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/NCT05985109</url>
    </required_header>
    <id_info>
      <org_study_id>CGOG-KREC-01</org_study_id>
      <nct_id>NCT05985109</nct_id>
    </id_info>
    <brief_title>KN 046 Plus Regorafenib in MSS Metastatic Colorectal Cancer</brief_title>
    <official_title>A Phase II Multi-cohort Clinical Study Evaluating The Efficacy and Safety of KN046 in Combination With Regorafenib for Metastatic Microsatellite-Stable Colorectal Cancer: a Phase II Multi-cohort Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Peking University Cancer Hospital &amp; Institute</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Peking University Cancer Hospital &amp; Institute</source>
    <oversight_info>
      <has_dmc>Yes</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>
        The study is an interventional Phase II clinical trial aiming to optimize immunotherapy&#xD;
        strategies for microsatellite-stable colorectal cancer. We will include three types of&#xD;
        metastatic colorectal cancer patients: those without liver metastasis, or carrying BRAF V600E&#xD;
        mutation, or unable to tolerate chemotherapy as their initial or second-line treatment. The&#xD;
        participants will receive a combination treatment of regorafenib and KN046 which is a&#xD;
        PD-L1/CTLA-4 bispecific antibody. Treatment efficacy and safety profile would be evaluated in&#xD;
        this study.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 15, 2023</start_date>
    <completion_date type="Anticipated">December 31, 2026</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2026</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Overall response rate</measure>
      <time_frame>Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose</time_frame>
      <description>Objective response rate (defined as CR+PR) will be reported based on investigator's evaluation.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Disease control rate</measure>
      <time_frame>Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose</time_frame>
      <description>Disease control rate (defined as CR+PR+SD) will be reported based on investigator's evaluation.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression free survival</measure>
      <time_frame>Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose</time_frame>
      <description>Progression-free survival (PFS) is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic progressive disease (PD) or death due to any cause.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration of response</measure>
      <time_frame>Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose</time_frame>
      <description>Duration of response (DOR) is defined as the time from the date of the first response to the first objective documentation of radiographic progressive disease (PD) or death due to any cause.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival</measure>
      <time_frame>Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose</time_frame>
      <description>Overall survival (OS) is defined as the time from the date of first dose to the date of death from any cause.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>treatment-related adverse event</measure>
      <time_frame>Informed consent to 30 days after last dose of treatment</time_frame>
      <description>A treatment-related adverse event (TRAE) is defined as any adverse event not present prior to the initiation of drug treatment or any adverse event already present that worsens in intensity or frequency following exposure to the drug treatment. TRAEs were graded using National Cancer Institute (NCI)-CTCAE version 5.0.</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">98</enrollment>
    <condition>Colorectal Cancer</condition>
    <arm_group>
      <arm_group_label>Non-liver metastasis cohort</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Arm A will include microsatellite-stable metastatic colorectal cancer patients who have no active liver metastasis. Patients are required to have received prior 5-Fu， oxaliplatin, and irinotecan treatment before enrollment.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>BRAF V600E mutant cohort</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Arm B will include microsatellite-stable metastatic colorectal cancer patients who have BRAF V600E mutation. Patients are required to have received prior 5-Fu， oxaliplatin, and irinotecan treatment before enrollment.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Front-line therapy cohort</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Arm C will include microsatellite-stable metastatic colorectal cancer patients who are unable or refuse to receive standard first-line or second-line treatment.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>KN046</intervention_name>
      <description>KN046 is a recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody that blocks both PD-L1 interaction with PD-1 and CTLA-4 interaction with CD80/CD86.</description>
      <arm_group_label>BRAF V600E mutant cohort</arm_group_label>
      <arm_group_label>Front-line therapy cohort</arm_group_label>
      <arm_group_label>Non-liver metastasis cohort</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>regorafenib</intervention_name>
