<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/NCT01713439</url>
  </required_header>
  <id_info>
    <org_study_id>H-6441 CYCHEALL</org_study_id>
    <secondary_id>CYCHEALL</secondary_id>
    <nct_id>NCT01713439</nct_id>
  </id_info>
  <brief_title>Allogeneic Neuroblastoma Cells for Relapsed/ Refractory Neuroblastoma, CYCHEALL</brief_title>
  <acronym>CYCHEALL</acronym>
  <official_title>Phase 1 Study of Chemokine and Cytokine Gene Modified Allogeneic Neuroblastoma Cells for Treatment of Relapsed/Refractory Neuroblastoma Using a Retroviral Vector (CYCHEALL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Methodist Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Center for Cell and Gene Therapy, Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Jude Children's Research Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Baylor College of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The patient's have neuroblastoma that has come back, or not gone away. The cancer is harder&#xD;
      to treat now. The investigators would like the patient's to be in this research study to&#xD;
      determine the safety and dosage of special cells that may make the patient's own immune&#xD;
      system fight the cancer. To do this the investigators will put two special genes into&#xD;
      neuroblastoma cancer cells that have been grown in the lab. The genes put in make the cancer&#xD;
      cells produce lymphotactin, a natural substance that attracts immune system cells to the&#xD;
      cancer, and IL-2 a natural substance that may help the immune system kill cancer cells. Some&#xD;
      of these cells will then be put into the patient's body. Studies of cancers in animals and in&#xD;
      cancer cells that are grown in laboratories suggest that substances like lymphotactin and&#xD;
      IL-2 do help the body kill cancer cells. A treatment similar to this has been used in twelve&#xD;
      children previously and similar treatments are being used in adults with other cancers. This&#xD;
      is a research study. The investigators do not know the best amount of special cells to use,&#xD;
      so different children will get different numbers of cells.&#xD;
&#xD;
      The purpose of this study is to learn the side effects and safe &quot;dosage&quot; of these special&#xD;
      cells. Participation in this study will last for 15 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators have grown neuroblastoma cells in the laboratory and put into them two&#xD;
      specially produced mouse viruses (retroviruses) that carry the lymphotactin and the IL-2&#xD;
      gene. These lymphotactin and IL-2 genes are meant to help the immune system fight the cancer.&#xD;
      The modified cancer cells will be injected under the patient's skin. There will be four&#xD;
      shots. The second and subsequent shots will have ten times as many cells producing&#xD;
      lymphotactin as the first. The patient will normally have these shots as an outpatient.&#xD;
      Depending on response (if the patient's cancer has stayed the same or gotten smaller), the&#xD;
      patient may be able to have four more of these shots.&#xD;
&#xD;
      Tests during and after treatment:&#xD;
&#xD;
      If the patient's blood has not been tested for HIV, the virus that causes AIDS, then the&#xD;
      investigators will need to do this test. If this virus is present, this research treatment&#xD;
      cannot be used.&#xD;
&#xD;
      Before the second shot, and then again about 2 weeks later, the investigators will remove&#xD;
      some of the modified cells from the patient's body and study them. This will be done by a&#xD;
      skin biopsy at the place where the cells were injected. These tests are to see whether the&#xD;
      changes made in the laboratory are killing cancer cells.&#xD;
&#xD;
      To study how the immunity is working in the patient's body blood samples will be taken two to&#xD;
      four days after each injection. This may be repeated 5-7 days after each injection if the&#xD;
      patient's doctor thinks that it is necessary. After the patient stops receiving the&#xD;
      injections, the blood draws will need to be repeated once a month for a year, and then once a&#xD;
      year for fifteen years.&#xD;
&#xD;
      The patient will need to come to the clinic on the days the investigators take blood and will&#xD;
      need to be seen at Texas Children's Cancer Center at weekly intervals for 6 weeks, then every&#xD;
      other week for 6 weeks, and then monthly for a year. Then the patient will be seen in clinic&#xD;
      or contacted by study personnel once a year for 15 years. Additional visits may be necessary.&#xD;
&#xD;
      To see if this research treatment is working, CAT scans, MRIs, or bone scans (these are&#xD;
      different types of x-rays)will be done. Investigators will also take a bone marrow biopsy&#xD;
      (bone marrow will be removed by use of a needle so that it can be looked at under the&#xD;
      microscope). These tests will be done prior to treatment and repeated eight weeks later. In&#xD;
      addition, if the patient receives the second set of four injections, these tests will be&#xD;
      repeated at six months. If the neuroblastoma is not responding (if it has gotten larger), the&#xD;
      investigators will offer the patient treatment with chemotherapy and/or radiation therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1997</start_date>
  <completion_date type="Actual">April 2016</completion_date>
  <primary_completion_date type="Actual">January 2001</primary_completion_date>
  <phase>Phase 1</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>To assess the safety of up to four subcutaneous (SC) injections of allogeneic neuroblastoma cells which have been genetically modified by measuring adverse events.</measure>
    <time_frame>8 weeks</time_frame>
    <description>The patients will be given four injections as per the protocol schedule with the evaluation at Week 8 (month 2). This will constitute a course and the evaluation of the dose limiting toxicity will be done during this course. Any patient having grade 4 toxicity or having progressive disease during the course will be considered a failure.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To assess the safety of up to eight (total) injections in patients who have received the first four injections without unacceptable toxicity and have evidence of stable disease or better after receiving these injections by measuring adverse events.</measure>
    <time_frame>6 months</time_frame>
    <description>The second course consists of administering another four injections as per the protocol schedule and evaluating at week 24 (6 months). The second course is conditional upon patients completing the first course with acceptable toxicity. This means that there will be at least 5 patients eligible to receive the second course.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To determine whether MHC restricted or unrestricted antitumor immune responses are induced by SC injection of modified allogeneic neuroblasts and the cell doses required to produce these effects measured by punch biopsies.</measure>
