<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/NCT04476459</url>
  </required_header>
  <id_info>
    <org_study_id>CARD</org_study_id>
    <nct_id>NCT04476459</nct_id>
  </id_info>
  <brief_title>Camrelizumab in Combination With Apatinib in Refractory and Relapsed DLBCL</brief_title>
  <official_title>Camrelizumab in Combination With Apatinib in in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma: a Phase Ib/II, Multicentre, Open-label, Single-arm Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Huiqiang Huang</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sun Yat-sen University</source>
  <oversight_info>
    <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 will evaluate the efficacy and safety of camrelizumab in combination with apatinib&#xD;
      in in patients with relapsed or refractory diffuse large B cell lymphoma failed from second&#xD;
      line chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with relapsed /refractory diffuse large B cell lymphoma usually have a bad&#xD;
      prognosis. These patients cannot be treated successfully with the conventional chemotherapy&#xD;
      of CHOP. Apatinib is a new type of oral tyrosine kinase inhibitor targeting VEGFR-2. Some&#xD;
      studies have shown that the combination of low-dose apatinib and camrelizumab shows a&#xD;
      synergistic effect in the exploration of multiple solid tumors, and the adverse reactions of&#xD;
      low-dose apatinib are significantly reduced, and the patients are well tolerated.The&#xD;
      investigators will evaluate the efficacy and safety of camrelizumab in combination with&#xD;
      apatinib in the patients with relapsed refractory diffuse large B cell lymphomafailed from&#xD;
      second line chemotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 23, 2020</start_date>
  <completion_date type="Anticipated">August 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2022</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>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>Overall Response Rate (ORR), Investigator-Assessed</measure>
    <time_frame>upto 24 months</time_frame>
    <description>Overall response was determined on the basis of investigator assessments according to lymphoma response to immunomodulatory therapy criteria (LYRIC) for Malignant Lymphoma, 2016. Tumor assessments were performed with CT/MRI with or without PET.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The optimal dosage of apatinib combined with camrelizumab</measure>
    <time_frame>up to 6 months</time_frame>
    <description>Maximum tolerable dose（MTD）and dose-limiting toxicity（DLT）of apatinib will be conducted in Phase Ib clinical studies. MTD and DLT is defined as protocol-defined apatinib related events.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>up to 36 months</time_frame>
    <description>The time between the start of randomization and the progression of the tumor (any aspect) or (for any reason) death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>up to 36 months</time_frame>
    <description>Time from randomization to death for any reason Time from randomization to death for any reason Time from randomization to death for any reason Time from randomization to death for any reason</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response</measure>
    <time_frame>up to 36 months</time_frame>
    <description>The time from the first assessment of CR or PR to PD (progressive disease) or death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time To Progression</measure>
    <time_frame>up to 36 months</time_frame>
    <description>Time from randomization to PD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Adverse Events (AEs)</measure>
    <time_frame>Up to 36 months</time_frame>
    <description>An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">33</enrollment>
  <condition>Diffuse Large B Cell Lymphoma</condition>
  <condition>High-grade B-cell Lymphoma</condition>
  <condition>Follicular Lymphoma Grade IIIb</condition>
  <condition>Transformed Lymphoma</condition>
  <condition>EBV-Positive DLBCL, Nos</condition>
  <condition>ALK-Positive Anaplastic Large Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>camrelizumab in combination with apatinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Apatinib should be given at a fixed time. On the day of camrelizumab infusion, Apatinib should be taken 30 minutes after the end of camrelizumab infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Camrelizumab</intervention_name>
    <description>Camrelizumab will be administered every 3 weeks up to 6 cycles during induction phase, and then every 4 weeks up to 12 cycles in maintenance phase if patients get CR or PR after induction phase.</description>
    <arm_group_label>camrelizumab in combination with apatinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apatinib</intervention_name>
    <description>Phase I: dose escalation phase. Patients will oral dosage as 250mg, 500mg or 750mg,qd, per day. Aim to evaluate MTD and DLT, RP2D.&#xD;
Phase II：Patients continuous oral apatinib as RP2D up to 6 cycles during induction phase, and then 250mg/d up to 1 year in maintenance phase if patients get CR or PR after induction phase.</description>
    <arm_group_label>camrelizumab in combination with apatinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age range 18-80 years old; male or female&#xD;
