<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/NCT03035331</url>
  </required_header>
  <id_info>
    <org_study_id>MC1685</org_study_id>
    <secondary_id>NCI-2017-00113</secondary_id>
    <secondary_id>MC1685</secondary_id>
    <secondary_id>P30CA015083</secondary_id>
    <secondary_id>P50CA097274</secondary_id>
    <nct_id>NCT03035331</nct_id>
  </id_info>
  <brief_title>Dendritic Cell Therapy, Cryosurgery, and Pembrolizumab in Treating Patients With Non-Hodgkin Lymphoma</brief_title>
  <official_title>Phase I/II Study of Dendritic Cell Therapy Delivered Intratumorally After Cryoablation and Anti-PD-1 Antibody (Pembrolizumab) for Patients With Non-Hodgkin Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I/II trial studies the best dose and side effects of dendritic cell therapy,&#xD;
      cryosurgery and pembrolizumab in treating patients with non-Hodgkin lymphoma. Vaccines, such&#xD;
      as dendritic cell therapy made from a person's tumor cells and white blood cells may help the&#xD;
      body build an effective immune response to kill tumor cells. Cryosurgery kills cancer cells&#xD;
      by freezing them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help&#xD;
      the body's immune system attack the cancer, and may interfere with the ability of tumor cells&#xD;
      to grow and spread. Giving dendritic cell therapy, cryosurgery and pembrolizumab may work&#xD;
      better at treating non-Hodgkin lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the optimal dose schedule, safety and tolerability as measured by the incidence&#xD;
      of significant toxicity of combination therapy with anti-PD-1 monoclonal antibody,&#xD;
      cryoablation, and intra-tumor injection of autologous dendritic cell into the cryoablated&#xD;
      tumor. (Phase I) II. Test the efficacy (overall response rate) of combination therapy with&#xD;
      anti-PD-1 monoclonal antibody, cryoablation, and intra-tumor injection of autologous&#xD;
      dendritic cell vaccine. (Phase II)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Evaluate the feasibility of this combination immunotherapy. (Phase I) II. Evaluate patient&#xD;
      quality of life. (Phase I) III. Evaluate the partial response (PR) and complete response (CR)&#xD;
      rate of this combination immunotherapy. (Phase II) IV. Evaluate the progression free&#xD;
      survival, treatment free survival, duration of response, disease-free rate at 2 years, and&#xD;
      overall survival of this combination immunotherapy. (Phase II) V. Evaluate the safety of this&#xD;
      combination immunotherapy. (Phase II)&#xD;
&#xD;
      CORRELATIVE OBJECTIVES:&#xD;
&#xD;
      I. Assess the effect of combination immunotherapy on patients' immune status and anti-tumor&#xD;
      immune response. (Phase II) II. Assess the potential association between PD-1/PD-L1/PD-L2&#xD;
      expression in tumor and blood with clinical efficacy. (Phase II) III. Assess the potential&#xD;
      association between tumor antigen mutations and antigen-specific immune response with&#xD;
      clinical efficacy. (Phase II) IV. Evaluate patient quality of life. (Phase II)&#xD;
&#xD;
      OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.&#xD;
&#xD;
      Patients receive pembrolizumab intravenously (IV) on day 1. Treatment repeats every 21 days&#xD;
      for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients&#xD;
      also receive dendritic cell therapy intratumorally (IT) on days 2, 8, and 15 of cycles 2 and&#xD;
      3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive&#xD;
      pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment&#xD;
      repeats every 21 days for up to 5 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity. Patients who are CR, PR, or stable disease (SD) after completion of&#xD;
      therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease&#xD;
      progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months during the first&#xD;
      year post-treatment, every 4 months during the second year post-treatment, and then every 6&#xD;
      months for up to 2 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 27, 2017</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">August 2024</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>Maximum tolerated dose (MTD)</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>MTD will be defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of complete responses of combination therapy with pembrolizumab, cryoablation, and intra-tumor injection of autologous dendritic cells (DC) at maximum tolerated dose (MTD) dose</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Complete response</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated. The response rate will be calculated, in each individual cohort as supplementary.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The distribution of survival time will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment free survival</measure>
    <time_frame>From registration to next treatment or death due to any cause, assessed up to 4 years</time_frame>
    <description>The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease free survival rate</measure>
    <time_frame>At 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From registration to death due to any cause, assessed up to 2 years</time_frame>
