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/NCT06004713</url>
    </required_header>
    <id_info>
      <org_study_id>LGH2023093</org_study_id>
      <nct_id>NCT06004713</nct_id>
    </id_info>
    <brief_title>Registry Study in MSI/dMMR Solid Tumors</brief_title>
    <official_title>Multi-center, Non-interventional, Prospective Registry Study on the Treatment of Solid Tumors With Mismatch Repair Deficiency or Microsatellite Instability</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>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 study is a multi-center, non-interventional, prospective clinical observational study,&#xD;
        aiming to evaluate the effectiveness and safety of subsequent treatment in dMMR/MSI solid&#xD;
        tumor patients who have never received ICIs under real-world conditions. Particular attention&#xD;
        is paid to the efficacy in populations where treatment plans are adjusted based on ctDNA, and&#xD;
        potential predictive or prognostic biomarkers are explored.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This study plans to enroll patients in the following four cohorts:&#xD;
  &#xD;
          -  Cohort A: Initially only receiving PD1/PDL1 monotherapy;&#xD;
  &#xD;
          -  Cohort B: Initially receiving simultaneous blockade of PD1/PDL1 and CTLA4;&#xD;
  &#xD;
          -  Cohort C: Initially receiving PD1/PDL1 monotherapy combined with chemotherapy or&#xD;
             targeted therapy;&#xD;
  &#xD;
          -  Cohort D: Initially not using ICIs, receiving other standard treatments for this tumor&#xD;
             type&#xD;
  &#xD;
        To explore the role of ctDNA testing in therapeutic decision-making, patients with the first&#xD;
        evaluation of SD in cohort A are divided into two groups: ctDNA testing/intervention group&#xD;
        (Group A1) and ctDNA testing/non-intervention group (Group A2). In group A1, if there is no&#xD;
        early response to ctDNA, the researchers and the patient will decide to add CTLA4 antibody or&#xD;
        other potentially effective treatments after thorough communication. If there is an early&#xD;
        response to ctDNA, then continue with PD1/PDL1 monoclonal antibody treatment. Patients in&#xD;
        group A2 undergo ctDNA testing, but still continue with PD1/PDL1 monoclonal antibody&#xD;
        treatment according to the RECIST v1.1 standard when the first evaluation of SD is made.&#xD;
        Meanwhile, explore the role of 1-year ctDNA-MRD in guiding treatment in patients with&#xD;
        long-term tumor control, and explore the guiding role of re-biopsy of tumor tissue or ctDNA&#xD;
        testing in helping making treatment regimen after progression on ICIs.&#xD;
  &#xD;
        Number of Subjects:&#xD;
  &#xD;
        • This study will recruit patients nationwide for data collection over a period of 3 years.&#xD;
        The plan is to enroll 100 cases in Cohort A, including 25 cases in Group A1 and 25 cases in&#xD;
        Group A2; 30 cases in Cohort B; 30 cases in Cohort C; and 30 cases in Cohort D.&#xD;
  &#xD;
        Inclusion Criteria:&#xD;
  &#xD;
          -  Signing an informed consent form and voluntarily joining this study;&#xD;
  &#xD;
          -  Age ≥18 years old; age should also be ≤75 years old in Cohorts B, C, D;&#xD;
  &#xD;
          -  Confirmed by histology or cytology as solid malignant tumor and confirmed by&#xD;
             immunohistochemistry as dMMR or confirmed by PCR/NGS method as MSI;&#xD;
  &#xD;
          -  The researcher determines that the patient can receive anti-tumor treatment;&#xD;
  &#xD;
          -  With evaluable lesions.&#xD;
  &#xD;
        Exclusion Criteria:&#xD;
  &#xD;
          -  Other malignant tumors within 5 years before enrollment, except for cured skin squamous&#xD;
             cell carcinoma, basal cell carcinoma, non-muscle invasive bladder cancer, localized&#xD;
             low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6 points and PSA ≤10&#xD;
             ng/mL at the time of prostate cancer diagnosis (if measured) patients who have undergone&#xD;
             radical treatment and have no prostate-specific antigen (PSA) biochemical recurrence can&#xD;
             participate in this study), in situ cervical/breast cancer, Lynch syndrome;&#xD;
  &#xD;
          -  There is evidence that the patient is a pregnant or lactating woman;&#xD;
  &#xD;
          -  Have previously received immunological checkpoint inhibitors or T cell co-stimulatory&#xD;
             drugs, including but not limited to PD1, CTLA4, LAG3 and other immune checkpoint&#xD;
             blockers, therapeutic vaccines, etc.; patients exposed to ICIs in perioperative setting&#xD;
