<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/NCT03751709</url>
  </required_header>
  <id_info>
    <org_study_id>IIT2017-05-MERIN-BLINHMCT</org_study_id>
    <nct_id>NCT03751709</nct_id>
  </id_info>
  <brief_title>Blinatumomab Plus HLA-Mismatched Cellular Therapy for Relapsed/Refractory CD19+ ALL</brief_title>
  <official_title>IIT2017-05-MERIN-BLINHMCT: Blinatumomab Plus HLA-Mismatched Cellular Therapy (HMCT) for Relapsed/Refractory CD19+ ALL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cedars-Sinai Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Cedars-Sinai Medical 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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Single center Phase 1 dose escalation trial of the combination of standard-of-care&#xD;
      blinatumomab plus Haplo-Mismatched Cellular Therapy (HMCT). HMCT refers to the infusion of&#xD;
      donor peripheral blood mononuclear cells collected via pheresis from a haploidentical family&#xD;
      member - the procedure is analogous to giving a donor lymphocyte infusion outside of the&#xD;
      setting of an allogeneic stem cell transplant; also known as 'microtransplantation'. The HMCT&#xD;
      is an unselected mix of lymphocytes and leukocytes, but the product dose escalation will be&#xD;
      done based on the T cell content.&#xD;
&#xD;
      Ten recipients are planned. Each subject will be administered one infusion of HMCT during the&#xD;
      first cycle of blinatumomab and two infusions during cycle two of blinatumomab; the CD3+ cell&#xD;
      dose of the HMCT infusion is governed by dose escalation / de-escalation following a Bayesian&#xD;
      method.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This single center, phase 1 study will examine the safety, side effects, and effectiveness of&#xD;
      combining the investigational use of Haplo-Mismatched Cellular Therapy (HMCT) in combination&#xD;
      with blinatumomab. Investigators plan to give HMCT starting on day 15, after the initial CRS&#xD;
      caused by blinatumomab has resolved. The investigational treatment will start with 1% of the&#xD;
      typical HMCT dose (10e6 CD3+ cells/kg) and will employ a modified dose escalation design as&#xD;
      an additional safety measure. The primary end points will be DLT of the combination of&#xD;
      blinatumomab and HMCT.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 14, 2020</start_date>
  <completion_date type="Anticipated">March 2025</completion_date>
  <primary_completion_date type="Actual">March 27, 2023</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>Incidence of DLTs</measure>
    <time_frame>up to 6 months</time_frame>
    <description>Number of Dose Limiting Toxicities experienced by patients undergoing HLA mismatched cellular therapy (HMCT) of allogenic CD3+ cells in combination with blinatumomab.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants experiencing complete response (CR) from time of transplant to one day following the second treatment</measure>
    <time_frame>up to 3 months</time_frame>
    <description>Bone marrow aspiration and local peripheral blood counts will be used to measure response. CR is defined as the following:&#xD;
Less than or equal to 5% blasts in the bone marrow&#xD;
No evidence of disease, AND&#xD;
Full recovery of peripheral blood counts: platelets &gt; 100,000/ul, and ANC &gt; 1000/ul</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants experiencing complete response with partial recovery of peripheral blood counts (CRh) from time of transplant to one day following the second treatment</measure>
    <time_frame>up to 3 months</time_frame>
    <description>Bone marrow aspiration and local peripheral blood counts will be used to measure response. CRh is defined as the following:&#xD;
Less than or equal to 5% blasts in the bone marrow&#xD;
No evidence of disease, AND&#xD;
Full recovery of peripheral blood counts: platelets &gt; 50,000/ul, and ANC &gt; 500/ul</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants experiencing complete response with incomplete count recovery (CRi) from time of transplant to one day following the second treatment</measure>
    <time_frame>up to 3 months</time_frame>
    <description>Bone marrow aspiration and local peripheral blood counts will be used to measure response. CRi is defined as the following:&#xD;
Less than or equal to 5% blasts in the bone marrow&#xD;
No evidence of disease, AND&#xD;
Full recovery of peripheral blood counts: platelets &gt; 100,000/ul, and ANC &gt; 1000/ul</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response blast-free hypoplastic or aplastic bone marrow from time of transplant to one day following the second treatment</measure>
    <time_frame>up to 3 months</time_frame>
