<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/NCT03240861</url>
  </required_header>
  <id_info>
    <org_study_id>15-000511</org_study_id>
    <secondary_id>NCI-2017-00896</secondary_id>
    <secondary_id>Ribas NYESO SCT Cancer</secondary_id>
    <nct_id>NCT03240861</nct_id>
  </id_info>
  <brief_title>Genetically Engineered PBMC and PBSC Expressing NY-ESO-1 TCR After a Myeloablative Conditioning Regimen to Treat Patients With Advanced Cancer</brief_title>
  <acronym>NYESO SCT</acronym>
  <official_title>Adoptive Transfer of NY-ESO-1 TCR Engineered Peripheral Blood Mononuclear Cells (PBMC) and Peripheral Blood Stem Cells (PBSC) After a Myeloablative Conditioning Regimen, With Administration of Interleukin-2, in Patients With Advanced Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jonsson Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>California Institute for Regenerative Medicine (CIRM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Jonsson Comprehensive Cancer Center</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 clinical trial evaluates the safety and feasibility of administering NY-ESO-1&#xD;
      TCR (T cell receptor)engineered peripheral blood mononuclear cells (PBMC) and peripheral&#xD;
      blood stem cells (PBSC) after a myeloablative conditioning regimen to treat patients with&#xD;
      cancer that has spread to other parts of the body. The conditioning chemotherapy makes room&#xD;
      in the patient?s bone marrow for new blood cells (PBMC) and blood-forming cells (stem cells)&#xD;
      to grow. Giving NY-ESO-1 TCR PBMC and stem cells after the conditioning chemotherapy is&#xD;
      intended to replace the immune system with new immune cells that have been redirected to&#xD;
      attack and kill the cancer cells and thereby improve immune system function against cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the safety of administering the combination of autologous peripheral blood&#xD;
      mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a reduced&#xD;
      intensity conditioning regimen, both of which have been genetically modified to express&#xD;
      NY-ESO-1 TCR.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the feasibility of delivering the combination of TCR transduced autologous&#xD;
      PBMC and CD34+ PBSC to patients.&#xD;
&#xD;
      II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR&#xD;
      transduced PBSC in serial peripheral blood samples.&#xD;
&#xD;
      III. Objective response rate (ORR).&#xD;
&#xD;
      EXPLORATORY OBJECTIVE:&#xD;
&#xD;
      I. To explore the use of positron emission tomography (PET)-based imaging using the PET&#xD;
      tracer 9-4-[18F]fluoro-3-(hydroxymethyl)butylguanine ([18F]FHBG) with the goal of determining&#xD;
      whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow,&#xD;
      differentiate into T cells and expand in secondary lymphoid organs and tumor deposits.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of&#xD;
      cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem&#xD;
      cells. Patients receive G-CSF subcutaneously (SC) on mobilization days 1-8 and plerixafor SC&#xD;
      on mobilization days 4-7, during mobilization, patients will undergo mobilized leukapheresis&#xD;
      to obtain PBSC. Patients also undergo an unmobilized leukapheresis on day -5 before infusion&#xD;
      of cells in order to obtain PBMC.&#xD;
&#xD;
      CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) on days -4 to&#xD;
      -2 and fludarabine IV over 30 minutes on days -3 to -2.&#xD;
&#xD;
      Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours,&#xD;
      patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive&#xD;
      aldesleukin (interleukin-2 (IL) or IL-2) SC twice daily (BID) for up to 7 days. Patients&#xD;
      undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60,&#xD;
      90, and 120. Patients receive the PET tracer 18F-FHBG IV, and after 1 hour, undergo&#xD;
      PET/computed tomography (CT) on days 25 and 120.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 2-3 months for 2 years,&#xD;
      every 6 months for 5 years, and annually for 15 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 26, 2017</start_date>
  <completion_date type="Anticipated">August 1, 2024</completion_date>
  <primary_completion_date type="Actual">September 7, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <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>Incidence of dose limiting toxicity</measure>
    <time_frame>Up to 90 days</time_frame>
    <description>Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the Common Toxicity Criteria at each study visit. Subjects will be monitored by medical histories, physical examinations and blood studies to detect potential toxicities from the treatment. If there are no dose limiting toxicities observed, the cohort will be expanded to 12 subjects. If 1/3 are observed, up to 6 subjects will be recruited. If less than 2/6 are observed, the cohort will be expanded to a total of 12 subjects. If a dose limiting toxicity is observed in 2 or more of 6 subjects, the</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Detection of replication competent retrovirus and replication competent lentivirus</measure>