             are allowed to be enrolled if disease relapse after more than 6 months since the last&#xD;
             dose of ICI;&#xD;
  &#xD;
          -  The researcher judges other situations that are not suitable for inclusion in the study&#xD;
  &#xD;
        Study endpoints:&#xD;
  &#xD;
        Primary endpoint:&#xD;
  &#xD;
        • The primary endpoint of Cohorts A, B, C, and D are: The progression-free survival (PFS)&#xD;
        determined by the researcher according to the RECIST 1.1 standard.&#xD;
  &#xD;
        Secondary endpoints:&#xD;
  &#xD;
          -  Efficacy endpoints:&#xD;
  &#xD;
               1. The secondary endpoints for study Cohorts A, B, C, and D include: the overall&#xD;
                  survival (OS), objective response rate (ORR), disease control rate (DCR), duration&#xD;
                  of response (DOR), time to response (TTR), and 6-month and 12-month&#xD;
                  progression-free survival rate of each treatment group; the OS, PFS, ORR, and DCR&#xD;
                  of each group's post-progression treatment plan; the proportion of each group using&#xD;
                  ctDNA-guided treatment.&#xD;
  &#xD;
               2. In Cohort A, the OS, PFS, ORR, DCR, DOR, TTR, 6-month and 12-month progression-free&#xD;
                  survival rate of Group A1 (ctDNA detection/intervention group) and Group A2 (ctDNA&#xD;
                  detection/non-intervention group).&#xD;
  &#xD;
               3. In patients with long-term disease control under ICIs treatment: the proportion of&#xD;
                  patients who are MRD-negative after one year, patients who are MRD-negative and&#xD;
                  stopped medication after one year, patients who are MRD-positive after one year,&#xD;
                  and patients who are MRD-positive and stopped medication after one year, as well as&#xD;
                  their OS, PFS, ORR, DCR, 6-month and 12-month progression-free survival rate.&#xD;
  &#xD;
               4. In patients resistant to ICIs treatment: the proportion of patients who retested&#xD;
                  tissue or blood genes at progression, as well as the proportion of patients who&#xD;
                  adjusted treatment plans based on gene testing and their OS, PFS, ORR, DCR, 6-month&#xD;
                  and 12-month progression-free survival rate.&#xD;
  &#xD;
               5. The proportion of patients using ctDNA-guided treatment and not using ctDNA-guided&#xD;
                  treatment, as well as their OS, PFS, ORR, DCR, 6-month and 12-month&#xD;
                  progression-free survival rate.&#xD;
  &#xD;
               6. Among each group: patients who are often excluded from clinical trials: their OS,&#xD;
                  PFS, ORR, DCR, DOR, TTR, 6-month and 12-month progression-free survival rate&#xD;
  &#xD;
          -  Safety endpoints (Cohort A, B, C, D): incidence of adverse events (AE) during treatment,&#xD;
             AE-related discontinuation rate, AE relief rate&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 2023</start_date>
    <completion_date type="Anticipated">February 2026</completion_date>
    <primary_completion_date type="Anticipated">February 2026</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Progression-free survival (PFS) determined by the researchers according to the RECIST 1.1 criteria..</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>
    </primary_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>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>
    </secondary_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>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>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_groups>4</number_of_groups>
    <enrollment type="Anticipated">190</enrollment>
    <condition>DMMR Cancer</condition>
    <condition>MSI-H</condition>
    <condition>Solid Tumor</condition>
    <arm_group>
      <arm_group_label>Cohort A</arm_group_label>
      <description>Patients will initially receive monotherapy PD1/PDL1 monoclonal antibody therapy.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort B</arm_group_label>
      <description>Patients will initially receive dual blockade of both PD1/PDL1 and CTLA4</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort C</arm_group_label>
      <description>Patients will initially receive PD1/PDL1 monoclonal antibody combined with chemotherapy or targeted therapy.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Cohort D</arm_group_label>
      <description>Patients will receive other standard treatments for this tumor other than ICIs.</description>
    </arm_group>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        1. Blood sample collection: Collect 10mL of peripheral blood in a purple EDTA-K2&#xD;
