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A Phase I Study of NK Cell Infusion Following Allogeneic Peripheral Blood Stem Cell Transplantation From Related or Matched Unrelated Donors in Pediatric Patients With Solid Tumors and Leukemias

NCT01287104

Description:

Background: - Bone marrow stem cells, which are found in the bone marrow and blood stream, can be collected and transplanted to treat a variety of types of cancer in a process known as hematopoietic stem cell transplantation (HSCT). When stem cells are taken from one person, most commonly a sibling or a family member, and then given to another person, this is referred to as allogeneic HSCT. Allogeneic HSCT has proven to be an especially effective treatment for patients with some types of cancers of the blood (leukemia) and certain solid tumors. The transplanted stem cells travel to the patient's bone marrow and begin producing normal blood cells, and also attack patient s cancer cells. - Because allogenic HSCT does not always prevent the cancer from returning, researchers are interested in determining whether another type of immune cell taken from the stem cell donor s white blood cells, called a "natural killer" (NK) cell, can be given in addition to the HSCT to help fight the tumor. In the laboratory, NK cells have been shown to kill tumor cells, but it is not yet know if this will occur when given to patients after HSCT. Objectives: - To determine the safety, effectiveness, and immune system response of giving NK white blood cells to individuals who have received allogeneic HSCT. - To identify possible side effects from the treatment. Eligibility: - Donors: Stem cell donors whose blood matches one of the recipients on six out of six HLA (blood immune marker) types. The donor may not be the identical twin of a recipient. - Recipients: Individuals between 4 and 35 years of age who have been diagnosed with pediatric solid tumors that have not responded to standard treatment, or individuals between 4 and 18 years of age who have been diagnosed with leukemia that has not responded to standard treatment. - Other eligibility requirements which include a physical exam and blood laboratory evaluation are included to make sure it is safe for both the donor to donate and the recipient to undergo the transplant procedure. Design: - Donors and recipients will be screened with a full medical history and physical examination, and will provide blood and urine samples; recipients will have tumor imaging studies and other tests as required by the researchers. - Donors: - Participants will receive filgrastim injections (to stimulate the bone marrow) for 1 week to make stem cells travel from bone marrow to blood. - Participants will provide stem cells and NK cells through apheresis. - Recipients: - Participants will have three cycles of chemotherapy to treat the underlying cancer and weaken the immune system so that it will accept the donor cells. - Participants will then receive preparative chemotherapy for the transplant and two days after the last dose of chemotherapy, participants will have allogenic HSCT using the donated stem cells. - Participants will receive an infusion of NK cells on days 7 and 35 after the HSCT. - Participants will remain in the hospital for monitoring after the HSCT and NK cell treatments, and will be followed closely as outpatients for the first 6 months after the transplant and then less frequently for at least 5 years.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Desmoplastic Small Round Cell Tumor
  • Ewing Sarcoma
  • Neuroblastoma
  • Rhabdomyosarcoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I Study of NK Cell Infusion Following Allogeneic Peripheral Blood Stem Cell Transplantation From Related or Matched Unrelated Donors in Pediatric Patients With Solid Tumors and Leukemias
  • Official Title: A Phase I Study of NK Cell Infusion Following Allogeneic Peripheral Blood Stem Cell Transplantation From Related or Matched Unrelated Donors in Pediatric Patients With Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 110073
  • SECONDARY ID: 11-C-0073
  • NCT ID: NCT01287104