    <description>The distribution of survival time will be estimated using the method of Kaplan-Meier.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be assessed by Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event at each evaluation will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Longitudinal analysis techniques will be utilized to determine the effect of time on treatment adverse events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be measured using the Functional Assessment of Cancer Therapy-lymphoma. The assessment will be scored according to the scoring algorithm. Changes from baseline will be calculated at each assessment time points. Mean change scores at each time point will be calculated to determine if quality of life is reduced over the course of treatment. Longitudinal techniques will be employed to describe changes over time.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Radiologic analysis</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Measurements of index lesion(s) (non-cryoablated lesion) will be evaluated over time for each patient as a marker of systemic immune and treatment response to pembrolizumab and localized treatment with cryoablation and dendritic cell therapy. The index lesion(s) will be selected by the treating physician/investigator and are noncryoablated node. The percent change from baseline in index lesion measurements will be assessed over time. Differences in values over time will be summarized descriptively and graphically. The whole body computed tomography (CT) or positron emission tomography/CT will be used to assess overall clinical response and time to progression using the standard Cheson criteria.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in immunologic correlates</measure>
    <time_frame>Baseline up to 4 years</time_frame>
    <description>Will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually, but will also be evaluated in terms of their relationships to one another; i.e., will use Spearman rank correlation coefficient to assess the correlations between baseline levels as well as between changes before and after treatment in these immunologic markers. In addition, these immunologic markers will be correlated with cancer and treatment- related outcomes (e.g. response, toxicities). Relationships will also be explored graphically using scatter plots.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">11</enrollment>
  <condition>Aggressive Non-Hodgkin Lymphoma</condition>
  <condition>Indolent Non-Hodgkin Lymphoma</condition>
  <condition>Recurrent Diffuse Large B-Cell Lymphoma</condition>
  <condition>Recurrent Follicular Lymphoma</condition>
  <condition>Recurrent Mantle Cell Lymphoma</condition>
  <condition>Recurrent Marginal Zone Lymphoma</condition>
  <condition>Recurrent Non-Hodgkin Lymphoma</condition>
  <condition>Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma</condition>
  <condition>Recurrent T-Cell Non-Hodgkin Lymphoma</condition>
  <condition>Small Lymphocytic Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Cryosurgery</intervention_name>
    <description>Undergo cryosurgery</description>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
    <other_name>Ablation, Cryo</other_name>
    <other_name>Cryoablation</other_name>
    <other_name>cryosurgical ablation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Dendritic Cell Therapy</intervention_name>
    <description>Given IT</description>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
    <other_name>Dendritic Cell Vaccine Therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Lambrolizumab</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pneumococcal 13-valent Conjugate Vaccine</intervention_name>
    <description>Given by injection</description>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
    <other_name>PCV 13</other_name>
    <other_name>PCV13 Vaccine</other_name>
    <other_name>Prevnar 13</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
          -  Histological confirmation of biopsy-proven non-Hodgkin lymphoma, excluding chronic&#xD;
             lymphocytic leukemia, primary central nervous system (CNS) lymphoma and Burkitt's&#xD;
             lymphoma; Note: small lymphocytic lymphoma (SLL) is allowed&#xD;
&#xD;
          -  Patients with indolent non-Hodgkin lymphoma (NHL) must have had &gt;= 1 regimen of&#xD;
             rituximab-containing regimen; Note: this includes follicular lymphoma (FL), marginal&#xD;
             lymphoma and mucosa-associated lymphoid tissue (MALT)&#xD;
&#xD;
          -  Patients with aggressive NHL must have had &gt;= 2 regimens; Note: This includes diffuse&#xD;
             large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), primary mediastinal large&#xD;
             B-cell lymphoma (PMBCL), and T cell lymphoma&#xD;
&#xD;
          -  Patient with aggressive NHL must have received prior therapy - at a minimum:&#xD;
&#xD;
               -  Anti-CD20 monoclonal antibody unless tumor is CD20 negative and&#xD;
&#xD;
               -  An anthracycline containing regimen&#xD;
&#xD;
               -  Transformed FL must have had therapy for FL and be refractory to chemotherapy for&#xD;
                  DLBCL&#xD;
&#xD;
          -  Chemotherapy refractory disease in aggressive NHL is defined as&#xD;
&#xD;
               -  Stable disease of =&lt; 12 months or progressive disease as best response to most&#xD;
                  recent chemotherapy containing regimen&#xD;
&#xD;
               -  Disease progression or recurrence =&lt; 12 months of prior autologous stem cell&#xD;
                  transplantation (SCT)&#xD;
&#xD;
          -  Patients with aggressive NHL must have failed autologous hematopoietic stem cell&#xD;
             transplantation (HSCT), or are ineligible or not consenting to autologous HSCT&#xD;
&#xD;
          -  Patient must have at least 3 measurable lesions that are &gt;= 1.5 cm in one dimension;&#xD;
             one of the lesions must be &gt;= 2.0 cm and is amenable to image-guided cryoablation and&#xD;