    <time_frame>Up to 12 months post cell administration</time_frame>
    <description>Will be assessed by polymerase chain reaction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of overall complete response</measure>
    <time_frame>From the time measurement criteria has been first met for complete response until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years</time_frame>
    <description>Will evaluate duration of overall complete response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of overall response</measure>
    <time_frame>From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years</time_frame>
    <description>Will evaluate duration of overall response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Persistence of transduced T cells</measure>
    <time_frame>Time Frame: Up to 2 years after transgenic cell adoptive transfer</time_frame>
    <description>Analysis will be performed using immune monitoring techniques. The number of days until the percentage of cells expressing both NYESO-&#xD;
1 TCR and CD3 drops below the baseline percentage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Engraftment and persistence of transduced progeny T cells</measure>
    <time_frame>Time Frame: Up to 2 years after transgenic cell adoptive transfer</time_frame>
    <description>Analysis will be performed using immune monitoring techniques. The number of days until the vector copy number in the progeny T cells is undetectable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Engraftment and persistence of transduced T cells and progeny T cells</measure>
    <time_frame>Time Frame: Up to 2 years after transgenic cell adoptive transfer</time_frame>
    <description>Analysis will be performed both using immune monitoring and molecular techniques.&#xD;
The number of days until the vector copy number in the T cells is undetectable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of generation NY-ESO-1 TCR transgenic T cells and NY-ESO-1 TCR/sr39TK transgenic stem cells that meet the lot release criteria</measure>
    <time_frame>Time Frame: Up to 1 month after transgenic cell adoptive transfer</time_frame>
    <description>Feasibility of manufacturing will be assessed as:&#xD;
The number of manufacturing products meeting the lot release criteria after an acceptable number of CD34+ cells have been obtained.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological monitoring will consist primarily of quantifying T cells bearing surface NY-ESO-1 TCR</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be assessed by NY-ESO-1126-157/MHC (major histocompatibility complex) dextramer analysis. Functional assays like enzyme-linked immunosorbent assay, intracellular cytokine staining, and/or multicytokine array assays will complement the results. Immunological assays will be compared between 1) pre-infusion peripheral blood mononuclear cells and peripheral blood stem cells, 2) an aliquot of the engineered peripheral blood lymphocytes and stem cells at the time of infusion and 3) cells recovered from patients? peripheral blood after adoptive transfer.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Potential objective responses to this combinatorial immunotherapy will be recorded following Response Evaluation Criteria in Solid Tumors version 1.1 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Persistence of TCR gene transduced cells</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be assessed by semi quantitative deoxyribonucleic acid-polymerase chain reaction using primers specific for vector sequence.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to disease progression</measure>
    <time_frame>Time from the date of cell infusion (day 0) to the date of progressive disease first documented, or death whichever occurs first, assessed up to 15 years</time_frame>
    <description>Will evaluate length of time until disease progression.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Regional uptake of 18F-FHBG within metastatic tumor sites and secondary lymphoid organs</measure>
    <time_frame>Up to 15 years</time_frame>
    <description>Will be quantified by standardized uptake values normalized to the body weight of the patient. As an internal quality control, standardized uptake values will also be determined for several normal organs, such as muscle, liver and lungs. These measurements will allow us to identify technical problems in the standardized uptake value calculations, such as partially paravenous tracer administration. Findings from non-invasive positron emission tomography imaging will be compared with results from immune monitoring assays in blood samples at different intervals after NY-ESO-1 TCR cell transplant.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>HLA-A*0201 Positive Cells Present</condition>
  <condition>Locally Advanced Malignant Neoplasm</condition>
  <condition>NY-ESO-1 Positive</condition>
  <condition>Unresectable Malignant Neoplasm</condition>
  <condition>Sarcoma</condition>