    <time_frame>3 weeks</time_frame>
    <description>For all the patients punch biopsies at the injection site will be done. From this a qualitative assessment of number of CD4 or CD8 or both types of cells will be made in order to understand the immune response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the antitumor effect by routine clinical response evaluation by imaging.</measure>
    <time_frame>8 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>Injection of allogeneic neuroblastoma cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Retrovirally transduced allogeneic neuroblastoma cell lines secreting the human interleukin-2 and lymphotactin genes are frozen and, when needed, are thawed, mixed and irradiated. Relapsed or refractory patients are then treated with a course of four injections of their gene-modified tumor cells according to the following schedule: The first two injections will be given at week 1 and week 2. Patients will then have a two-week rest and the remaining two injections will be given at week 4 and week 5. A complete evaluation for evidence of toxicity and response will be performed at week 8 after a 3 week rest. At the 8 week evaluation, in the absence of progressive disease requiring therapy without excessive toxicity and if more transduced cells are available, the patient will have the option to receive four additional SC injections each separated by 1 month at the higher of the two dosage levels they originally received.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Injection of allogeneic neuroblastoma cells</intervention_name>
    <description>Patients will receive a fixed dose of IL-2 gene modified tumor cells (10^7/kg, 10^8 max) already shown to be safe from a previous protocol, and an escalating dose of Lptn transduced tumor cells, beginning at 10^4/kg and rising to 10^7/kg (10^8 max). Patients will be assigned to an appropriate dose level for injection # 1. Injection #2 will contain 10 times more Lptn transduced cells than injection #1, until the max dose (10^8) has been reached in the first injection. The dose of injections 3 through 8 will be the same as the dose of injection #2. Initial injection volumes will be &lt;1ml and should be injected in a single site. Only if these first patients show no undue local toxicity (including tumor cell growth) will multiple injection sites be used for subsequent high cell-dose studies.</description>
    <arm_group_label>Injection of allogeneic neuroblastoma cells</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All patients under 21 years of age at diagnosis with recurrent, advanced stage&#xD;
             neuroblastoma shall be eligible for this protocol.&#xD;
&#xD;
          -  Patients must have a life expectancy of at least 8 weeks.&#xD;
&#xD;
          -  Patients must have recovered from the toxic effects of all prior chemotherapy before&#xD;
             entering this study, and have an absolute lymphocyte and neutrophil count of &gt;500/mm3&#xD;
             each.&#xD;
&#xD;
          -  Patients must not be currently receiving any investigational agents or have not&#xD;
             received any tumor vaccines within the previous six months.&#xD;
&#xD;
          -  Patients must have bilirubin &lt;1.5 mg%.&#xD;
&#xD;
          -  Patients must have creatinine &lt;1.5 mg/dl.&#xD;
&#xD;
          -  Patients must have ECOG performance status of 0-2 as below:&#xD;
&#xD;
        Grade Activity&#xD;
&#xD;
          -  0 Up and about, no restriction.&#xD;
&#xD;
          -  1 Ambulatory, no strenuous activity.&#xD;
&#xD;
          -  2 Ambulatory, capable of self-care appropriate for age.Up and about &gt;50% of time, but&#xD;
             unable to carry out any physical activities or attend school.&#xD;
&#xD;
          -  3 Limited self-care only. Up and about &lt;50% of time.&#xD;
&#xD;
          -  4 Disabled, no self care. Bedridden or confined to chair.&#xD;
&#xD;
          -  Patients must be willing to utilize one of the more effective birth control methods&#xD;
             during the study and for six(6) months after the study is concluded. The male partner&#xD;
             should use a condom.&#xD;
&#xD;
          -  Patients or legal guardians must sign an informed consent indicating that they are&#xD;
             aware this is a research study and have been told of its possible benefits and toxic&#xD;
             side effects. Patients or their guardians will be given a copy of the consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients must not be HIV-positive.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Malcom Brenner, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Houston Methodist Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Children's Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>October 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>July 10, 2023</last_update_submitted>
  <last_update_submitted_qc>July 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Baylor College of Medicine</investigator_affiliation>
    <investigator_full_name>Malcolm Brenner</investigator_full_name>
    <investigator_title>Director/Professor Center for Gene Therapy</investigator_title>
  </responsible_party>
  <keyword>Relapsed/Refractory Neuroblastoma</keyword>
  <keyword>Retroviral vector injections</keyword>
  <keyword>Allogeneic neuroblastoma cells</keyword>
  <keyword>Lymphotactin</keyword>
  <keyword>Interleukin-2 (IL-2)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroblastoma</mesh_term>
  </condition_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/NCT01713439
org study id: H-6441 CYCHEALL
secondary id: CYCHEALL
nct id: NCT01713439
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The patient's have neuroblastoma that has come back, or not gone away. The cancer is harder
      to treat now. The investigators would like the patient's to be in this research study to
      determine the safety and dosage of special cells that may make the patient's own immune
      system fight the cancer. To do this the investigators will put two special genes into
      neuroblastoma cancer cells that have been grown in the lab. The genes put in make the cancer
      cells produce lymphotactin, a natural substance that attracts immune system cells to the
      cancer, and IL-2 a natural substance that may help the immune system kill cancer cells. Some
      of these cells will then be put into the patient's body. Studies of cancers in animals and in
      cancer cells that are grown in laboratories suggest that substances like lymphotactin and
      IL-2 do help the body kill cancer cells. A treatment similar to this has been used in twelve
      children previously and similar treatments are being used in adults with other cancers. This
      is a research study. The investigators do not know the best amount of special cells to use,
      so different children will get different numbers of cells.