      <description>Regorafenib is a multi-target tyrosine kinase inhibitors and is one of the standard third-line therapy in mCRC</description>
      <arm_group_label>BRAF V600E mutant cohort</arm_group_label>
      <arm_group_label>Front-line therapy cohort</arm_group_label>
      <arm_group_label>Non-liver metastasis cohort</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          I01. Subjects are able to comprehend the informed consent form, voluntarily participate,&#xD;
          and sign the informed consent form.&#xD;
  &#xD;
          I02. Subjects are ≥18 years old on the day of signing the informed consent form, with no&#xD;
          gender restrictions.&#xD;
  &#xD;
          I03. Histologically confirmed colorectal adenocarcinoma, including signet ring cell&#xD;
          carcinoma and mucinous adenocarcinoma.&#xD;
  &#xD;
          I04. According to RECIST 1.1 criteria, there should be at least one measurable or evaluable&#xD;
          lesion at baseline. If the subject has only one measurable or evaluable lesion at baseline,&#xD;
          the lesion must not have been exposed to radiotherapy previously, or there must be evidence&#xD;
          of significant progression after radiotherapy treatment completion.&#xD;
  &#xD;
          I05. ECOG performance status of 0 or 1. I06. Expected survival ≥3 months. I07. Archived&#xD;
          tumor tissue samples or freshly obtained tumor tissue samples are available.&#xD;
  &#xD;
          I08. Female subjects of childbearing potential or male subjects with partners of&#xD;
          childbearing potential agree to use highly effective contraception from 7 days before the&#xD;
          first dose until 120 days after the last dose. Female subjects of childbearing potential&#xD;
          must have a negative serum pregnancy test within 7 days before the first dose.&#xD;
  &#xD;
          I09. Subjects have the ability and willingness to comply with the study protocol's visits,&#xD;
          treatment plan, laboratory tests, and other study-related procedures.&#xD;
  &#xD;
          I10. Within the first 7 days of initial dosing, subjects should have good organ function:&#xD;
  &#xD;
          HGB ≥ 80g/L NEU ≥ 1.0*10^9/L PLT ≥ 75*10^9/L Cr≤1.5×ULN or CrCl≥50mL/min（ Cockcroft-Gault&#xD;
          method） TBiL ≤ 1.5×ULN ALT and AST ≤3 ×ULN； for patients with liver metastasis ALT and AST&#xD;
          ≤5 ×ULN urine protein &lt;2+；if urine protein ≥ 2+，24 hour urinary protein quantity &lt;2g； INR，&#xD;
          APTT，PT ≤ 1.5 ×ULN&#xD;
  &#xD;
          I11. For each cohort, the previous treatment history must meet the following conditions:&#xD;
  &#xD;
          Cohort A: pMMR/MSS mCRC with no BRAF V600E mutation, who failed fluoropyrimidine,&#xD;
          oxaliplatin, and irinotecan treatments, and without definitive active liver metastases at&#xD;
          enrollment (judged by the investigator based on medical history and imaging).&#xD;
  &#xD;
          Cohort B: pMMR/MSS mCRC with BRAF V600E mutation, who failed fluoropyrimidine, oxaliplatin,&#xD;
          and irinotecan treatments.&#xD;
  &#xD;
          Cohort C: MSS mCRC that has not intolerant or unsuitable for or refuse to receive standard&#xD;
          first-line or second-line chemotherapy.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          E01. Subjects with untreated active brain metastases or meningeal metastases; if the&#xD;
          subject's brain metastases have been treated and the metastases are stable (brain imaging&#xD;
          at least 4 weeks before the first dose shows stable lesions, and there is no evidence of&#xD;
          new neurological symptoms or the neurological symptoms have returned to baseline), then&#xD;
          enrollment is allowed.&#xD;
  &#xD;
          E02. Subjects with a history of gastrointestinal perforation or fistula within 6 months&#xD;
          before the first dose. If the perforation or fistula has been treated with resection or&#xD;
          repair, and the disease is judged to be recovered or improved by the investigator, then&#xD;
          enrollment is allowed.&#xD;
  &#xD;
          E03. Subjects who have received any other interventional clinical trial or any other&#xD;
          antitumor treatment within 28 days or 5 half-lives before the first dose (whichever is&#xD;
          shorter). Palliative radiotherapy for bone metastases to relieve symptoms is permitted.&#xD;
  &#xD;
          E04. Subjects who have undergone major surgery within 28 days before the first dose (e.g.,&#xD;
          major abdominal or thoracic surgery; excluding drainage, diagnostic puncture, or peripheral&#xD;
          vascular access replacement).&#xD;
  &#xD;
          E05. Subjects who require systemic corticosteroids (≥10 mg/day prednisone or equivalent) or&#xD;
          immunosuppressive therapy for a continuous 7-day period within 14 days before the first&#xD;
          dose. Inhaled or locally applied steroids and physiological replacement doses of steroids&#xD;
          due to adrenal insufficiency are allowed. Short-term (≤7 days) corticosteroids for&#xD;
          prophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune diseases (e.g.,&#xD;
          delayed hypersensitivity reaction caused by exposure to allergens) are allowed.&#xD;
  &#xD;