             anticoagulant blood collection tube. If the blood plasma cannot be separated within the&#xD;
             specified time, a Streck (EDTA-K3) blood collection tube can be used, and the patient's&#xD;
             name, sample type, and collection time should be marked on the tube wall.&#xD;
  &#xD;
          2. Plasma Separation: Whole blood samples are centrifuged at 4°C or room temperature, at&#xD;
             1800g for 10 minutes. Except for 0.5mL of whole blood reserved, all the whole blood is&#xD;
             separated into plasma as much as possible. After centrifugation, carefully collect the&#xD;
             upper layer of plasma into a new, labeled 5mL low-adsorption centrifuge tube, and&#xD;
             finally seal with a sealing film for future use.&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          The estimated start time of this study is August 2023, and data will be collected from&#xD;
          enrolled patients nationwide over a period of 3 years. It is planned to enroll 100 patients&#xD;
          in Cohort A, including 25 in Group A1 and 25 in Group A2. It is planned to enroll 30&#xD;
          patients in Cohort B, 30 in Cohort C, and 30 in Cohort D.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Sign the informed consent form and voluntarily participate in this study;&#xD;
  &#xD;
            -  Age ≥ 18 years old; age should also be ≤75 years old in Cohorts B, C, D;&#xD;
  &#xD;
            -  Histologically or cytologically confirmed to have a solid malignant tumor and&#xD;
               confirmed by immunohistochemistry to be dMMR or confirmed by PCR/NGS to be MSI;&#xD;
  &#xD;
            -  The researcher determines that the patient can receive anti-tumor treatment;&#xD;
  &#xD;
            -  Have evaluable lesions&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Other malignant tumors within 5 years before joining the study, except for cured skin&#xD;
               squamous cell carcinoma, basal cell carcinoma, non-muscle invasive bladder cancer,&#xD;
               localized low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6 points,&#xD;
               and prostate cancer diagnosed with PSA ≤10 ng/mL (if measured). Patients who have&#xD;
               received radical treatment and have no prostate specific antigen (PSA) biochemical&#xD;
               recurrence can participate in this study), cervical/breast carcinoma in situ, and&#xD;
               Lynch syndrome;&#xD;
  &#xD;
            -  Evidence already exists that the patient is a pregnant or lactating woman;&#xD;
  &#xD;
            -  Previous treatment with immune checkpoint inhibitors or T cell co-stimulatory drugs,&#xD;
               including but not limited to PD1, CTLA4, LAG3, and other immune checkpoint blockers,&#xD;
               therapeutic vaccines, etc.; patients exposed to ICIs in perioperative setting are&#xD;
               allowed to be enrolled if disease relapse after more than 6 months since the last dose&#xD;
               of ICIs;&#xD;
  &#xD;
            -  Other situations deemed by the researcher to be unsuitable for inclusion in the study&#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>zhenghang Wang</last_name>
      <role>Study Director</role>
      <affiliation>Peking University Cancer Hospital &amp; Institute</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>zhenghang Wang</last_name>
      <phone>18813186790</phone>
      <email>zhenghang_wang@bjmu.edu.cn</email>
    </overall_contact>
    <reference>
      <citation>Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019 Aug 1;30(8):1232-1243. doi: 10.1093/annonc/mdz116.</citation>
      <PMID>31056702</PMID>
    </reference>
    <reference>
      <citation>Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8.</citation>
      <PMID>28596308</PMID>
    </reference>
    <reference>
      <citation>Wang Z, Zhao X, Gao C, Gong J, Wang X, Gao J, Li Z, Wang J, Yang B, Wang L, Zhang B, Zhou Y, Wang D, Li X, Bai Y, Li J, Shen L. Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment. J Immunother Cancer. 2020 Nov;8(2):e001297. doi: 10.1136/jitc-2020-001297.</citation>
      <PMID>33172882</PMID>
    </reference>
    <reference>
      <citation>Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699.</citation>
      <PMID>33264544</PMID>
    </reference>
    <reference>
      <citation>Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel). 2021 Feb 6;13(4):651. doi: 10.3390/cancers13040651.</citation>
      <PMID>33561950</PMID>
    </reference>
    <reference>
      <citation>Chida K, Kawazoe A, Kawazu M, Suzuki T, Nakamura Y, Nakatsura T, Kuwata T, Ueno T, Kuboki Y, Kotani D, Kojima T, Taniguchi H, Mano H, Ikeda M, Shitara K, Endo I, Yoshino T. A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clin Cancer Res. 2021 Jul 1;27(13):3714-3724. doi: 10.1158/1078-0432.CCR-21-0401. Epub 2021 Apr 29.</citation>