             multiple vaccine injections as determined by interventional radiology and principal&#xD;
             investigator (PI) (including tumors that can be safely accessed using imaging guidance&#xD;
             and treated with minimal risk to adjacent structures)&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1000/mm^3 (obtained =&lt; 14 days prior to&#xD;
             registration)&#xD;
&#xD;
          -  Absolute lymphocyte count &gt;= 200/mm^3 (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Platelet count &gt;= 50,000/mm^3 (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Hemoglobin &gt;= 8.0 g/dL (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x upper limit of normal (ULN), unless due to Gilbert's disease&#xD;
             (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Aspartate transaminase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and&#xD;
             alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) =&lt; 2.5 x ULN&#xD;
             (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x ULN or calculated creatinine clearance &gt;= 60 mL/min for subject&#xD;
             with creatinine ˃ 1.5 x institutional ULN (obtained =&lt; 14 days prior to registration)&#xD;
&#xD;
          -  Negative serum pregnancy test for women of childbearing potential =&lt; 7 days prior to&#xD;
             registration; Note: a second pregnancy test may be required =&lt; 72 hours prior to&#xD;
             receiving the first dose of study medication&#xD;
&#xD;
          -  Negative human immunodeficiency virus (HIV), hepatitis B and C, and tuberculosis (TB)&#xD;
             test&#xD;
&#xD;
          -  Provide written informed consent&#xD;
&#xD;
          -  Willing to return to the enrolling institution for follow-up (during active treatment&#xD;
             and active monitoring phase of the study)&#xD;
&#xD;
          -  Ability to complete questionnaire(s) by themselves or with assistance&#xD;
&#xD;
          -  Willing to provide tissue and blood samples for research purposes&#xD;
&#xD;
          -  Willing to use adequate contraception while on the study and until 120 days after the&#xD;
             last dose of study drug&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any of the following because this study involves an investigational agent whose&#xD;
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are&#xD;
             unknown:&#xD;
&#xD;
               -  Pregnant women&#xD;
&#xD;
               -  Nursing women&#xD;
&#xD;
          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment&#xD;
             of the investigator, would make the patient inappropriate for entry into this study or&#xD;
             interfere significantly with the proper assessment of safety and toxicity of the&#xD;
             prescribed regimens&#xD;
&#xD;
          -  Serious non-malignant disease such as active infection, symptomatic congestive heart&#xD;
             failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social&#xD;
             situations or other conditions which in the opinion of the investigator would&#xD;
             compromise protocol objectives&#xD;
&#xD;
          -  Currently receiving or have received any other investigational agent considered as a&#xD;
             treatment for the primary neoplasm =&lt; 28 days or within 4 half-lives (whichever is&#xD;
             shorter) of the agent prior to registration&#xD;
&#xD;
          -  History of other primary malignancy requiring systemic treatment within 6 months of&#xD;
             protocol enrollment; patients must not be receiving chemotherapy or immunotherapy for&#xD;
             another cancer; patients must not have another active malignancy requiring active&#xD;
             treatment with the following acceptable EXCEPTIONS:&#xD;
&#xD;
               -  Basal cell carcinoma, squamous cell carcinoma, or melanoma of the skin that has&#xD;
                  undergone or will undergo potentially curative therapy&#xD;
&#xD;
               -  In situ cervical cancer that has undergone or will undergo potentially curative&#xD;
                  therapy&#xD;
&#xD;
          -  Prior allogeneic bone marrow or peripheral blood stem cell transplantation&#xD;
&#xD;
          -  Prior autologous bone marrow or peripheral blood stem cell transplantation =&lt; 100 days&#xD;
             prior to registration or if recovery from the transplant is inadequate&#xD;
&#xD;
          -  Major surgery other than diagnostic surgery =&lt; 4 weeks prior to registration&#xD;
&#xD;
          -  Prior chemotherapy or radiation therapy =&lt; 2 weeks prior to registration or who has&#xD;
             not recovered (i.e. to =&lt; grade 1 or baseline) from an adverse event due to the&#xD;
             previously administered therapy&#xD;
&#xD;
          -  History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine or any&#xD;
             component of the formulation, including diphtheria toxoid&#xD;
&#xD;
          -  Active autoimmune disease such as Crohn's disease, rheumatoid arthritis, Sjogren's&#xD;
             disease, systemic lupus erythematosus, or similar conditions requiring systemic&#xD;
             treatment within the past 3 months or a documented history of clinically severe&#xD;
             autoimmune disease/syndrome difficult to control in the past&#xD;
&#xD;
               -  EXCEPTIONS:&#xD;
&#xD;
                    -  Vitiligo or resolved childhood asthma/atopy&#xD;
&#xD;
                    -  Intermittent use of bronchodilators or local steroid injections&#xD;
&#xD;
                    -  Hypothyroidism stable on hormone replacement,&#xD;