&#xD;
          2. DLBCL, or follicular lymphoma grade 3B, or transformed DLBCL, EBV (+) DLBCL, ALK (+)&#xD;
             DLBCL, high-grade lymphoma were confirmed by histopathology examination;&#xD;
&#xD;
          3. Failed from standard first-line rituximab-contained chemotherapy, and relapsed or&#xD;
             refractory after second-line regimens with or without rituximab.&#xD;
&#xD;
          4. Estimated survival time &gt; 3 months.&#xD;
&#xD;
          5. There must be at least one evaluate able or measurable lesion that meets the LYRIC&#xD;
             2016 Malignant Lymphoma criteria [evaluable lesion: 18F-fluorodeoxyglucose/Positron&#xD;
             Emission Tomography (18FDG/PET) examination showing increased lymph node or extranodal&#xD;
             uptake (higher than liver) and PET and/or computed tomography (Computed Tomography)&#xD;
             CT) features are consistent with lymphoma findings; lesions can be measured: nodular&#xD;
             lesions &gt; 15mm or extranodal lesions &gt; 10mm (if the only measurable lesion has&#xD;
             received radiotherapy in the past, there must be evidence of radiological progress&#xD;
             after radiotherapy), and accompanied by increased 18FDG uptake). Except for this,&#xD;
             there is no measurable increase in diffuse 18FDG uptake in the liver;&#xD;
&#xD;
          6. ECOG performance status 0-2.&#xD;
&#xD;
          7. Prior chemotherapy and radiotherapy should have been completed more than 4 weeks.&#xD;
&#xD;
          8. Adequate organ and bone marrow function, no severe hematopoietic dysfunction, cardiac,&#xD;
             pulmonary, liver, kidney, thyroid dysfunction and immune deficiency (no blood&#xD;
             transfusion, granulocyte colony stimulating factor or other medical support was&#xD;
             received within 14 days prior to the use of the research drug): 1) The absolute value&#xD;
             of neutrophils (&gt;1.5×10^9/L); 2) platelet count (&gt; 75×10^9/L); 3) Hemoglobin (&gt; 9&#xD;
             g/dL); 4) Upper Limit Normal (ULN) or creatinine clearance rate (&gt;40 mL/min) of serum&#xD;
             creatinine (&lt;1.5 times normal value upper limit) (estimated by Cockcroft-Gault&#xD;
             formula); 5) Serum total bilirubin &lt; 1.5 times ULN; 6) Aspartate Aminotransferase&#xD;
             (AST), Alanine Aminotransferase (ALT) = 2.5 times ULN; 7) Coagulation function:&#xD;
             International Normalized Ratio (INR) = 1.5 times ULN; Prothrombin Time (PT), Activated&#xD;
             Partial Thromboplastin Time (APTT) = 1.5 times ULN (unless the subject is receiving&#xD;
             anticoagulant therapy and PT and APTT are using anticoagulant therapy at screening&#xD;
             time). Within the expected range; 8) Thyrotropin (TSH) or free thyroxine (FT4) or free&#xD;
             triiodothyronine (FT3) were all within the normal range (+10%);&#xD;
&#xD;
          9. There was no evidence that subjects had difficulty breathing at rest, and the measured&#xD;
             value of pulse oximetry at rest was more than 92%;&#xD;
&#xD;
         10. Participants must pass a pulmonary function test (PFT) to confirm that forced&#xD;
             expiratory volume (FEV1)/forced vital capacity (FVC) in the first second is more than&#xD;
             60%, unless it is a large mediastinal mass caused by lymphoma that cannot meet this&#xD;
             standard; carbon monoxide diffusion (DLCO), FEV1 and FVC are all above 50% of the&#xD;
             predicted value; all PFT results must be obtained within four weeks before the first&#xD;
             administration;&#xD;
&#xD;
         11. Female patients of childbearing age must have a negative pregnancy test at the time of&#xD;
             enrollment and are willing to use reliable contraceptive methods, i.e. barrier&#xD;
             methods, oral contraceptives, implant methods, skin contraception, long-acting&#xD;
             injection contraceptives, intrauterine devices, or tubal ligation;&#xD;
&#xD;
         12. Paraffin tissue specimens or fresh puncture tissue specimens are available;&#xD;
&#xD;
         13. Volunteers who signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Primary central nervous system lymphoma or secondary central nervous system&#xD;
             involvement;&#xD;
&#xD;
          2. Hemophagocytic syndrome;&#xD;
&#xD;
          3. Previously treated with immunological checkpoint inhibitors (PD-1, PD-L1, CTLA-4,&#xD;
             etc.);&#xD;
&#xD;
          4. Previously treated with Apatinib.&#xD;
&#xD;
          5. Patients with active autoimmune diseases requiring systematic treatment in the past&#xD;
             two years (hormone replacement therapy is not considered systematic treatment, such as&#xD;
             type I diabetes mellitus, hypothyroidism requiring only thyroxine replacement therapy,&#xD;
             adrenocortical dysfunction or pituitary dysfunction requiring only physiological doses&#xD;
             of glucocorticoid replacement therapy); Patients with autoimmune diseases who do not&#xD;
             require systematic treatment within two years can be enrolled;&#xD;
&#xD;
          6. Begin the study on subjects requiring systemic glucocorticoid therapy or other&#xD;
             immunosuppressive therapy for a given condition within 14 days before treatment&#xD;