      <PMID>33926917</PMID>
    </reference>
    <reference>
      <citation>Wang Z, Wang X, Xu Y, Li J, Zhang X, Peng Z, Hu Y, Zhao X, Dong K, Zhang B, Gao C, Zhao X, Chen H, Cai J, Bai Y, Sun Y, Shen L. Mutations of PI3K-AKT-mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med. 2022 Apr 21;20(1):133. doi: 10.1186/s12916-022-02327-y.</citation>
      <PMID>35443723</PMID>
    </reference>
    <reference>
      <citation>Wang Z, Zhang Q, Qi C, Bai Y, Zhao F, Chen H, Li Z, Wang X, Chen M, Gong J, Peng Z, Zhang X, Cai J, Chen S, Zhao X, Shen L, Li J. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer. 2022 Jun;10(6):e004703. doi: 10.1136/jitc-2022-004703.</citation>
      <PMID>35705314</PMID>
    </reference>
    <reference>
      <citation>Malla M, Loree JM, Kasi PM, Parikh AR. Using Circulating Tumor DNA in Colorectal Cancer: Current and Evolving Practices. J Clin Oncol. 2022 Aug 20;40(24):2846-2857. doi: 10.1200/JCO.21.02615. Epub 2022 Jul 15.</citation>
      <PMID>35839443</PMID>
    </reference>
    <reference>
      <citation>Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W, Abdullah SE, Higgs BW, Dennis PA, van der Heijden MS, Segal NH, Chaft JE, Hembrough T, Barrett JC, Hellmann MD. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov. 2020 Dec;10(12):1842-1853. doi: 10.1158/2159-8290.CD-20-0047. Epub 2020 Aug 14.</citation>
      <PMID>32816849</PMID>
    </reference>
    <reference>
      <citation>Kasi PM, Budde G, Krainock M, Aushev VN, Koyen Malashevich A, Malhotra M, Olshan P, Billings PR, Aleshin A. Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. J Immunother Cancer. 2022 Jan;10(1):e003312. doi: 10.1136/jitc-2021-003312.</citation>
      <PMID>35101943</PMID>
    </reference>
    <reference>
      <citation>Luo J, Wu S, Rizvi H, Zhang Q, Egger JV, Osorio JC, Schoenfeld AJ, Plodkowski AJ, Ginsberg MS, Callahan MK, Maher C, Shoushtari AN, Postow MA, Voss MH, Kotecha RR, Gupta A, Raja R, Kris MG, Hellmann MD. Deciphering radiological stable disease to immune checkpoint inhibitors. Ann Oncol. 2022 Aug;33(8):824-835. doi: 10.1016/j.annonc.2022.04.450. Epub 2022 May 6.</citation>
      <PMID>35533926</PMID>
    </reference>
    <reference>
      <citation>Bui QL, Mas L, Hollebecque A, Tougeron D, de la Fouchardiere C, Pudlarz T, Alouani E, Guimbaud R, Taieb J, Andre T, Colle R, Cohen R. Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer. Cancers (Basel). 2022 Jan 14;14(2):406. doi: 10.3390/cancers14020406.</citation>
      <PMID>35053568</PMID>
    </reference>
    <reference>
      <citation>Hollebecque A, Chung HC, de Miguel MJ, Italiano A, Machiels JP, Lin CC, Dhani NC, Peeters M, Moreno V, Su WC, Chow KH, Galvao VR, Carlsen M, Yu D, Szpurka AM, Zhao Y, Schmidt SL, Gandhi L, Xu X, Bang YJ. Safety and Antitumor Activity of alpha-PD-L1 Antibody as Monotherapy or in Combination with alpha-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors. Clin Cancer Res. 2021 Dec 1;27(23):6393-6404. doi: 10.1158/1078-0432.CCR-21-0261. Epub 2021 Aug 31.</citation>
      <PMID>34465599</PMID>
    </reference>
    <reference>
      <citation>Chen M, Wang Z, Liu Z, Liu N, Fang W, Zhang H, Jin X, Li J, Zhao W, Qu H, Song F, Chang Z, Li Y, Tang Y, Xu C, Zhang X, Wang X, Peng Z, Cai J, Li J, Shen L. The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study. Cancers (Basel). 2022 Oct 21;14(20):5158. doi: 10.3390/cancers14205158.</citation>
      <PMID>36291942</PMID>
    </reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>August 16, 2023</study_first_submitted>
    <study_first_submitted_qc>August 21, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 22, 2023</study_first_posted>
    <last_update_submitted>August 21, 2023</last_update_submitted>
    <last_update_submitted_qc>August 21, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 22, 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>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/NCT06004713
  org study id: LGH2023093
  nct id: NCT06004713
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  This study is a multi-center, non-interventional, prospective clinical observational study,
        aiming to evaluate the effectiveness and safety of subsequent treatment in dMMR/MSI solid
        tumor patients who have never received ICIs under real-world conditions. Particular attention
        is paid to the efficacy in populations where treatment plans are adjusted based on ctDNA, and
        potential predictive or prognostic biomarkers are explored.
  This study plans to enroll patients in the following four cohorts:
  