&#xD;
                    -  Diabetes stable with current management&#xD;
&#xD;
                    -  History of positive Coombs test but no evidence of hemolysis&#xD;
&#xD;
                    -  Psoriasis not requiring systemic treatment&#xD;
&#xD;
                    -  Conditions not expected to recur in the absence of an external trigger&#xD;
&#xD;
          -  Coagulopathy, including the use of Coumadin or heparin anticoagulants that cannot be&#xD;
             discontinued for the cryoablation procedure; NOTE: heparin for line patency without&#xD;
             detectable lab abnormalities for coagulation will be allowed&#xD;
&#xD;
          -  Corticosteroid use =&lt; 2 weeks prior to registration; NOTE: patients must be off&#xD;
             corticosteroids for at least 2 weeks prior to registration; this includes oral, IV,&#xD;
             subcutaneous, or inhaled route of administration; patients on chronic corticosteroid&#xD;
             for adrenal insufficiency or other reasons may enroll if they receive less than 10&#xD;
             mg/day of prednisone (or equivalent)&#xD;
&#xD;
          -  Active CNS malignancy&#xD;
&#xD;
          -  Evidence of interstitial lung disease or active, non-infectious pneumonitis&#xD;
&#xD;
          -  Received a live vaccine =&lt; 30 days prior to registration&#xD;
&#xD;
          -  New York Heart Association classification III or IV cardiovascular disease or recent&#xD;
             myocardial infarction or unstable angina pectoris or cardiac arrhythmia =&lt; 30 days&#xD;
             prior to registration&#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>Yi Lin</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>January 26, 2017</study_first_submitted>
  <study_first_submitted_qc>January 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>August 10, 2023</last_update_submitted>
  <last_update_submitted_qc>August 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 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>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
    <mesh_term>Lymphoma, T-Cell</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Vaccines</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03035331
org study id: MC1685
secondary id: NCI-2017-00113
secondary id: MC1685
secondary id: P30CA015083
secondary id: P50CA097274
nct id: NCT03035331
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I/II trial studies the best dose and side effects of dendritic cell therapy,
      cryosurgery and pembrolizumab in treating patients with non-Hodgkin lymphoma. Vaccines, such
      as dendritic cell therapy made from a person's tumor cells and white blood cells may help the
      body build an effective immune response to kill tumor cells. Cryosurgery kills cancer cells
      by freezing them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help
      the body's immune system attack the cancer, and may interfere with the ability of tumor cells
      to grow and spread. Giving dendritic cell therapy, cryosurgery and pembrolizumab may work
      better at treating non-Hodgkin lymphoma.
PRIMARY OBJECTIVES:

      I. Evaluate the optimal dose schedule, safety and tolerability as measured by the incidence
      of significant toxicity of combination therapy with anti-PD-1 monoclonal antibody,
      cryoablation, and intra-tumor injection of autologous dendritic cell into the cryoablated
      tumor. (Phase I) II. Test the efficacy (overall response rate) of combination therapy with
      anti-PD-1 monoclonal antibody, cryoablation, and intra-tumor injection of autologous
      dendritic cell vaccine. (Phase II)

      SECONDARY OBJECTIVES:

      I. Evaluate the feasibility of this combination immunotherapy. (Phase I) II. Evaluate patient
      quality of life. (Phase I) III. Evaluate the partial response (PR) and complete response (CR)
      rate of this combination immunotherapy. (Phase II) IV. Evaluate the progression free
      survival, treatment free survival, duration of response, disease-free rate at 2 years, and
      overall survival of this combination immunotherapy. (Phase II) V. Evaluate the safety of this
      combination immunotherapy. (Phase II)

      CORRELATIVE OBJECTIVES:

      I. Assess the effect of combination immunotherapy on patients' immune status and anti-tumor
      immune response. (Phase II) II. Assess the potential association between PD-1/PD-L1/PD-L2
      expression in tumor and blood with clinical efficacy. (Phase II) III. Assess the potential
      association between tumor antigen mutations and antigen-specific immune response with
      clinical efficacy. (Phase II) IV. Evaluate patient quality of life. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

      Patients receive pembrolizumab intravenously (IV) on day 1. Treatment repeats every 21 days
      for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients
      also receive dendritic cell therapy intratumorally (IT) on days 2, 8, and 15 of cycles 2 and
      3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive
      pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment
      repeats every 21 days for up to 5 cycles in the absence of disease progression or
      unacceptable toxicity. Patients who are CR, PR, or stable disease (SD) after completion of
      therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months during the first
      year post-treatment, every 4 months during the second year post-treatment, and then every 6
      months for up to 2 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD)
time frame: Up to 4 years
description: MTD will be defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients.
