<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/NCT04407741</url>
  </required_header>
  <id_info>
    <org_study_id>CHN-PLAGH-BT-055</org_study_id>
    <nct_id>NCT04407741</nct_id>
  </id_info>
  <brief_title>Phase Ⅰ/Ⅱ Study of SHR2554 in Combination With SHR1701 in Patients With Advanced Solid Tumors and B-cell Lymphomas</brief_title>
  <official_title>An Open-Label Phase Ⅰ/Ⅱ Study of EZH2 Inhibitor SHR2554 in Combination With Anti-PD-L1/TGFβ Antibody SHR1701 in Patients With Advanced or Metastatic Solid Tumors and Relapsed/Refractory B-cell Lymphomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chinese PLA General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chinese PLA General Hospital</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 potency of immune checkpoint blockade is limited in most solid malignancies, one possible&#xD;
      reason for which is tumor microenvironment. Enhancer of zeste homolog 2 (EZH2) as a&#xD;
      epigenetic target for cancer therapy has attracted significant interest. The combination of&#xD;
      EZH2 inhibitors and programmed death-1 ligands/ transforming growth factor-β (PD-L1/TGFβ)&#xD;
      blockade may enhance the efficiency of immunotherapy.The primary objective of this study in&#xD;
      phase Ⅰstage is to assess the safety, feasibility of EZH2 inhibitor SHR2554 in combination&#xD;
      with anti-PD-L1/TGFβ antibody SHR1701 in advanced pretreated solid tumors and b-cell&#xD;
      lymphomas. The phase Ⅱ stage of this study is to primarily evaluate the efficacy of SHR2554&#xD;
      plus SHR1701 and the epigenetic modulating effect of SHR2554.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Immune checkpoint blockade has led to great strides in the management of various cancers,&#xD;
      however, durable response could be seen in approximately 20% of treated patients with most&#xD;
      solid malignancies. Immunosuppressive entities such as transforming growth factor-β (TGF-β)&#xD;
      in the tumor microenvironment (TME) remain a major impediment. Enhancer of zeste homolog 2&#xD;
      (EZH2) is the core component of the polycomb group complex, which play a major role in&#xD;
      cellular proliferation and differentiation. EZH2 aberration has been seen in a wide range of&#xD;
      solid tumors and hematological malignancies, affecting tumor progression and immune cells in&#xD;
      the tumor microenvironment, and it is associated with poor clinical prognosis and outcomes.&#xD;
      EZH2 is not only an activator of gene expression through different pathways, but also a&#xD;
      critical epigenetic repressor through histone methylation. Therefore, EZH2 has attracted&#xD;
      significant interest as a potential epigenetic target for cancer treatment. It is&#xD;
      hypothesized that the combination of EZH2 inhibitors and programmed death-1 ligands/&#xD;
      transforming growth factor-β (PD-L1/TGFβ) blockade could enhance the efficiency of&#xD;
      immunotherapy.&#xD;
&#xD;
      The primary objective of this study in phase Ⅰstage is to assess the safety, feasibility of&#xD;
      EZH2 inhibitor SHR2554 in combination with anti-PD-L1/TGFβ antibody SHR1701 in advanced&#xD;
      pretreated solid tumors and b-cell lymphomas. The second objectives include characterizing&#xD;
      the pharmacokinetics of SHR2554 in combination with SHR1701, evaluating the preliminary&#xD;
      efficacy of SHR2554 plus SHR1701 and the epigenetic modulating effect of SHR2554 in its&#xD;
      combination with anti-PD-L1/TGFβ antibody. The exploratory objectives are to evaluate the&#xD;
      pathological, immunological or clinical predictive factors for efficacy and toxicity. Based&#xD;
      on the data of safety, efficacy and recommended dose level obtained from phase Ⅰtrial, this&#xD;
      study moves into phase Ⅱ stage, in which enrolled subjects are randomized to SHR2554 plus SHR&#xD;
      1701 or SHR1701 monotherapy, to primarily evaluate the efficacy of SHR2554 plus SHR1701 and&#xD;
      the epigenetic modulating effect of SHR2554. The second objectives include evaluating safety&#xD;
      and other efficacy parameters, such as overall response rate (ORR), disease control rate&#xD;
      (DCR), duration of response (DOR) and overall survival (OS). The exploratory objectives are&#xD;
      to evaluate laboratory predicting biomarkers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 1, 2020</start_date>
  <completion_date type="Anticipated">December 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">March 1, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>In phase I period, patients that meet inclusion and exclusion criteria are enrolled to evaluate the safety, feasibility and pharmacokinetics of SHR2554 plus SHR1701. In the following phase II period, based on the recommended dose level from phase I study, enrolled patients are randomized to trial group (SHR2554 plus SHR1701) and control group (SHR1701) to assess the clinical efficacy of SHR2554 plus SHR1701 and immunomodulating effect of SHR2554 to SHR1701 in each cohort.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Median amount of time subject survives without disease progression following the initiation of treatment</measure>