    <description>Bone marrow aspiration and local peripheral blood counts will be used to measure response. Blast-free hypoplastic or aplastic bone marrow response is defined as the following:&#xD;
Less than or equal to 5% blasts in the bone marrow&#xD;
No evidence of disease, AND&#xD;
Full recovery of peripheral blood counts: platelets &gt; 50,000/ul, and ANC &gt; 500/ul</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease burden measured as the minimal residual disease (MRD) response from time of transplant to one day following the second treatment</measure>
    <time_frame>up to 3 months</time_frame>
    <description>MRD remission is defined as the occurrence of an MRD level below 10^-4 measured by quantitative reverse transcription polymerase chain reaction (PCR) or flow cytometry.&#xD;
Complete response defined as: no detectable leukemic cells by PCR or flow cytometry.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>B-Cell Acute Lymphoblastic Leukaemia</condition>
  <condition>ALL, Adult</condition>
  <condition>B-ALL</condition>
  <arm_group>
    <arm_group_label>Subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Blinatumomab+Haplo-Mismatched Cell Therapy (HMCT)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Blinatumomab</intervention_name>
    <description>Blinatumomab per package insert - via continuous infusion days 1-28 of Cycle 1 and Cycle 2, every 42 days.</description>
    <arm_group_label>Subjects</arm_group_label>
    <other_name>Blincyto</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Haplo-Mismatched Cell Therapy (HMCT)</intervention_name>
    <description>HMCT infusion Cycle 1, Day 15 and Cycle 2, Day 8 &amp; Day 15</description>
    <arm_group_label>Subjects</arm_group_label>
    <other_name>HMCT; 'primary DLI; 'microtransplantation'</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia. Patients with minimal residual&#xD;
             disease detected by NGS &gt; 10e-6 or multiparameter flow cytometry &gt; 10e-5 in blood or&#xD;
             bone marrow are eligible.&#xD;
&#xD;
          -  Patients must belong to one of the following 'high risk' categories: (i) at least 2nd&#xD;
             relapse or refractory to at least one salvage therapy (ii) relapse after autologous&#xD;
             stem cell transplantation, (iii) any relapse in a patient with no immediate allogeneic&#xD;
             transplant option (such as advanced age, comorbidity, lack of identified donor, or&#xD;
             patient refusal) (iv) Patients with Ph+ ALL will be allowed on the trial at the&#xD;
             discretion of the treating physician if they are no longer candidates for further TKI&#xD;
             based therapy. Prior therapy with a minimum of 2 prior 2nd/3rd generation TKI is&#xD;
             required. (TKI therapy is not allowed while on trial).&#xD;
&#xD;
          -  Patients with prior blinatumomab treatment are eligible if last treatment was at least&#xD;
             3 months prior to C1D1, patient's blasts are confirmed to express CD19, and patient&#xD;
             did not develop Grade 4 toxicities with prior blinatumomab therapy.&#xD;
&#xD;
          -  Age ≥ 18 years.&#xD;
&#xD;
          -  Patient has at least one medically fit first- or second-degree family member who is a&#xD;
             potential haploidentical donor. In addition, the prospective donor is willing to&#xD;
             voluntarily donate peripheral blood cells, and sign consent forms. For minors, consent&#xD;
             will be obtained from parent/guardian (assent from the minor is required).&#xD;
&#xD;
          -  Patients must have adequate organ function as defined below (note there are no marrow&#xD;
             function criteria, cytopenias will not result in exclusion):&#xD;
&#xD;
               -  Serum creatinine ≤ 2.0 x the upper limits of institutional normal (ULN)&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5x the upper limits of institutional normal, unless elevated&#xD;
                  bilirubin is attributed to liver involvement of leukemia or Gilbert's disease.&#xD;
&#xD;
               -  AST/ALT ≤ 2.5 x the upper limits of institutional normal (≤ 5 x ULN for patients&#xD;
                  with suspected liver involvement of leukemia).&#xD;
&#xD;
          -  ECOG performance status of 0, 1, or 2, and estimated survival of at least 3 months.&#xD;
&#xD;
          -  Patients must be able to understand and agree to sign an IRB-approved informed consent&#xD;
             form.&#xD;
&#xD;
          -  The effects of treatment on the developing human fetus are unknown. For this reason,&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control or complete abstinence) prior to study&#xD;
             entry, for the duration of study, and for two months after study participation. Should&#xD;
             a woman become pregnant or suspect she is pregnant while participating in this study,&#xD;