             [allowing subjects to use local, ocular, intra-articular, intranasal and inhaled&#xD;
             glucocorticoid therapy (with very low systemic absorption); and allowing short-term (&lt;&#xD;
             7 days) glucocorticoid prophylaxis (e.g., contrast agent overdose) Sensitivity) or for&#xD;
             the treatment of non-autoimmune diseases (e.g. delayed hypersensitivity caused by&#xD;
             contact allergens), except for tumor reduction due to large tumor burden (prednisone&#xD;
             30mg, bid × 5 days or equivalent dose of other glucocorticoid therapy);&#xD;
&#xD;
          7. In the past five years, patients with other malignant tumors have undergone radical&#xD;
             treatment, except for basal cell carcinoma of skin, squamous cell carcinoma of skin,&#xD;
             carcinoma in situ of breast and carcinoma in situ of cervix;&#xD;
&#xD;
          8. Begin the study and receive systemic antineoplastic therapy within 28 days before&#xD;
             treatment, including chemotherapy, immunotherapy, biotherapy (cancer vaccine,&#xD;
             cytokines, or growth factors that control cancer), etc.;&#xD;
&#xD;
          9. The study began with AHST(Autologous Hemopoietic Stem Cell Transplantation) within&#xD;
             1month before treatment or Allo-HSCT(Allogeneic Hematopoietic Stem Cell&#xD;
             Transplantation) within 3 months before treatment;&#xD;
&#xD;
         10. The study began with major surgery within 28 days before treatment or radiotherapy&#xD;
             within 90 days before treatment;&#xD;
&#xD;
         11. Start the study and receive Chinese herbal medicine or Chinese 12.patent medicine&#xD;
             treatment within 7 days before treatment;&#xD;
&#xD;
         12. Begin research on live vaccination (except influenza attenuated vaccine) within 28&#xD;
             days before treatment;&#xD;
&#xD;
         13. History of human immunodeficiency virus (HIV) infection and/or patients with acquired&#xD;
             immunodeficiency syndrome are known;&#xD;
&#xD;
         14. Patients with active hepatitis B or active hepatitis C. Patients who are positive for&#xD;
             hepatitis B Surface Antigen (HBsAg) or hepatitis C Virus (HCV) antibodies at screening&#xD;
             stage must pass further detection of hepatitis B Virus (HBV) DNA titer (no more than&#xD;
             2500 copies/mL or 500 IU/mL) and HCV RNA (no more than the lower limit of the&#xD;
             detection method) in the row. In addition to active hepatitis B or hepatitis C&#xD;
             infections requiring treatment, group trials can be conducted. Hepatitis B carriers,&#xD;
             stable hepatitis B (DNA titer should not be higher than 2500 copies/mL or 500 IU/mL)&#xD;
             after drug treatment, and cured hepatitis C patients can be enrolled in the group; 19.&#xD;
             Patients with active pulmonary tuberculosis;&#xD;
&#xD;
         15. Start studying any active infections requiring systemic anti-infective treatment&#xD;
             within 14 days of treatment.&#xD;
&#xD;
         16. Pregnant or lactating women;&#xD;
&#xD;
         17. People with known history of alcoholism or drug abuse;&#xD;
&#xD;
         18. History of interstitial lung disease or non-infectious pneumonia. Subjects who had&#xD;
             previously had non-infectious pneumonia caused by drugs or radiation but had no&#xD;
             symptoms were allowed to enter the group;&#xD;
&#xD;
         19. Past psychiatric history; incapacitated or restricted;&#xD;
&#xD;
         20. According to the researchers' judgment, patients' underlying condition may increase&#xD;
             their risk of receiving research drug treatment, or confuse their judgment on toxic&#xD;
             reactions;&#xD;
&#xD;
         21. Other researchers consider it unsuitable for patients to participate in this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Huiqiang Huang, Professor</last_name>
    <phone>+86 020 87343350</phone>
    <email>huanghq@sysucc.org.cn</email>
  </overall_contact>
  <location>
    <facility>
      <name>Department of Medical Oncology, Sun Yat-sen University Cancer Center,</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>HuiQiang Huang</last_name>
      <phone>86-020-87343350</phone>
      <email>huanghq@sysucc.org.cn</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>July 15, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>March 10, 2021</last_update_submitted>
  <last_update_submitted_qc>March 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 15, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
    <investigator_full_name>Huiqiang Huang</investigator_full_name>
    <investigator_title>professor</investigator_title>
  </responsible_party>
  <keyword>DLBCL</keyword>
  <keyword>relapsed</keyword>
  <keyword>refractory</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
    <mesh_term>Lymphoma, Large-Cell, Anaplastic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apatinib</mesh_term>
  </intervention_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/NCT04476459
org study id: CARD
nct id: NCT04476459
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This study will evaluate the efficacy and safety of camrelizumab in combination with apatinib
      in in patients with relapsed or refractory diffuse large B cell lymphoma failed from second
      line chemotherapy.