    <time_frame>up to 36 months</time_frame>
    <description>The primary endpoint is progression free survival (PFS) after treatment. PFS is defined as the time from first treatment to the date of the first documented tumor progression or death due to any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with treatment related adverse events as assessed by CTCAE v5.0.</measure>
    <time_frame>Up to 90 days after the last dose of study drugs.</time_frame>
    <description>Establishing the safety profile following the initiation of treatment and grading these toxicities by CTCAE v5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percentage of subjects respond to treatment.</measure>
    <time_frame>up to 36 months</time_frame>
    <description>Overall response rate is defined as the sum of partial responses and complete responses.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median amount of times subjects alive after treatment</measure>
    <time_frame>up tp 36 months</time_frame>
    <description>The median overall survival (OS) time is defined as the time from enrollment to the date of death.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Solid Tumor</condition>
  <condition>Lymphoma</condition>
  <arm_group>
    <arm_group_label>SHR2554+ SHR1701</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug: SHR2554 recommended dose from phase Ⅰstudy, PO, twice a day, every 3 weeks SHR1701 30mg/kg IV over 30 minutes on day 1, every 3 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SHR1701</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug: SHR1701 30mg/kg IV over 30 minutes on day 1, every 3 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SHR2554+SHR1701</intervention_name>
    <description>SHR2554: recommended dose from phase I trial, PO, twice a day. SHR1701: 30mg/kg, IV, over 30 minutes</description>
    <arm_group_label>SHR2554+ SHR1701</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SHR1701</intervention_name>
    <description>SHR1701: 30mg/kg, IV, over 30 minutes</description>
    <arm_group_label>SHR1701</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Age from 18 to 70 years with estimated life expectancy &gt;3 months.&#xD;
&#xD;
          -  2. Histopathological confirmed locally advanced or metastatic systematically&#xD;
             pretreated epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK)&#xD;
             / c-ros oncogene 1 receptor kinase (ROS1) /BRAF negative non-small cell lung cancer&#xD;
             (adenocarcinoma or squamous cell carcinoma), pancreatic adenocarcinoma,&#xD;
             cholangiocarcinoma, gastrointestinal adenocarcinoma, triple-negative breast cancer and&#xD;
             relapsed/refractory B-cell lymphoma (All enrolled subjects with above solid carcinoma&#xD;
             are required to have received at least first-line systematic therapy and subjects with&#xD;
             R/R B-cell lymphoma need a history of at least two lines of previous treatment; For&#xD;
             solid carcinoma subjects enrolled in phase Ⅱ period, their previous treatment lines&#xD;
             are limited to no more than four lines; Besides previously treated subjects, subjects&#xD;
             with initially diagnosed pancreatic adenocarcinoma or cholangiocarcinoma are also&#xD;
             eligible for enrollment in phase Ⅱ period).&#xD;
&#xD;
          -  3. Have at least one measurable target lesion, determined by the site study team based&#xD;
             on RECIST 1.1 and immune related RECIST.&#xD;
&#xD;
          -  4. Fresh tumor samples or formalin-fixed paraffin embedded tumor archival samples&#xD;
             within 3 months are necessary; Fresh tumor samples are preferred. Subjects are willing&#xD;
             to accept tumor re-biopsy in the process of this study.&#xD;
&#xD;
          -  5. Previous treatment must be completed for more than 4 weeks prior to the enrollment&#xD;
             of this study, and subjects have recovered to &lt;= grade 1 toxicity.&#xD;
&#xD;
          -  6. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 1 at&#xD;
             the time of enrollment.&#xD;
&#xD;
          -  7. Have adequate organ function, as defined in the table below, which should be&#xD;
             confirmed within 2 weeks prior to the first dose of study drugs.&#xD;
&#xD;
               -  Leukocytes greater than or equal to 3.0 ×10^9/L.&#xD;
&#xD;
               -  Absolute neutrophil counts greater than or equal to 1.0 ×10^9/L.&#xD;
&#xD;
               -  Platelets greater than or equal to 100 ×10^9/L.&#xD;
&#xD;
               -  Hemoglobin greater than or equal to 90 g/L.&#xD;
&#xD;
               -  Total bilirubin less than or equal to 2 x ULN.&#xD;
&#xD;
               -  Serum albumin should be no less than 30 g/L.&#xD;
&#xD;
               -  Alanine aminotransferase or Aspartate aminotransferase less than 2 x Upper Limit&#xD;
                  of Normal (ULN).&#xD;
&#xD;
               -  Measured creatinine clearance ≥ 60 mL per min.&#xD;
&#xD;
          -  8. Previous treatment with anti-PD-1/PD-L1 antibodies or cytotoxic T lymphocyte&#xD;
             associated antigen 4 (CTLA-4) inhibitors are allowed.&#xD;
&#xD;
