gt; 450 msec (for male) or 470 msec (for&#xD;
               female), use of cardiac pacemaker, left ventricular ejection fraction (LVEF) &lt;50%,&#xD;
               clinically significant arrhythmia that requires intervention, cardiac troponin I or T&#xD;
               &gt; 2.0 ULN, poorly controlled diabetes (HbA1c &gt; 9%), hypertension (systolic pressure &gt;&#xD;
               160 mmHg or diastolic pressure &gt; 100mmHg), or other medical conditions as determined&#xD;
               by the Investigator. Patients with stable atrial fibrillation or flutter are eligible&#xD;
               for study entry at the discretion of the Investigator;&#xD;
  &#xD;
           16. Any other serious underlying medical (e.g. active gastric ulcer, uncontrolled&#xD;
               seizures, cerebrovascular incidents, gastrointestinal bleeding, severe signs and&#xD;
               symptoms of coagulation and clotting disorders, cardiac conditions), psychiatric,&#xD;
               psychological, familial or geographical condition that, in the judgment of the&#xD;
               Investigator, may interfere with the planned staging, treatment and follow-up, affect&#xD;
               patient compliance or place the patient at high risk for treatmentrelated&#xD;
               complications;&#xD;
  &#xD;
           17. Concurrent malignancy &lt; 5 years prior to entry other than adequately treated cervical&#xD;
               carcinoma-in-situ, localized squamous cell cancer of the skin, basal cell carcinoma,&#xD;
               localized prostate cancer, ductal carcinoma in situ of the breast, or &lt; T1 urothelial&#xD;
               carcinoma. Patients with prostate cancer that is under active surveillance are&#xD;
               eligible.;&#xD;
  &#xD;
           18. Pregnant or nursing women.;&#xD;
  &#xD;
           19. Active hepatitis B：HBsAg positive and HBV-DNA&gt;ULN; Active hepatitis C：HCV-Ab positive&#xD;
               and HCV-RNA&gt;ULN；&#xD;
  &#xD;
           20. Known HIV infection；&#xD;
  &#xD;
           21. B-NHL patient that received autologous stem cell transplant 6 months prior to study&#xD;
               screening, or historically received organ or allogeneic stem cell/bone marrow&#xD;
               transplant;&#xD;
  &#xD;
           22. B-ALL patients that received transplantation treatment within 3 months prior to&#xD;
               enrollment in the study.;&#xD;
  &#xD;
           23. Subjects who in the judgement of the Investigator are not suited to participate in&#xD;
               this trial.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>JUNYUAN QI, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Institute of Hematology &amp; Blood Diseases Hospital, China</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>ZHEN JING, MM</last_name>
      <phone>86-21-50582090</phone>
      <email>zhen.jing@cytocares.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>InstituteHBDH</name>
        <address>
          <city>Tianjin</city>
          <state>Tianjin</state>
          <zip>300020</zip>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>ZHEN JING, MM</last_name>
        <phone>86-21-50582090</phone>
        <email>jing.zhen@cytocares.com</email>
      </contact>
      <investigator>
        <last_name>JUNYUAN QI, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 28, 2023</study_first_submitted>
    <study_first_submitted_qc>September 12, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 14, 2023</study_first_posted>
    <last_update_submitted>September 12, 2023</last_update_submitted>
    <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 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>Leukemia</mesh_term>
      <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
      <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
      <mesh_term>Hematologic Neoplasms</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/NCT06037018
  org study id: CC312-001(C)
  nct id: NCT06037018
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  This is a Phase 1, open-label, dose-escalation study to evaluate the safety, PK, PD and
        immunogenicity of CC312 following intravenous doses of CC312 in patients with relapsed and
        refractory (r/r) CD19 expressing B-cell non-Hodgkin lymphoma and B-cell lymphocytic leukemia.
  This study is an accelerated dose titration design divided into 2 parts.
  
        Part 1 of the study is an accelerated dose-escalation design involving 5 dose levels: 0.3,
        0.6, 1.2, 2.4 and 4.8 mcg given intravenously (IV) with cohorts of one patient per dose
        level. Patients in this part will receive 1 priming dose (D-7) and 1 intermediate dose of
        CC312 (D-3) on the first week, followed by twice weekly dosing of escalated dose for three
        weeks beginning on the second week. The dose limiting toxicity (DLT) observation period will
        be 28 days. The optimal priming dose and intermediate dose level will be determined in this
        part.
  