          -  Cohort A: Initially only receiving PD1/PDL1 monotherapy;
  
          -  Cohort B: Initially receiving simultaneous blockade of PD1/PDL1 and CTLA4;
  
          -  Cohort C: Initially receiving PD1/PDL1 monotherapy combined with chemotherapy or
             targeted therapy;
  
          -  Cohort D: Initially not using ICIs, receiving other standard treatments for this tumor
             type
  
        To explore the role of ctDNA testing in therapeutic decision-making, patients with the first
        evaluation of SD in cohort A are divided into two groups: ctDNA testing/intervention group
        (Group A1) and ctDNA testing/non-intervention group (Group A2). In group A1, if there is no
        early response to ctDNA, the researchers and the patient will decide to add CTLA4 antibody or
        other potentially effective treatments after thorough communication. If there is an early
        response to ctDNA, then continue with PD1/PDL1 monoclonal antibody treatment. Patients in
        group A2 undergo ctDNA testing, but still continue with PD1/PDL1 monoclonal antibody
        treatment according to the RECIST v1.1 standard when the first evaluation of SD is made.
        Meanwhile, explore the role of 1-year ctDNA-MRD in guiding treatment in patients with
        long-term tumor control, and explore the guiding role of re-biopsy of tumor tissue or ctDNA
        testing in helping making treatment regimen after progression on ICIs.
  
        Number of Subjects:
  
        • This study will recruit patients nationwide for data collection over a period of 3 years.
        The plan is to enroll 100 cases in Cohort A, including 25 cases in Group A1 and 25 cases in
        Group A2; 30 cases in Cohort B; 30 cases in Cohort C; and 30 cases in Cohort D.
  
        Inclusion Criteria:
  
          -  Signing an informed consent form and voluntarily joining this study;
  
          -  Age ≥18 years old; age should also be ≤75 years old in Cohorts B, C, D;
  
          -  Confirmed by histology or cytology as solid malignant tumor and confirmed by
             immunohistochemistry as dMMR or confirmed by PCR/NGS method as MSI;
  
          -  The researcher determines that the patient can receive anti-tumor treatment;
  
          -  With evaluable lesions.
  
        Exclusion Criteria:
  
          -  Other malignant tumors within 5 years before enrollment, except for cured skin squamous
             cell carcinoma, basal cell carcinoma, non-muscle invasive bladder cancer, localized
             low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6 points and PSA ≤10
             ng/mL at the time of prostate cancer diagnosis (if measured) patients who have undergone
             radical treatment and have no prostate-specific antigen (PSA) biochemical recurrence can
             participate in this study), in situ cervical/breast cancer, Lynch syndrome;
  
          -  There is evidence that the patient is a pregnant or lactating woman;
  
          -  Have previously received immunological checkpoint inhibitors or T cell co-stimulatory
             drugs, including but not limited to PD1, CTLA4, LAG3 and other immune checkpoint
             blockers, therapeutic vaccines, etc.; patients exposed to ICIs in perioperative setting
             are allowed to be enrolled if disease relapse after more than 6 months since the last
             dose of ICI;
  
          -  The researcher judges other situations that are not suitable for inclusion in the study
  
        Study endpoints:
  
        Primary endpoint:
  
        • The primary endpoint of Cohorts A, B, C, and D are: The progression-free survival (PFS)
        determined by the researcher according to the RECIST 1.1 standard.
  