          -  9. Ability to understand and sign a written informed consent document.&#xD;
&#xD;
          -  10.Women of child-bearing potential must agree to use adequate contraception (hormonal&#xD;
             or barrier method of birth control; abstinence) prior to study entry, and up to 90&#xD;
             days after the last dose of the drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Active, known or suspected autoimmune diseases.&#xD;
&#xD;
          -  2. Known brain metastases or active central nervous system (CNS). Subjects with CNS&#xD;
             metastases who were treated with radiotherapy for at least 3 months prior to&#xD;
             enrollment, have no central nervous symptoms and are off corticosteroids, are eligible&#xD;
             for enrollment, but require a brain MRI screening.&#xD;
&#xD;
          -  3. Subjects are being treated with either corticosteroids (&gt;10 mg daily prednisone&#xD;
             equivalent) or other immunosuppressive medications within 14 days of enrollment.&#xD;
&#xD;
          -  4. History of severe hypersensitive reactions to other monoclonal antibodies.&#xD;
&#xD;
          -  5. History of allergy or intolerance to study drug components.&#xD;
&#xD;
          -  6. Substance abuse, medical, psychological or social conditions that may interfere&#xD;
             with the patient's participation in the study or evaluation of the study results.&#xD;
&#xD;
          -  7. History or concurrent condition of interstitial lung disease of any grade or&#xD;
             severely impaired pulmonary function.&#xD;
&#xD;
          -  8. Uncontrolled intercurrent illness, including ongoing or active systemic infection,&#xD;
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia&#xD;
             (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric&#xD;
             illness/social situations and any other illness that would limit compliance with study&#xD;
             requirements and jeopardize the safety of the patient.&#xD;
&#xD;
          -  9. History of human immunodeficiency virus (HIV) infection or acquired&#xD;
             immunodeficiency syndrome (AIDS).&#xD;
&#xD;
          -  10. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy&#xD;
             test performed within 7 days before the enrollment, and a negative result must be&#xD;
             documented.&#xD;
&#xD;
          -  11. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for&#xD;
             curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial&#xD;
             bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades&#xD;
             lamina propria)].&#xD;
&#xD;
          -  12. Vaccination within 30 days of study enrollment.&#xD;
&#xD;
          -  13. Active bleeding or known hemorrhagic tendency.&#xD;
&#xD;
          -  14. Subjects with unhealed surgical wounds for more than 30 days.&#xD;
&#xD;
          -  15. Being participating any other trials or withdraw within 4 weeks.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Weidong Han, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Department of Bio-therapeutic, Chinese PLA General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Weidong Han, PhD</last_name>
    <phone>+86-10-66937463</phone>
    <email>hanwdrsw@sina.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kaichao Feng, MD</last_name>
    <phone>+86-10-55499341</phone>
    <email>timothyfkc@126.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Biotherapeutic, Chinese PLA General Hospital</name>
      <address>
        <city>Beijing</city>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>KAICHAO FENG, MD</last_name>
      <phone>+86-10-55499341</phone>
      <email>timothyfkc@126.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>November 23, 2022</last_update_submitted>
  <last_update_submitted_qc>November 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chinese PLA General Hospital</investigator_affiliation>
    <investigator_full_name>Han weidong</investigator_full_name>
    <investigator_title>Director of Bio-therapeutic Department, Professor</investigator_title>
  </responsible_party>
  <keyword>Anti-PD-L1/TGFβ</keyword>
  <keyword>EZH2</keyword>
  <keyword>SHR2554</keyword>
  <keyword>SHR1701</keyword>
  <keyword>Advanced</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04407741
org study id: CHN-PLAGH-BT-055
nct id: NCT04407741
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The potency of immune checkpoint blockade is limited in most solid malignancies, one possible
      reason for which is tumor microenvironment. Enhancer of zeste homolog 2 (EZH2) as a
      epigenetic target for cancer therapy has attracted significant interest. The combination of
      EZH2 inhibitors and programmed death-1 ligands/ transforming growth factor-β (PD-L1/TGFβ)
      blockade may enhance the efficiency of immunotherapy.The primary objective of this study in
      phase Ⅰstage is to assess the safety, feasibility of EZH2 inhibitor SHR2554 in combination
      with anti-PD-L1/TGFβ antibody SHR1701 in advanced pretreated solid tumors and b-cell
      lymphomas. The phase Ⅱ stage of this study is to primarily evaluate the efficacy of SHR2554
      plus SHR1701 and the epigenetic modulating effect of SHR2554.