  <arm_group>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF SC on mobilization days 1-8 and plerixafor SC on mobilization days 4-7. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells.&#xD;
CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan IV on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2.&#xD;
Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin SC BID for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive 18F-FHBG IV, and after 1 hour, undergo PET/CT on days 25 and 120.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>18F-FHBG</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>Reporter Probe 18F-FHBG</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Aldesleukin</intervention_name>
    <description>Given SC</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>125-L-Serine-2-133-interleukin 2</other_name>
    <other_name>Proleukin</other_name>
    <other_name>r-serHuIL-2</other_name>
    <other_name>Recombinant Human IL-2</other_name>
    <other_name>Recombinant Human Interleukin-2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Busulfan</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>1, 4-Bis[methanesulfonoxy]butane</other_name>
    <other_name>BUS</other_name>
    <other_name>Bussulfam</other_name>
    <other_name>Busulfanum</other_name>
    <other_name>Busulfex</other_name>
    <other_name>Busulphan</other_name>
    <other_name>CB 2041</other_name>
    <other_name>CB-2041</other_name>
    <other_name>Glyzophrol</other_name>
    <other_name>GT 41</other_name>
    <other_name>GT-41</other_name>
    <other_name>Joacamine</other_name>
    <other_name>Methanesulfonic Acid Tetramethylene Ester</other_name>
    <other_name>Methanesulfonic acid, tetramethylene ester</other_name>
    <other_name>Mielucin</other_name>
    <other_name>Misulban</other_name>
    <other_name>Misulfan</other_name>
    <other_name>Mitosan</other_name>
    <other_name>Myeleukon</other_name>
    <other_name>Myeloleukon</other_name>
    <other_name>Myelosan</other_name>
    <other_name>Mylecytan</other_name>
    <other_name>Myleran</other_name>
    <other_name>Sulfabutin</other_name>
    <other_name>Tetramethylene Bis(methanesulfonate)</other_name>
    <other_name>Tetramethylene bis[methanesulfonate]</other_name>
    <other_name>WR-19508</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Cellular Therapy</intervention_name>
    <description>Given LV-NYESO TCR/sr39TK PBSC IV and RV-NYESO TCR PBMC IV</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>Cell Therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Computed Tomography</intervention_name>
    <description>Undergo PET/CT</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>CAT</other_name>
    <other_name>CAT Scan</other_name>
    <other_name>Computerized Axial Tomography</other_name>
    <other_name>Computerized Tomography</other_name>
    <other_name>CT</other_name>
    <other_name>CT SCAN</other_name>
    <other_name>tomography</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Filgrastim</intervention_name>
    <description>Given SC</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>Filgrastim XM02</other_name>
    <other_name>Filgrastim-sndz</other_name>
    <other_name>G-CSF</other_name>
    <other_name>Granix</other_name>
    <other_name>Neupogen</other_name>
    <other_name>r-metHuG-CSF</other_name>
    <other_name>Recombinant Methionyl Human Granulocyte Colony Stimulating Factor</other_name>
    <other_name>rG-CSF</other_name>
    <other_name>Tbo-filgrastim</other_name>
    <other_name>Tevagrastim</other_name>
    <other_name>Zarxio</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>Fluradosa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Leukapheresis</intervention_name>
    <description>Undergo leukapheresis</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>Leukocytopheresis</other_name>
    <other_name>Therapeutic Leukopheresis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Plerixafor</intervention_name>
    <description>Given SC</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>AMD 3100</other_name>
    <other_name>JM-3100</other_name>
    <other_name>Mozobil</other_name>
    <other_name>SDZ SID 791</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Positron Emission Tomography</intervention_name>
    <description>Undergo PET/CT</description>
    <arm_group_label>Treatment (Genetically engineered PBMC and PBSC)</arm_group_label>
    <other_name>Medical Imaging, Positron Emission Tomography</other_name>
    <other_name>PET</other_name>
    <other_name>PET SCAN</other_name>
    <other_name>Positron Emission Tomography Scan</other_name>
    <other_name>Positron-Emission Tomography</other_name>
    <other_name>proton magnetic resonance spectroscopic imaging</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stage IV or locally advanced unresectable cancers for which no alternative therapies&#xD;
             with proven survival advantage are available&#xD;
&#xD;
          -  NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commercially&#xD;
             available NY-ESO-1 antibodies&#xD;
&#xD;
          -  HLA-A*0201 (HLA-A2.1) positivity by molecular subtyping&#xD;