Patients with relapsed /refractory diffuse large B cell lymphoma usually have a bad
      prognosis. These patients cannot be treated successfully with the conventional chemotherapy
      of CHOP. Apatinib is a new type of oral tyrosine kinase inhibitor targeting VEGFR-2. Some
      studies have shown that the combination of low-dose apatinib and camrelizumab shows a
      synergistic effect in the exploration of multiple solid tumors, and the adverse reactions of
      low-dose apatinib are significantly reduced, and the patients are well tolerated.The
      investigators will evaluate the efficacy and safety of camrelizumab in combination with
      apatinib in the patients with relapsed refractory diffuse large B cell lymphomafailed from
      second line chemotherapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate (ORR), Investigator-Assessed
time frame: upto 24 months
description: Overall response was determined on the basis of investigator assessments according to lymphoma response to immunomodulatory therapy criteria (LYRIC) for Malignant Lymphoma, 2016. Tumor assessments were performed with CT/MRI with or without PET.
measure: The optimal dosage of apatinib combined with camrelizumab
time frame: up to 6 months
description: Maximum tolerable dose（MTD）and dose-limiting toxicity（DLT）of apatinib will be conducted in Phase Ib clinical studies. MTD and DLT is defined as protocol-defined apatinib related events.
measure: Progression-free Survival
time frame: up to 36 months
description: The time between the start of randomization and the progression of the tumor (any aspect) or (for any reason) death
measure: Overall Survival
time frame: up to 36 months
description: Time from randomization to death for any reason Time from randomization to death for any reason Time from randomization to death for any reason Time from randomization to death for any reason
measure: Duration of Response
time frame: up to 36 months
description: The time from the first assessment of CR or PR to PD (progressive disease) or death from any cause
measure: Time To Progression
time frame: up to 36 months
description: Time from randomization to PD
measure: Percentage of Participants With Adverse Events (AEs)
time frame: Up to 36 months
description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
arm group label: camrelizumab in combination with apatinib
arm group type: Experimental
description: Apatinib should be given at a fixed time. On the day of camrelizumab infusion, Apatinib should be taken 30 minutes after the end of camrelizumab infusion
intervention type: Drug
intervention name: Camrelizumab
description: Camrelizumab will be administered every 3 weeks up to 6 cycles during induction phase, and then every 4 weeks up to 12 cycles in maintenance phase if patients get CR or PR after induction phase.
arm group label: camrelizumab in combination with apatinib
intervention type: Drug
intervention name: Apatinib
description: Phase I: dose escalation phase. Patients will oral dosage as 250mg, 500mg or 750mg,qd, per day. Aim to evaluate MTD and DLT, RP2D.
Phase II：Patients continuous oral apatinib as RP2D up to 6 cycles during induction phase, and then 250mg/d up to 1 year in maintenance phase if patients get CR or PR after induction phase.
arm group label: camrelizumab in combination with apatinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Huiqiang Huang, Professor
phone: +86 020 87343350
email: huanghq@sysucc.org.cn
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor-Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Huiqiang Huang
investigator title: professor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Lymphoma, Large-Cell, Anaplastic
mesh term: Apatinib
sharing ipd: No