      The purpose of this study is to learn the side effects and safe "dosage" of these special
      cells. Participation in this study will last for 15 years.
The investigators have grown neuroblastoma cells in the laboratory and put into them two
      specially produced mouse viruses (retroviruses) that carry the lymphotactin and the IL-2
      gene. These lymphotactin and IL-2 genes are meant to help the immune system fight the cancer.
      The modified cancer cells will be injected under the patient's skin. There will be four
      shots. The second and subsequent shots will have ten times as many cells producing
      lymphotactin as the first. The patient will normally have these shots as an outpatient.
      Depending on response (if the patient's cancer has stayed the same or gotten smaller), the
      patient may be able to have four more of these shots.

      Tests during and after treatment:

      If the patient's blood has not been tested for HIV, the virus that causes AIDS, then the
      investigators will need to do this test. If this virus is present, this research treatment
      cannot be used.

      Before the second shot, and then again about 2 weeks later, the investigators will remove
      some of the modified cells from the patient's body and study them. This will be done by a
      skin biopsy at the place where the cells were injected. These tests are to see whether the
      changes made in the laboratory are killing cancer cells.

      To study how the immunity is working in the patient's body blood samples will be taken two to
      four days after each injection. This may be repeated 5-7 days after each injection if the
      patient's doctor thinks that it is necessary. After the patient stops receiving the
      injections, the blood draws will need to be repeated once a month for a year, and then once a
      year for fifteen years.