&#xD;
          -  Age greater than or equal to 16 years old; if patients 16-17 years old are enrolled in&#xD;
             the trial, they will only be enrolled after 3 patients &gt;= 18 years old have been&#xD;
             treated, and the treatment has been shown to be safe&#xD;
&#xD;
          -  A minimum of one measurable lesion defined as:&#xD;
&#xD;
               -  Meeting the criteria for measurable disease according to Response Evaluation&#xD;
                  Criteria in Solid Tumors (RECIST)&#xD;
&#xD;
               -  Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be&#xD;
                  accurately measured and recorded by color photography with a ruler to document&#xD;
                  the size of the target lesion(s)&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1&#xD;
&#xD;
          -  Adequate bone marrow and major organ function to undergo a PBSC transplant determined&#xD;
             within 30-60 days prior to enrollment using standard phase 1 criteria for organ&#xD;
             function defined as:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt;= 1.5 x 10^9 cells/L&#xD;
&#xD;
               -  Platelets &gt;= 100 x 10^9/L&#xD;
&#xD;
               -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
               -  Aspartate and alanine aminotransferases (AST, ALT) =&lt; 2.5 x ULN (upper limit of&#xD;
                  normal) (=&lt; 5 x ULN, if documented liver metastases are present)&#xD;
&#xD;
               -  Total bilirubin =&lt; 2 x ULN (except patients with documented Gilbert?s syndrome)&#xD;
&#xD;
               -  Creatinine &lt; 2 mg/dl (or a glomerular filtration rate &gt; 60)&#xD;
&#xD;
          -  Must be willing and able to accept at least three leukapheresis procedures&#xD;
&#xD;
          -  Must be willing and able to undergo three research PET scans&#xD;
&#xD;
          -  Must be willing and able to provide written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to purify &gt;= 2.5 x 10^6 CD34-enriched cells/kg of patient weight from the&#xD;
             pooled G-CSF mobilized leukapheresis products&#xD;
&#xD;
          -  Previously known hypersensitivity to any of the agents used in this study; known&#xD;
             sensitivity to busulfan or fludarabine&#xD;
&#xD;
          -  Received systemic treatment for cancer, including immunotherapy, within 28 days prior&#xD;
             to initiation of conditioning chemotherapy administration within this protocol&#xD;
&#xD;
          -  Potential requirement for systemic corticosteroids or concurrent immunosuppressive&#xD;
             drugs based on prior history or received systemic steroids within the last 2 weeks&#xD;
             prior to enrollment (inhaled or topical steroids at standard doses are allowed)&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired&#xD;
             immune deficiency state, which would increase the risk of opportunistic infections and&#xD;
             other complications during chemotherapy-induced lymphodepletion; if there is a&#xD;
             positive result in the infectious disease testing that was not previously known, the&#xD;
             patient will be referred to their primary physician and/or infectious disease&#xD;
             specialist&#xD;
&#xD;
          -  Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would&#xD;
             increase the likelihood of hepatic toxicities from the chemotherapy conditioning&#xD;
             regimen and supportive treatments; if there is a positive result in the infectious&#xD;
             disease testing that was not previously known, the patient will be referred to their&#xD;
             primary physician and/or infectious disease specialist&#xD;
&#xD;
          -  Dementia or significantly altered mental status that would prohibit the understanding&#xD;
             or rendering of informed consent and compliance with the requirements of this protocol&#xD;
&#xD;
          -  Known clinically active brain metastases; prior evidence of brain metastasis&#xD;
             successfully treated with surgery or radiation therapy will not be exclusion for&#xD;
             participation as long as they are deemed under control at the time of study enrollment&#xD;
             and there are no neurological signs of potential brain metastases&#xD;
&#xD;
          -  Pregnancy or breast-feeding; female patients must be surgically sterile or be&#xD;
             postmenopausal for two years, or must agree to use effective contraception during the&#xD;
             period of treatment and for 6 months afterwards; all female patients with reproductive&#xD;
             potential must have a negative pregnancy test (serum/urine) within 14 days from&#xD;
             starting the conditioning chemotherapy; the definition of effective contraception will&#xD;
             be based on the judgment of the study investigators&#xD;
&#xD;
          -  Since IL-2 is administered following cell infusion:&#xD;
&#xD;
               -  Patients will be excluded if they have a history of clinically significant&#xD;