             she should inform her treating physician immediately.&#xD;
&#xD;
          -  Written informed consent obtained from subject and ability for subject to comply with&#xD;
             the requirements of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior allogeneic stem cell transplant&#xD;
&#xD;
          -  Prior treatment with fludarabine or cladribine within the last six months prior to&#xD;
             C1D1, or treatment with antithymocyte globulin (ATG) or alemtuzumab within the last 1&#xD;
             year.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Pregnant and/or lactating.&#xD;
&#xD;
          -  Who have had non-biopsy surgery in the last 10 days.&#xD;
&#xD;
          -  Who have active CNS disease. Patients with previously treated leptomeningeal disease&#xD;
             without evidence of remaining leukemia cells by spinal fluid will be eligible.&#xD;
             Intrathecal chemo may be given for prophylaxis for patients who previously had CNS&#xD;
             involvement but have now cleared the CSF, at the discretion of the treating physician.&#xD;
             Recommend to avoid IT chemotherapy for a few days before or after HMCT infusion.&#xD;
&#xD;
          -  History or presence of clinically relevant CNS pathology such as epilepsy, childhood&#xD;
             or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia,&#xD;
             Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis&#xD;
             (patients with minor prior stroke who are cognitively intact and capable of performing&#xD;
             all ADLs are permitted).&#xD;
&#xD;
          -  Patients with known active autoimmune disorder.&#xD;
&#xD;
          -  Known infection with HIV virus.&#xD;
&#xD;
          -  Patients concurrently taking the following drugs are excluded: mycophenolate,&#xD;
             cyclosporine, prednisone &gt; 20mg/day, or immunosuppressive agents (low dose maintenance&#xD;
             chemotherapy - POMP, hydroxyurea, low dose prednisone - is allowed until 24 hours&#xD;
             prior to starting blinatumomab).&#xD;
&#xD;
          -  Patients known to have active hepatitis B or C (Hepatitis B positive patients are&#xD;
             allowed if they are on appropriate antiviral agents such as lamivudine).&#xD;
&#xD;
          -  Subject likely to not be available to complete all protocol-required study visits or&#xD;
             procedures, including follow-up visits, and/or to comply with all required study&#xD;
             procedures to the best of the subject and Investigator's knowledge.&#xD;
&#xD;
        History or evidence of any other clinically significant disorder, condition or disease&#xD;
        (with the exception of those outlined above) that, in the opinion of the Investigator or&#xD;
        Amgen physician, if consulted, would pose a risk to subject safety or interfere with the&#xD;
        study evaluation, procedures or completion.&#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>Noah Merin, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</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>November 19, 2018</study_first_submitted>
  <study_first_submitted_qc>November 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 23, 2018</study_first_posted>
  <last_update_submitted>July 14, 2023</last_update_submitted>
  <last_update_submitted_qc>July 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cedars-Sinai Medical Center</investigator_affiliation>
    <investigator_full_name>Noah Merin</investigator_full_name>
    <investigator_title>Assistant Clinical Professor, Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Haplo-Mismatched Cellular Therapy</keyword>
  <keyword>Acute Lymphoblastic Leukemia</keyword>
  <keyword>ALL</keyword>
  <keyword>B-ALL</keyword>
  <keyword>donor lymphocyte</keyword>
  <keyword>DLI</keyword>
  <keyword>blinatumomab</keyword>
  <keyword>bispecific</keyword>
  <keyword>microtransplantation</keyword>
  <keyword>microtransplant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Blinatumomab</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/NCT03751709
org study id: IIT2017-05-MERIN-BLINHMCT
nct id: NCT03751709
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Single center Phase 1 dose escalation trial of the combination of standard-of-care
      blinatumomab plus Haplo-Mismatched Cellular Therapy (HMCT). HMCT refers to the infusion of
      donor peripheral blood mononuclear cells collected via pheresis from a haploidentical family
      member - the procedure is analogous to giving a donor lymphocyte infusion outside of the
      setting of an allogeneic stem cell transplant; also known as 'microtransplantation'. The HMCT
      is an unselected mix of lymphocytes and leukocytes, but the product dose escalation will be
      done based on the T cell content.