        Secondary endpoints:
  
          -  Efficacy endpoints:
  
               1. The secondary endpoints for study Cohorts A, B, C, and D include: the overall
                  survival (OS), objective response rate (ORR), disease control rate (DCR), duration
                  of response (DOR), time to response (TTR), and 6-month and 12-month
                  progression-free survival rate of each treatment group; the OS, PFS, ORR, and DCR
                  of each group's post-progression treatment plan; the proportion of each group using
                  ctDNA-guided treatment.
  
               2. In Cohort A, the OS, PFS, ORR, DCR, DOR, TTR, 6-month and 12-month progression-free
                  survival rate of Group A1 (ctDNA detection/intervention group) and Group A2 (ctDNA
                  detection/non-intervention group).
  
               3. In patients with long-term disease control under ICIs treatment: the proportion of
                  patients who are MRD-negative after one year, patients who are MRD-negative and
                  stopped medication after one year, patients who are MRD-positive after one year,
                  and patients who are MRD-positive and stopped medication after one year, as well as
                  their OS, PFS, ORR, DCR, 6-month and 12-month progression-free survival rate.
  
               4. In patients resistant to ICIs treatment: the proportion of patients who retested
                  tissue or blood genes at progression, as well as the proportion of patients who
                  adjusted treatment plans based on gene testing and their OS, PFS, ORR, DCR, 6-month
                  and 12-month progression-free survival rate.
  
               5. The proportion of patients using ctDNA-guided treatment and not using ctDNA-guided
                  treatment, as well as their OS, PFS, ORR, DCR, 6-month and 12-month
                  progression-free survival rate.
  
               6. Among each group: patients who are often excluded from clinical trials: their OS,
                  PFS, ORR, DCR, DOR, TTR, 6-month and 12-month progression-free survival rate
  
          -  Safety endpoints (Cohort A, B, C, D): incidence of adverse events (AE) during treatment,
             AE-related discontinuation rate, AE relief rate
  observational model: Cohort
  time perspective: Prospective
  measure: Progression-free survival (PFS) determined by the researchers according to the RECIST 1.1 criteria..
  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: 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: 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: 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: 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: Cohort A
  description: Patients will initially receive monotherapy PD1/PDL1 monoclonal antibody therapy.
  arm group label: Cohort B
  description: Patients will initially receive dual blockade of both PD1/PDL1 and CTLA4
  arm group label: Cohort C
  description: Patients will initially receive PD1/PDL1 monoclonal antibody combined with chemotherapy or targeted therapy.
  arm group label: Cohort D
  description: Patients will receive other standard treatments for this tumor other than ICIs.
  1. Blood sample collection: Collect 10mL of peripheral blood in a purple EDTA-K2
             anticoagulant blood collection tube. If the blood plasma cannot be separated within the
             specified time, a Streck (EDTA-K3) blood collection tube can be used, and the patient's
             name, sample type, and collection time should be marked on the tube wall.
  