                  electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence&#xD;
                  of ischemia on a cardiac stress test (stress thallium, stress multigated&#xD;
                  acquisition [MUGA], dobutamine echocardiogram or other stress test)&#xD;
&#xD;
               -  Similarly, patients with a baseline left ventricular ejection fraction (LVEF) &lt;&#xD;
                  45% will be excluded.&#xD;
&#xD;
               -  Patients with ECG results of any conduction delays (PR interval &gt; 200 ms,&#xD;
                  corrected QT [QTC] &gt; 480 ms), sinus bradycardia (resting heart rate &lt; 50 beats&#xD;
                  per minute), sinus tachycardia (heart rate &gt;120 beats per minute) will be&#xD;
                  evaluated by a cardiologist prior to starting the trial; patients with any&#xD;
                  arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy&#xD;
                  (defined as &gt; 20 premature ventricular contractions [PVCs] per minute),&#xD;
                  ventricular tachycardia or 3rd degree heart block will be excluded from the study&#xD;
                  unless cleared by a cardiologist&#xD;
&#xD;
               -  Patients with pulmonary function test abnormalities as evidenced by a (forced&#xD;
                  expiratory volume 1 [FEV1]/forced vital capacity [FVC ] &lt; 70% of predicted for&#xD;
                  normality will be excluded&#xD;
&#xD;
          -  Bone marrow involvement based on PET/CT scan at screening&#xD;
&#xD;
          -  Active or recent herpes simplex virus (HSV) infection or cytomegalovirus (CMV) based&#xD;
             on symptoms with positive swab culture and/or positive IgM (immunoglobulin M)&#xD;
             screening&#xD;
&#xD;
          -  Liver metastases with no other metastatic sites&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Theodore Scott Nowicki, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>UCLA / Jonsson Comprehensive Cancer Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Theodore Scott Nowicki, M.D., PhD</last_name>
    <phone>310-206-2090</phone>
    <email>TNowicki@mednet.ucla.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Antonio Ribas, M.D.</last_name>
    <phone>310-206-3928</phone>
    <email>aribas@mednet.ucla.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>UCLA / Jonsson Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Theodore Nowicki, MD</last_name>
      <phone>310-206-2090</phone>
      <email>TNowicki@mednet.ucla.edu</email>
    </contact>
    <investigator>
      <last_name>Theodore Nowicki, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>June 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2017</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>T cells</keyword>
  <keyword>stem cells</keyword>
  <keyword>gene therapy</keyword>
  <keyword>NYESO</keyword>
  <keyword>Sarcoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Sarcoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aldesleukin</mesh_term>
    <mesh_term>Plerixafor</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Busulfan</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
    <mesh_term>Lenograstim</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/NCT03240861
org study id: 15-000511
secondary id: NCI-2017-00896
secondary id: Ribas NYESO SCT Cancer
nct id: NCT03240861
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I clinical trial evaluates the safety and feasibility of administering NY-ESO-1
      TCR (T cell receptor)engineered peripheral blood mononuclear cells (PBMC) and peripheral
      blood stem cells (PBSC) after a myeloablative conditioning regimen to treat patients with
      cancer that has spread to other parts of the body. The conditioning chemotherapy makes room
      in the patient?s bone marrow for new blood cells (PBMC) and blood-forming cells (stem cells)
      to grow. Giving NY-ESO-1 TCR PBMC and stem cells after the conditioning chemotherapy is
      intended to replace the immune system with new immune cells that have been redirected to
      attack and kill the cancer cells and thereby improve immune system function against cancer.
PRIMARY OBJECTIVE:

      I. To determine the safety of administering the combination of autologous peripheral blood
      mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a reduced
      intensity conditioning regimen, both of which have been genetically modified to express
      NY-ESO-1 TCR.

      SECONDARY OBJECTIVES:

      I. To determine the feasibility of delivering the combination of TCR transduced autologous
      PBMC and CD34+ PBSC to patients.

      II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR
      transduced PBSC in serial peripheral blood samples.

      III. Objective response rate (ORR).

      EXPLORATORY OBJECTIVE:

      I. To explore the use of positron emission tomography (PET)-based imaging using the PET
      tracer 9-4-[18F]fluoro-3-(hydroxymethyl)butylguanine ([18F]FHBG) with the goal of determining
      whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow,
      differentiate into T cells and expand in secondary lymphoid organs and tumor deposits.