      Ten recipients are planned. Each subject will be administered one infusion of HMCT during the
      first cycle of blinatumomab and two infusions during cycle two of blinatumomab; the CD3+ cell
      dose of the HMCT infusion is governed by dose escalation / de-escalation following a Bayesian
      method.
This single center, phase 1 study will examine the safety, side effects, and effectiveness of
      combining the investigational use of Haplo-Mismatched Cellular Therapy (HMCT) in combination
      with blinatumomab. Investigators plan to give HMCT starting on day 15, after the initial CRS
      caused by blinatumomab has resolved. The investigational treatment will start with 1% of the
      typical HMCT dose (10e6 CD3+ cells/kg) and will employ a modified dose escalation design as
      an additional safety measure. The primary end points will be DLT of the combination of
      blinatumomab and HMCT.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of DLTs
time frame: up to 6 months
description: Number of Dose Limiting Toxicities experienced by patients undergoing HLA mismatched cellular therapy (HMCT) of allogenic CD3+ cells in combination with blinatumomab.
measure: Number of participants experiencing complete response (CR) from time of transplant to one day following the second treatment
time frame: up to 3 months
description: Bone marrow aspiration and local peripheral blood counts will be used to measure response. CR is defined as the following:
Less than or equal to 5% blasts in the bone marrow
No evidence of disease, AND
Full recovery of peripheral blood counts: platelets > 100,000/ul, and ANC > 1000/ul
measure: Number of participants experiencing complete response with partial recovery of peripheral blood counts (CRh) from time of transplant to one day following the second treatment
time frame: up to 3 months
description: Bone marrow aspiration and local peripheral blood counts will be used to measure response. CRh is defined as the following:
Less than or equal to 5% blasts in the bone marrow
No evidence of disease, AND
Full recovery of peripheral blood counts: platelets > 50,000/ul, and ANC > 500/ul
measure: Number of participants experiencing complete response with incomplete count recovery (CRi) from time of transplant to one day following the second treatment
time frame: up to 3 months
description: Bone marrow aspiration and local peripheral blood counts will be used to measure response. CRi is defined as the following:
Less than or equal to 5% blasts in the bone marrow
No evidence of disease, AND
Full recovery of peripheral blood counts: platelets > 100,000/ul, and ANC > 1000/ul
measure: Response blast-free hypoplastic or aplastic bone marrow from time of transplant to one day following the second treatment
time frame: up to 3 months
description: Bone marrow aspiration and local peripheral blood counts will be used to measure response. Blast-free hypoplastic or aplastic bone marrow response is defined as the following:
Less than or equal to 5% blasts in the bone marrow
No evidence of disease, AND
Full recovery of peripheral blood counts: platelets > 50,000/ul, and ANC > 500/ul
measure: Disease burden measured as the minimal residual disease (MRD) response from time of transplant to one day following the second treatment
time frame: up to 3 months
description: MRD remission is defined as the occurrence of an MRD level below 10^-4 measured by quantitative reverse transcription polymerase chain reaction (PCR) or flow cytometry.
Complete response defined as: no detectable leukemic cells by PCR or flow cytometry.
arm group label: Subjects
arm group type: Experimental
description: Blinatumomab+Haplo-Mismatched Cell Therapy (HMCT)
intervention type: Drug
intervention name: Blinatumomab
description: Blinatumomab per package insert - via continuous infusion days 1-28 of Cycle 1 and Cycle 2, every 42 days.
arm group label: Subjects
other name: Blincyto
intervention type: Other
intervention name: Haplo-Mismatched Cell Therapy (HMCT)
description: HMCT infusion Cycle 1, Day 15 and Cycle 2, Day 8 & Day 15
arm group label: Subjects
other name: HMCT; 'primary DLI; 'microtransplantation'
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Noah Merin, MD PhD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center Samuel Oschin Comprehensive Cancer Institute
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Cedars-Sinai Medical Center
investigator full name: Noah Merin
investigator title: Assistant Clinical Professor, Principal Investigator
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
mesh term: Blinatumomab