          E06. Subjects who have received live vaccines (including attenuated live vaccines) within&#xD;
          28 days before the first dose.&#xD;
  &#xD;
          E07. Subjects with interstitial lung disease or a history of non-infectious pneumonia&#xD;
          requiring oral or intravenous corticosteroid treatment.&#xD;
  &#xD;
          E08. Subjects with active autoimmune diseases requiring systemic treatment within 2 years&#xD;
          before the start of the study or those considered at risk of recurrence or planned&#xD;
          treatment for autoimmune diseases as judged by the investigator. Exclusions include a) skin&#xD;
          diseases that do not require systemic treatment (e.g., vitiligo, alopecia, psoriasis, or&#xD;
          eczema); b) hypothyroidism caused by autoimmune thyroiditis, requiring stable doses of&#xD;
          hormone replacement therapy; c) type 1 diabetes requiring stable doses of insulin&#xD;
          replacement therapy; d) childhood asthma fully resolved with no need for intervention in&#xD;
          adulthood; e) the investigator judges that the disease will not relapse without external&#xD;
          triggering factors.&#xD;
  &#xD;
          E09. Subjects with a history of other malignant tumors within 5 years, excluding cured skin&#xD;
          squamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma, localized&#xD;
          low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and prostate-specific&#xD;
          antigen (PSA) ≤10 ng/mL (if measured) in patients who have undergone curative treatment and&#xD;
          have no biochemical recurrence of prostate-specific antigen (PSA)), in situ cervical/breast&#xD;
          carcinoma, or Lynch syndrome.&#xD;
  &#xD;
          E10. Subjects with uncontrolled comorbidities, including but not limited to: a) active HBV&#xD;
          or HCV infection; b) subjects who are HBsAg positive and/or HCV antibody positive during&#xD;
          screening must undergo HBV DNA and/or HCV RNA testing. Only subjects with HBV DNA ≤500&#xD;
          IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can be enrolled; HBV DNA monitoring will&#xD;
          be at the discretion of the investigator based on the subject's condition during the trial;&#xD;
          c) known HIV infection or AIDS history; d) active tuberculosis; e) active infection or&#xD;
          systemic use of anti-infective drugs for more than 1 week within 28 days before the first&#xD;
          dose; fever of unknown cause within 2 weeks before the first dose; f) uncontrolled&#xD;
          hypertension (resting blood pressure ≥160/100 mmHg), symptomatic congestive heart failure&#xD;
          (NYHA II-IV), unstable angina or myocardial infarction within 6 months, or the presence of&#xD;
          QTc prolongation or the risk of arrhythmia (baseline QTc &gt;470 msec &lt;Fridericia method&#xD;
          correction&gt;, difficult-to-correct hypokalemia, long QT syndrome, atrial fibrillation with&#xD;
          resting heart rate &gt;100 bpm, or severe valvular heart disease); g) active bleeding that&#xD;
          cannot be controlled after medical treatment.&#xD;
  &#xD;
          E11. Toxicity from previous antitumor treatments has not recovered to Grade ≤2 (NCI-CTCAE&#xD;
          v5.0) or baseline, except for alopecia, skin pigmentation (allowed at any level), and&#xD;
          immune-related adverse reactions requiring physiological replacement (e.g., hypothyroidism,&#xD;
          hypopituitarism, type 1 diabetes).&#xD;
  &#xD;
          E12. History of allogeneic bone marrow or organ transplantation. E13. Previous history of&#xD;
          allergic reactions, hypersensitivity reactions, or intolerance to antibody drugs (e.g.,&#xD;
          severe allergic reactions, immune-mediated hepatotoxicity, immune-mediated&#xD;
          thrombocytopenia, or anemia).&#xD;
  &#xD;
          E14. Pregnant and/or lactating females. E15. Other conditions that, in the investigator's&#xD;
          opinion, may affect the safety or compliance of the study drug treatment, including but not&#xD;
          limited to moderate to large pleural/ascites/pericardial effusion, uncorrectable&#xD;
          pleural/ascites/pericardial effusion, intestinal obstruction or subacute intestinal&#xD;
          obstruction, psychiatric disorders, etc.&#xD;
  &#xD;
          E16. Previous treatment with any immune checkpoint inhibitors or T-cell co-stimulatory&#xD;
          drugs, including but not limited to PD-1/PD-L1, CTLA-4, LAG3, and other immune checkpoint&#xD;
          inhibitors, therapeutic vaccines, etc.&#xD;
  &#xD;
          E17. Previous treatment with regorafenib.&#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>Lin Shen</last_name>
      <role>Principal Investigator</role>
      <affiliation>Peking University Cancer Hospital &amp; Institute</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Ting Xu, MD</last_name>
      <phone>18201137836</phone>
      <email>xtlmhxt@163.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>zhenghang Wang, MD</last_name>
      <phone>01088196561</phone>
      <email>zhenghang_wang@bjmu.edu.cn</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Beijing Cancer Hospital</name>
        <address>
          <city>Beijing</city>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Zhenghang Wang</last_name>