          2. Plasma Separation: Whole blood samples are centrifuged at 4°C or room temperature, at
             1800g for 10 minutes. Except for 0.5mL of whole blood reserved, all the whole blood is
             separated into plasma as much as possible. After centrifugation, carefully collect the
             upper layer of plasma into a new, labeled 5mL low-adsorption centrifuge tube, and
             finally seal with a sealing film for future use.
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: zhenghang Wang
  role: Study Director
  affiliation: Peking University Cancer Hospital & Institute
  last name: zhenghang Wang
  phone: 18813186790
  email: zhenghang_wang@bjmu.edu.cn
  citation: Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019 Aug 1;30(8):1232-1243. doi: 10.1093/annonc/mdz116.
  PMID: 31056702
  citation: Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8.
  PMID: 28596308
  citation: Wang Z, Zhao X, Gao C, Gong J, Wang X, Gao J, Li Z, Wang J, Yang B, Wang L, Zhang B, Zhou Y, Wang D, Li X, Bai Y, Li J, Shen L. Plasma-based microsatellite instability detection strategy to guide immune checkpoint blockade treatment. J Immunother Cancer. 2020 Nov;8(2):e001297. doi: 10.1136/jitc-2020-001297.
  PMID: 33172882
  citation: Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699.
  PMID: 33264544
  citation: Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel). 2021 Feb 6;13(4):651. doi: 10.3390/cancers13040651.
  PMID: 33561950
  citation: Chida K, Kawazoe A, Kawazu M, Suzuki T, Nakamura Y, Nakatsura T, Kuwata T, Ueno T, Kuboki Y, Kotani D, Kojima T, Taniguchi H, Mano H, Ikeda M, Shitara K, Endo I, Yoshino T. A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clin Cancer Res. 2021 Jul 1;27(13):3714-3724. doi: 10.1158/1078-0432.CCR-21-0401. Epub 2021 Apr 29.
  PMID: 33926917
  citation: Wang Z, Wang X, Xu Y, Li J, Zhang X, Peng Z, Hu Y, Zhao X, Dong K, Zhang B, Gao C, Zhao X, Chen H, Cai J, Bai Y, Sun Y, Shen L. Mutations of PI3K-AKT-mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med. 2022 Apr 21;20(1):133. doi: 10.1186/s12916-022-02327-y.
  PMID: 35443723
  citation: Wang Z, Zhang Q, Qi C, Bai Y, Zhao F, Chen H, Li Z, Wang X, Chen M, Gong J, Peng Z, Zhang X, Cai J, Chen S, Zhao X, Shen L, Li J. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer. 2022 Jun;10(6):e004703. doi: 10.1136/jitc-2022-004703.
  PMID: 35705314
  citation: Malla M, Loree JM, Kasi PM, Parikh AR. Using Circulating Tumor DNA in Colorectal Cancer: Current and Evolving Practices. J Clin Oncol. 2022 Aug 20;40(24):2846-2857. doi: 10.1200/JCO.21.02615. Epub 2022 Jul 15.
  PMID: 35839443
  citation: Zhang Q, Luo J, Wu S, Si H, Gao C, Xu W, Abdullah SE, Higgs BW, Dennis PA, van der Heijden MS, Segal NH, Chaft JE, Hembrough T, Barrett JC, Hellmann MD. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov. 2020 Dec;10(12):1842-1853. doi: 10.1158/2159-8290.CD-20-0047. Epub 2020 Aug 14.
  PMID: 32816849
  citation: Kasi PM, Budde G, Krainock M, Aushev VN, Koyen Malashevich A, Malhotra M, Olshan P, Billings PR, Aleshin A. Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. J Immunother Cancer. 2022 Jan;10(1):e003312. doi: 10.1136/jitc-2021-003312.
  PMID: 35101943
  citation: Luo J, Wu S, Rizvi H, Zhang Q, Egger JV, Osorio JC, Schoenfeld AJ, Plodkowski AJ, Ginsberg MS, Callahan MK, Maher C, Shoushtari AN, Postow MA, Voss MH, Kotecha RR, Gupta A, Raja R, Kris MG, Hellmann MD. Deciphering radiological stable disease to immune checkpoint inhibitors. Ann Oncol. 2022 Aug;33(8):824-835. doi: 10.1016/j.annonc.2022.04.450. Epub 2022 May 6.
  PMID: 35533926
  citation: Bui QL, Mas L, Hollebecque A, Tougeron D, de la Fouchardiere C, Pudlarz T, Alouani E, Guimbaud R, Taieb J, Andre T, Colle R, Cohen R. Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer. Cancers (Basel). 2022 Jan 14;14(2):406. doi: 10.3390/cancers14020406.
  PMID: 35053568
  citation: Hollebecque A, Chung HC, de Miguel MJ, Italiano A, Machiels JP, Lin CC, Dhani NC, Peeters M, Moreno V, Su WC, Chow KH, Galvao VR, Carlsen M, Yu D, Szpurka AM, Zhao Y, Schmidt SL, Gandhi L, Xu X, Bang YJ. Safety and Antitumor Activity of alpha-PD-L1 Antibody as Monotherapy or in Combination with alpha-TIM-3 Antibody in Patients with Microsatellite Instability-High/Mismatch Repair-Deficient Tumors. Clin Cancer Res. 2021 Dec 1;27(23):6393-6404. doi: 10.1158/1078-0432.CCR-21-0261. Epub 2021 Aug 31.
  PMID: 34465599
  citation: Chen M, Wang Z, Liu Z, Liu N, Fang W, Zhang H, Jin X, Li J, Zhao W, Qu H, Song F, Chang Z, Li Y, Tang Y, Xu C, Zhang X, Wang X, Peng Z, Cai J, Li J, Shen L. The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study. Cancers (Basel). 2022 Oct 21;14(20):5158. doi: 10.3390/cancers14205158.
  PMID: 36291942
  responsible party type: Sponsor
  mesh term: Neoplasms
  sharing ipd: No