      OUTLINE:

      G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of
      cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem
      cells. Patients receive G-CSF subcutaneously (SC) on mobilization days 1-8 and plerixafor SC
      on mobilization days 4-7, during mobilization, patients will undergo mobilized leukapheresis
      to obtain PBSC. Patients also undergo an unmobilized leukapheresis on day -5 before infusion
      of cells in order to obtain PBMC.

      CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) on days -4 to
      -2 and fludarabine IV over 30 minutes on days -3 to -2.

      Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours,
      patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive
      aldesleukin (interleukin-2 (IL) or IL-2) SC twice daily (BID) for up to 7 days. Patients
      undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60,
      90, and 120. Patients receive the PET tracer 18F-FHBG IV, and after 1 hour, undergo
      PET/computed tomography (CT) on days 25 and 120.

      After completion of study treatment, patients are followed up every 2-3 months for 2 years,
      every 6 months for 5 years, and annually for 15 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of dose limiting toxicity
time frame: Up to 90 days
description: Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the Common Toxicity Criteria at each study visit. Subjects will be monitored by medical histories, physical examinations and blood studies to detect potential toxicities from the treatment. If there are no dose limiting toxicities observed, the cohort will be expanded to 12 subjects. If 1/3 are observed, up to 6 subjects will be recruited. If less than 2/6 are observed, the cohort will be expanded to a total of 12 subjects. If a dose limiting toxicity is observed in 2 or more of 6 subjects, the
measure: Detection of replication competent retrovirus and replication competent lentivirus
time frame: Up to 12 months post cell administration
description: Will be assessed by polymerase chain reaction.
measure: Duration of overall complete response
time frame: From the time measurement criteria has been first met for complete response until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years
description: Will evaluate duration of overall complete response.
measure: Duration of overall response
time frame: From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years
description: Will evaluate duration of overall response.
measure: Persistence of transduced T cells
time frame: Time Frame: Up to 2 years after transgenic cell adoptive transfer
description: Analysis will be performed using immune monitoring techniques. The number of days until the percentage of cells expressing both NYESO-
1 TCR and CD3 drops below the baseline percentage.
measure: Engraftment and persistence of transduced progeny T cells
time frame: Time Frame: Up to 2 years after transgenic cell adoptive transfer
description: Analysis will be performed using immune monitoring techniques. The number of days until the vector copy number in the progeny T cells is undetectable.
measure: Engraftment and persistence of transduced T cells and progeny T cells
time frame: Time Frame: Up to 2 years after transgenic cell adoptive transfer
description: Analysis will be performed both using immune monitoring and molecular techniques.
The number of days until the vector copy number in the T cells is undetectable.
measure: Feasibility of generation NY-ESO-1 TCR transgenic T cells and NY-ESO-1 TCR/sr39TK transgenic stem cells that meet the lot release criteria
time frame: Time Frame: Up to 1 month after transgenic cell adoptive transfer
description: Feasibility of manufacturing will be assessed as:
The number of manufacturing products meeting the lot release criteria after an acceptable number of CD34+ cells have been obtained.
measure: Immunological monitoring will consist primarily of quantifying T cells bearing surface NY-ESO-1 TCR
time frame: Up to 15 years
description: Will be assessed by NY-ESO-1126-157/MHC (major histocompatibility complex) dextramer analysis. Functional assays like enzyme-linked immunosorbent assay, intracellular cytokine staining, and/or multicytokine array assays will complement the results. Immunological assays will be compared between 1) pre-infusion peripheral blood mononuclear cells and peripheral blood stem cells, 2) an aliquot of the engineered peripheral blood lymphocytes and stem cells at the time of infusion and 3) cells recovered from patients? peripheral blood after adoptive transfer.
measure: Objective response
time frame: Up to 15 years
description: Potential objective responses to this combinatorial immunotherapy will be recorded following Response Evaluation Criteria in Solid Tumors version 1.1 criteria.
measure: Persistence of TCR gene transduced cells
time frame: Up to 15 years
description: Will be assessed by semi quantitative deoxyribonucleic acid-polymerase chain reaction using primers specific for vector sequence.
measure: Time to disease progression
time frame: Time from the date of cell infusion (day 0) to the date of progressive disease first documented, or death whichever occurs first, assessed up to 15 years
description: Will evaluate length of time until disease progression.