        <email>zhenghang_wang@bjmu.edu.cn</email>
      </contact>
      <contact_backup>
        <last_name>Ting Xu</last_name>
        <email>xtlmhxt@163.com</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 2, 2023</study_first_submitted>
    <study_first_submitted_qc>August 2, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 26, 2023</last_update_submitted>
    <last_update_submitted_qc>August 26, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 29, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Peking University Cancer Hospital &amp; Institute</investigator_affiliation>
      <investigator_full_name>Shen Lin</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Colorectal Neoplasms</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- 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/NCT05985109
  org study id: CGOG-KREC-01
  nct id: NCT05985109
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  The study is an interventional Phase II clinical trial aiming to optimize immunotherapy
        strategies for microsatellite-stable colorectal cancer. We will include three types of
        metastatic colorectal cancer patients: those without liver metastasis, or carrying BRAF V600E
        mutation, or unable to tolerate chemotherapy as their initial or second-line treatment. The
        participants will receive a combination treatment of regorafenib and KN046 which is a
        PD-L1/CTLA-4 bispecific antibody. Treatment efficacy and safety profile would be evaluated in
        this study.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Overall response rate
  time frame: Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
  description: Objective response rate (defined as CR+PR) will be reported based on investigator's evaluation.
  measure: Disease control rate
  time frame: Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
  description: Disease control rate (defined as CR+PR+SD) will be reported based on investigator's evaluation.
  measure: Progression free survival
  time frame: Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
  description: Progression-free survival (PFS) is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic progressive disease (PD) or death due to any cause.
  measure: Duration of response
  time frame: Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
  description: Duration of response (DOR) is defined as the time from the date of the first response to the first objective documentation of radiographic progressive disease (PD) or death due to any cause.
  measure: Overall survival
  time frame: Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 24 months post-dose
  description: Overall survival (OS) is defined as the time from the date of first dose to the date of death from any cause.
  measure: treatment-related adverse event
  time frame: Informed consent to 30 days after last dose of treatment
  description: A treatment-related adverse event (TRAE) is defined as any adverse event not present prior to the initiation of drug treatment or any adverse event already present that worsens in intensity or frequency following exposure to the drug treatment. TRAEs were graded using National Cancer Institute (NCI)-CTCAE version 5.0.
  arm group label: Non-liver metastasis cohort
  arm group type: Experimental
  description: Arm A will include microsatellite-stable metastatic colorectal cancer patients who have no active liver metastasis. Patients are required to have received prior 5-Fu， oxaliplatin, and irinotecan treatment before enrollment.
  arm group label: BRAF V600E mutant cohort
  arm group type: Experimental
  description: Arm B will include microsatellite-stable metastatic colorectal cancer patients who have BRAF V600E mutation. Patients are required to have received prior 5-Fu， oxaliplatin, and irinotecan treatment before enrollment.
  arm group label: Front-line therapy cohort
  arm group type: Experimental
  description: Arm C will include microsatellite-stable metastatic colorectal cancer patients who are unable or refuse to receive standard first-line or second-line treatment.
  intervention type: Drug
  intervention name: KN046
  description: KN046 is a recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody that blocks both PD-L1 interaction with PD-1 and CTLA-4 interaction with CD80/CD86.
  arm group label: BRAF V600E mutant cohort
  arm group label: Front-line therapy cohort
  arm group label: Non-liver metastasis cohort
  intervention type: Drug
  intervention name: regorafenib
  description: Regorafenib is a multi-target tyrosine kinase inhibitors and is one of the standard third-line therapy in mCRC
  arm group label: BRAF V600E mutant cohort
  arm group label: Front-line therapy cohort
  arm group label: Non-liver metastasis cohort
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Lin Shen
  role: Principal Investigator
  affiliation: Peking University Cancer Hospital & Institute
  last name: Ting Xu, MD
  phone: 18201137836
  email: xtlmhxt@163.com
  last name: zhenghang Wang, MD
  phone: 01088196561
  email: zhenghang_wang@bjmu.edu.cn
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: Peking University Cancer Hospital & Institute
  investigator full name: Shen Lin
  investigator title: Professor
  mesh term: Colorectal Neoplasms
  sharing ipd: No