measure: Proportion of complete responses of combination therapy with pembrolizumab, cryoablation, and intra-tumor injection of autologous dendritic cells (DC) at maximum tolerated dose (MTD) dose
time frame: Up to 4 years
description: The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated.
measure: Complete response
time frame: Up to 4 years
description: The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated. The response rate will be calculated, in each individual cohort as supplementary.
measure: Progression free survival
time frame: Up to 4 years
description: The distribution of survival time will be estimated using the method of Kaplan-Meier.
measure: Treatment free survival
time frame: From registration to next treatment or death due to any cause, assessed up to 4 years
description: The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.
measure: Duration of response
time frame: Up to 4 years
description: The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.
measure: Disease free survival rate
time frame: At 2 years
measure: Overall survival
time frame: From registration to death due to any cause, assessed up to 2 years
description: The distribution of survival time will be estimated using the method of Kaplan-Meier.
measure: Incidence of adverse events
time frame: Up to 4 years
description: Will be assessed by Common Terminology Criteria for Adverse Events version 4.0. The maximum grade for each type of adverse event at each evaluation will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Longitudinal analysis techniques will be utilized to determine the effect of time on treatment adverse events.
measure: Quality of life
time frame: Up to 4 years
description: Will be measured using the Functional Assessment of Cancer Therapy-lymphoma. The assessment will be scored according to the scoring algorithm. Changes from baseline will be calculated at each assessment time points. Mean change scores at each time point will be calculated to determine if quality of life is reduced over the course of treatment. Longitudinal techniques will be employed to describe changes over time.
measure: Radiologic analysis
time frame: Up to 4 years
description: Measurements of index lesion(s) (non-cryoablated lesion) will be evaluated over time for each patient as a marker of systemic immune and treatment response to pembrolizumab and localized treatment with cryoablation and dendritic cell therapy. The index lesion(s) will be selected by the treating physician/investigator and are noncryoablated node. The percent change from baseline in index lesion measurements will be assessed over time. Differences in values over time will be summarized descriptively and graphically. The whole body computed tomography (CT) or positron emission tomography/CT will be used to assess overall clinical response and time to progression using the standard Cheson criteria.
measure: Change in immunologic correlates
time frame: Baseline up to 4 years
description: Will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually, but will also be evaluated in terms of their relationships to one another; i.e., will use Spearman rank correlation coefficient to assess the correlations between baseline levels as well as between changes before and after treatment in these immunologic markers. In addition, these immunologic markers will be correlated with cancer and treatment- related outcomes (e.g. response, toxicities). Relationships will also be explored graphically using scatter plots.
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
arm group type: Experimental
description: Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Procedure
intervention name: Cryosurgery
description: Undergo cryosurgery
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
other name: Ablation, Cryo
other name: Cryoablation
other name: cryosurgical ablation
intervention type: Biological
intervention name: Dendritic Cell Therapy
description: Given IT
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
other name: Dendritic Cell Vaccine Therapy
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
intervention type: Biological
intervention name: Pembrolizumab
description: Given IV
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
other name: Keytruda
other name: Lambrolizumab
other name: MK-3475
other name: SCH 900475
intervention type: Biological
intervention name: Pneumococcal 13-valent Conjugate Vaccine
description: Given by injection
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
other name: PCV 13
other name: PCV13 Vaccine
other name: Prevnar 13
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
other name: Quality of Life Assessment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Yi Lin
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Non-Hodgkin
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Lymphoma, T-Cell
mesh term: Recurrence
mesh term: Pembrolizumab
mesh term: Vaccines