      The patient will need to come to the clinic on the days the investigators take blood and will
      need to be seen at Texas Children's Cancer Center at weekly intervals for 6 weeks, then every
      other week for 6 weeks, and then monthly for a year. Then the patient will be seen in clinic
      or contacted by study personnel once a year for 15 years. Additional visits may be necessary.

      To see if this research treatment is working, CAT scans, MRIs, or bone scans (these are
      different types of x-rays)will be done. Investigators will also take a bone marrow biopsy
      (bone marrow will be removed by use of a needle so that it can be looked at under the
      microscope). These tests will be done prior to treatment and repeated eight weeks later. In
      addition, if the patient receives the second set of four injections, these tests will be
      repeated at six months. If the neuroblastoma is not responding (if it has gotten larger), the
      investigators will offer the patient treatment with chemotherapy and/or radiation therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To assess the safety of up to four subcutaneous (SC) injections of allogeneic neuroblastoma cells which have been genetically modified by measuring adverse events.
time frame: 8 weeks
description: The patients will be given four injections as per the protocol schedule with the evaluation at Week 8 (month 2). This will constitute a course and the evaluation of the dose limiting toxicity will be done during this course. Any patient having grade 4 toxicity or having progressive disease during the course will be considered a failure.
measure: To assess the safety of up to eight (total) injections in patients who have received the first four injections without unacceptable toxicity and have evidence of stable disease or better after receiving these injections by measuring adverse events.
time frame: 6 months
description: The second course consists of administering another four injections as per the protocol schedule and evaluating at week 24 (6 months). The second course is conditional upon patients completing the first course with acceptable toxicity. This means that there will be at least 5 patients eligible to receive the second course.
measure: To determine whether MHC restricted or unrestricted antitumor immune responses are induced by SC injection of modified allogeneic neuroblasts and the cell doses required to produce these effects measured by punch biopsies.
time frame: 3 weeks
description: For all the patients punch biopsies at the injection site will be done. From this a qualitative assessment of number of CD4 or CD8 or both types of cells will be made in order to understand the immune response.
measure: Assess the antitumor effect by routine clinical response evaluation by imaging.
time frame: 8 weeks
arm group label: Injection of allogeneic neuroblastoma cells
arm group type: Experimental
description: Retrovirally transduced allogeneic neuroblastoma cell lines secreting the human interleukin-2 and lymphotactin genes are frozen and, when needed, are thawed, mixed and irradiated. Relapsed or refractory patients are then treated with a course of four injections of their gene-modified tumor cells according to the following schedule: The first two injections will be given at week 1 and week 2. Patients will then have a two-week rest and the remaining two injections will be given at week 4 and week 5. A complete evaluation for evidence of toxicity and response will be performed at week 8 after a 3 week rest. At the 8 week evaluation, in the absence of progressive disease requiring therapy without excessive toxicity and if more transduced cells are available, the patient will have the option to receive four additional SC injections each separated by 1 month at the higher of the two dosage levels they originally received.
intervention type: Biological
intervention name: Injection of allogeneic neuroblastoma cells
description: Patients will receive a fixed dose of IL-2 gene modified tumor cells (10^7/kg, 10^8 max) already shown to be safe from a previous protocol, and an escalating dose of Lptn transduced tumor cells, beginning at 10^4/kg and rising to 10^7/kg (10^8 max). Patients will be assigned to an appropriate dose level for injection # 1. Injection #2 will contain 10 times more Lptn transduced cells than injection #1, until the max dose (10^8) has been reached in the first injection. The dose of injections 3 through 8 will be the same as the dose of injection #2. Initial injection volumes will be <1ml and should be injected in a single site. Only if these first patients show no undue local toxicity (including tumor cell growth) will multiple injection sites be used for subsequent high cell-dose studies.
arm group label: Injection of allogeneic neuroblastoma cells
criteria: 
gender: All
minimum age: N/A
maximum age: 21 Years
healthy volunteers: No
last name: Malcom Brenner, MD, PhD
role: Principal Investigator
affiliation: Baylor College of Medicine
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Baylor College of Medicine
investigator full name: Malcolm Brenner
investigator title: Director/Professor Center for Gene Therapy
mesh term: Neuroblastoma