Immune checkpoint blockade has led to great strides in the management of various cancers,
      however, durable response could be seen in approximately 20% of treated patients with most
      solid malignancies. Immunosuppressive entities such as transforming growth factor-β (TGF-β)
      in the tumor microenvironment (TME) remain a major impediment. Enhancer of zeste homolog 2
      (EZH2) is the core component of the polycomb group complex, which play a major role in
      cellular proliferation and differentiation. EZH2 aberration has been seen in a wide range of
      solid tumors and hematological malignancies, affecting tumor progression and immune cells in
      the tumor microenvironment, and it is associated with poor clinical prognosis and outcomes.
      EZH2 is not only an activator of gene expression through different pathways, but also a
      critical epigenetic repressor through histone methylation. Therefore, EZH2 has attracted
      significant interest as a potential epigenetic target for cancer treatment. It is
      hypothesized that the combination of EZH2 inhibitors and programmed death-1 ligands/
      transforming growth factor-β (PD-L1/TGFβ) blockade could enhance the efficiency of
      immunotherapy.

      The primary objective of this study in phase Ⅰstage is to assess the safety, feasibility of
      EZH2 inhibitor SHR2554 in combination with anti-PD-L1/TGFβ antibody SHR1701 in advanced
      pretreated solid tumors and b-cell lymphomas. The second objectives include characterizing
      the pharmacokinetics of SHR2554 in combination with SHR1701, evaluating the preliminary
      efficacy of SHR2554 plus SHR1701 and the epigenetic modulating effect of SHR2554 in its
      combination with anti-PD-L1/TGFβ antibody. The exploratory objectives are to evaluate the
      pathological, immunological or clinical predictive factors for efficacy and toxicity. Based
      on the data of safety, efficacy and recommended dose level obtained from phase Ⅰtrial, this
      study moves into phase Ⅱ stage, in which enrolled subjects are randomized to SHR2554 plus SHR
      1701 or SHR1701 monotherapy, to primarily evaluate the efficacy of SHR2554 plus SHR1701 and
      the epigenetic modulating effect of SHR2554. The second objectives include evaluating safety
      and other efficacy parameters, such as overall response rate (ORR), disease control rate
      (DCR), duration of response (DOR) and overall survival (OS). The exploratory objectives are
      to evaluate laboratory predicting biomarkers.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: In phase I period, patients that meet inclusion and exclusion criteria are enrolled to evaluate the safety, feasibility and pharmacokinetics of SHR2554 plus SHR1701. In the following phase II period, based on the recommended dose level from phase I study, enrolled patients are randomized to trial group (SHR2554 plus SHR1701) and control group (SHR1701) to assess the clinical efficacy of SHR2554 plus SHR1701 and immunomodulating effect of SHR2554 to SHR1701 in each cohort.
primary purpose: Treatment
masking: None (Open Label)
measure: Median amount of time subject survives without disease progression following the initiation of treatment
time frame: up to 36 months
description: The primary endpoint is progression free survival (PFS) after treatment. PFS is defined as the time from first treatment to the date of the first documented tumor progression or death due to any cause.
measure: Number of subjects with treatment related adverse events as assessed by CTCAE v5.0.
time frame: Up to 90 days after the last dose of study drugs.
description: Establishing the safety profile following the initiation of treatment and grading these toxicities by CTCAE v5.0
measure: The percentage of subjects respond to treatment.
time frame: up to 36 months
description: Overall response rate is defined as the sum of partial responses and complete responses.
measure: Median amount of times subjects alive after treatment
time frame: up tp 36 months
description: The median overall survival (OS) time is defined as the time from enrollment to the date of death.
arm group label: SHR2554+ SHR1701
arm group type: Experimental
description: Drug: SHR2554 recommended dose from phase Ⅰstudy, PO, twice a day, every 3 weeks SHR1701 30mg/kg IV over 30 minutes on day 1, every 3 weeks
arm group label: SHR1701
arm group type: Experimental
description: Drug: SHR1701 30mg/kg IV over 30 minutes on day 1, every 3 weeks
intervention type: Drug
intervention name: SHR2554+SHR1701
description: SHR2554: recommended dose from phase I trial, PO, twice a day. SHR1701: 30mg/kg, IV, over 30 minutes
arm group label: SHR2554+ SHR1701
intervention type: Drug
intervention name: SHR1701
description: SHR1701: 30mg/kg, IV, over 30 minutes
arm group label: SHR1701
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Weidong Han, PhD
role: Study Director
affiliation: Department of Bio-therapeutic, Chinese PLA General Hospital
last name: Weidong Han, PhD
phone: +86-10-66937463
email: hanwdrsw@sina.com
last name: Kaichao Feng, MD
phone: +86-10-55499341
email: timothyfkc@126.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Chinese PLA General Hospital
investigator full name: Han weidong
investigator title: Director of Bio-therapeutic Department, Professor
mesh term: Lymphoma
sharing ipd: No