measure: Regional uptake of 18F-FHBG within metastatic tumor sites and secondary lymphoid organs
time frame: Up to 15 years
description: Will be quantified by standardized uptake values normalized to the body weight of the patient. As an internal quality control, standardized uptake values will also be determined for several normal organs, such as muscle, liver and lungs. These measurements will allow us to identify technical problems in the standardized uptake value calculations, such as partially paravenous tracer administration. Findings from non-invasive positron emission tomography imaging will be compared with results from immune monitoring assays in blood samples at different intervals after NY-ESO-1 TCR cell transplant.
arm group label: Treatment (Genetically engineered PBMC and PBSC)
arm group type: Experimental
description: G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF SC on mobilization days 1-8 and plerixafor SC on mobilization days 4-7. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells.
CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan IV on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2.
Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin SC BID for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive 18F-FHBG IV, and after 1 hour, undergo PET/CT on days 25 and 120.
intervention type: Other
intervention name: 18F-FHBG
description: Given IV
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: Reporter Probe 18F-FHBG
intervention type: Biological
intervention name: Aldesleukin
description: Given SC
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: 125-L-Serine-2-133-interleukin 2
other name: Proleukin
other name: r-serHuIL-2
other name: Recombinant Human IL-2
other name: Recombinant Human Interleukin-2
intervention type: Drug
intervention name: Busulfan
description: Given IV
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: 1, 4-Bis[methanesulfonoxy]butane
other name: BUS
other name: Bussulfam
other name: Busulfanum
other name: Busulfex
other name: Busulphan
other name: CB 2041
other name: CB-2041
other name: Glyzophrol
other name: GT 41
other name: GT-41
other name: Joacamine
other name: Methanesulfonic Acid Tetramethylene Ester
other name: Methanesulfonic acid, tetramethylene ester
other name: Mielucin
other name: Misulban
other name: Misulfan
other name: Mitosan
other name: Myeleukon
other name: Myeloleukon
other name: Myelosan
other name: Mylecytan
other name: Myleran
other name: Sulfabutin
other name: Tetramethylene Bis(methanesulfonate)
other name: Tetramethylene bis[methanesulfonate]
other name: WR-19508
intervention type: Biological
intervention name: Cellular Therapy
description: Given LV-NYESO TCR/sr39TK PBSC IV and RV-NYESO TCR PBMC IV
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: Cell Therapy
intervention type: Procedure
intervention name: Computed Tomography
description: Undergo PET/CT
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: CAT
other name: CAT Scan
other name: Computerized Axial Tomography
other name: Computerized Tomography
other name: CT
other name: CT SCAN
other name: tomography
intervention type: Biological
intervention name: Filgrastim
description: Given SC
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: Filgrastim XM02
other name: Filgrastim-sndz
other name: G-CSF
other name: Granix
other name: Neupogen
other name: r-metHuG-CSF
other name: Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
other name: rG-CSF
other name: Tbo-filgrastim
other name: Tevagrastim
other name: Zarxio
intervention type: Drug
intervention name: Fludarabine
description: Given IV
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: Fluradosa
intervention type: Procedure
intervention name: Leukapheresis
description: Undergo leukapheresis
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: Leukocytopheresis
other name: Therapeutic Leukopheresis
intervention type: Drug
intervention name: Plerixafor
description: Given SC
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: AMD 3100
other name: JM-3100
other name: Mozobil
other name: SDZ SID 791
intervention type: Procedure
intervention name: Positron Emission Tomography
description: Undergo PET/CT
arm group label: Treatment (Genetically engineered PBMC and PBSC)
other name: Medical Imaging, Positron Emission Tomography
other name: PET
other name: PET SCAN
other name: Positron Emission Tomography Scan
other name: Positron-Emission Tomography
other name: proton magnetic resonance spectroscopic imaging
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Theodore Scott Nowicki, M.D.
role: Principal Investigator
affiliation: UCLA / Jonsson Comprehensive Cancer Center
last name: Theodore Scott Nowicki, M.D., PhD
phone: 310-206-2090
email: TNowicki@mednet.ucla.edu
last name: Antonio Ribas, M.D.
phone: 310-206-3928
email: aribas@mednet.ucla.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Sarcoma
mesh term: Aldesleukin
mesh term: Plerixafor
mesh term: Fludarabine
mesh term: Busulfan
mesh term: Interleukin-2
mesh term: Lenograstim