        Part 2-A will follow a standard 3 + 3 dose escalation design using five dose levels: 9.6, 16,
        24, 34 and 45 μg to obtain data on the safety and tolerability of CC312. Patients in this
        part will receive priming dose and intermediate dose of CC312 established in Part 1 before
        given the treatment dose. MTD or RP2D will be determined in Part 2-A and tested in expanded
        population(Part 2-B).
  
        Part 2-B is planned for cohorts of 6-10 patients with B-cell non-Hodgkin lymphoma or B-cell
        lymphocytic leukemia receiving priming/ treatment dose levels as defined in the Part 1 and
        Part 2-A study.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Dose limiting toxicities (DLTs)
  time frame: From the first infusion of CC312 till the end of the 28 days DLT（Dose Limiting Toxicity）observation period.
  description: Toxicity will be evaluated according to the NCI CTCAE, Version 5.0, except CRS which will be graded according to ASTCT Consensus Grading for CRS.
  measure: Incidence and severity of adverse event (AE)
  time frame: From the first infusion of CC312 until 28 days following the end of treatment.
  description: Overall numbers of participants with any AE, including any laboratory abnormality, treatment-emergent adverse event (TEAE), and serious adverse events (SAE). Severity (toxicity grade) for each AE will be determined using the NCI CTCAE, version 5.0; except cytokine release syndrom (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which will be graded according to ASTCT Consensus Grading.
  measure: Pharmacokinetics (PK): serum concentration
  time frame: Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose and multiple-timepoints-post-dose; Cycle 2 and subsequent cycle: 1 hour-pre-dose; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.
  description: Blood samples will be collected to analysis serum concentration of CC312. Derived PK parameters will be calculated using the non-compartmental model.
  measure: Pharmacodynamics (PD): cytokine analysis
  time frame: Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose and multiple-timepoints-post-dose; Cycle 2 and subsequent cycle: 1 hour-pre-dose; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.
  description: Peripheral blood will be collected for CRS-related cytokine analysis in all dose escalation cohorts.
  measure: Pharmacodynamics (PD): immunophenotyping
  time frame: Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose and multiple-timepoints-post-dose; Cycle 2 and subsequent cycle: 1 hour-pre-dose; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.
  description: Peripheral blood will be collected for immunophenotyping (including the activation of CD4+ and CD8+ T cells, and depletion of B cells) in all dose escalation cohorts.
  measure: Immunogenicity: anti-CC312 antibody
  time frame: Cycle 1: baseline (Day -10~Day -8); 1 hour-pre-dose on Day-7/Day 8. Cycle 2 and subsequent cycle: within 1 hour before infusion on Day 1/Day 15; after the end of treatment (EOT)/withdraw/at the end of study (EOS). Length of each cycle: 28 days.
  description: The proportions of participants with positive anti-drug antibody (ADA) status and those with positive neutralizing anti-drug antibody (NAb) status will be presented by descriptive statistics.
  measure: Tumor response to CC312
  time frame: From the first infusion of CC312 until 28 days following the end of treatment.
  description: B-NHL, B-ALL and CLL will be evaluated by Lugano criteria, NCCN Guidelines 2021, and iwCLL guidelines 2008, respectively. Therapeutic endpoints includes: overall response rate [ORR] (including complete remission [CR] and partial remission [PR]), duration of overall response [DOR], disease control rate [DCR], and relapse-free survival [RFS] in participants.
  arm group label: CC312
  arm group type: Experimental
  intervention type: Biological
  intervention name: CC312
  description: Doses from 0.3 to 45 µg/dose by intravenous infusion
  arm group label: CC312
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: JUNYUAN QI, MD
  role: Principal Investigator
  affiliation: Institute of Hematology & Blood Diseases Hospital, China
  last name: ZHEN JING, MM
  phone: 86-21-50582090
  email: zhen.jing@cytocares.com
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  country: China
  responsible party type: Sponsor
  mesh term: Leukemia
  mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
  mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
  mesh term: Hematologic Neoplasms