Conditions

  • Leukemia
  • Lymphoma

Interventions

DrugSynonymsArms
NK Cell Infusion1
Stem Cell Infusion1

Purpose

Background: - Bone marrow stem cells, which are found in the bone marrow and blood stream, can be collected and transplanted to treat a variety of types of cancer in a process known as hematopoietic stem cell transplantation (HSCT). When stem cells are taken from one person, most commonly a sibling or a family member, and then given to another person, this is referred to as allogeneic HSCT. Allogeneic HSCT has proven to be an especially effective treatment for patients with some types of cancers of the blood (leukemia) and certain solid tumors. The transplanted stem cells travel to the patient's bone marrow and begin producing normal blood cells, and also attack patient s cancer cells. - Because allogenic HSCT does not always prevent the cancer from returning, researchers are interested in determining whether another type of immune cell taken from the stem cell donor s white blood cells, called a "natural killer" (NK) cell, can be given in addition to the HSCT to help fight the tumor. In the laboratory, NK cells have been shown to kill tumor cells, but it is not yet know if this will occur when given to patients after HSCT. Objectives: - To determine the safety, effectiveness, and immune system response of giving NK white blood cells to individuals who have received allogeneic HSCT. - To identify possible side effects from the treatment. Eligibility: - Donors: Stem cell donors whose blood matches one of the recipients on six out of six HLA (blood immune marker) types. The donor may not be the identical twin of a recipient. - Recipients: Individuals between 4 and 35 years of age who have been diagnosed with pediatric solid tumors that have not responded to standard treatment, or individuals between 4 and 18 years of age who have been diagnosed with leukemia that has not responded to standard treatment. - Other eligibility requirements which include a physical exam and blood laboratory evaluation are included to make sure it is safe for both the donor to donate and the recipient to undergo the transplant procedure. Design: - Donors and recipients will be screened with a full medical history and physical examination, and will provide blood and urine samples; recipients will have tumor imaging studies and other tests as required by the researchers. - Donors: - Participants will receive filgrastim injections (to stimulate the bone marrow) for 1 week to make stem cells travel from bone marrow to blood. - Participants will provide stem cells and NK cells through apheresis. - Recipients: - Participants will have three cycles of chemotherapy to treat the underlying cancer and weaken the immune system so that it will accept the donor cells. - Participants will then receive preparative chemotherapy for the transplant and two days after the last dose of chemotherapy, participants will have allogenic HSCT using the donated stem cells. - Participants will receive an infusion of NK cells on days 7 and 35 after the HSCT. - Participants will remain in the hospital for monitoring after the HSCT and NK cell treatments, and will be followed closely as outpatients for the first 6 months after the transplant and then less frequently for at least 5 years.

Detailed Description

      Background

        -  Despite progress in pediatric oncology, some patient subsets with hematologic
           malignancies and pediatric solid tumors continue to experience extremely poor overall
           survival. Allogeneic Hematopoietic Stem Cell Transplant (HSCT) is effective in some
           high-risk hematologic malignancies.

        -  Allogeneic HSCT can be performed safely in these patient populations, but disease
           recurrence is common and new approaches to enhance the antitumor effect of this therapy
           are needed. NK mediated killing appears to confer improved outcomes after HSCT for
           patients with AML and ALL, and NK cell infusions have induced complete remissions in
           patients with AML.

        -  Preclinical data demonstrates that activated NK cells readily kill pediatric solid
           tumors and leukemias, that large numbers of activated NK cells can be generated ex vivo
           using artificial APCs and that the post-transplant period may be favorable for expansion
           and survival of adoptively transferred NK cells.

      Objectives

        -  To assess the feasibility and toxicity of infusing escalating doses of donor-derived
           activated NK cell donor lymphocyte infusions (NK-DLI) on Days 7 plus or minus 2 days and
           49 plus or minus 7 days following HLA-matched T cell depleted (TCD) PBSCT in patients
           with metastatic or recurrent pediatric solid tumors and high risk leukemias who have
           unrelated donors or related donors;

        -  To determine if patients treated in this manner experience rapid, sustained donor
           engraftment and acceptable rates of aGVHD (less than 25% incidence of grade III or grade
           IV).

      Eligibility

      -Patients 4-35 years with hematologic malignancies (e.g., ALL, AML, CML, HD, NHL), with a 5/6
      or 6/6 HLA-matched related or 9/10 or 10/10 HLA matched unrelated donor.

      Design

        -  Pre-transplant disease specific immune depleting chemotherapy and the preparative
           regimen will be the same as that used previously on 02-C-0259 and 01-C-0125, for those
           patients undergoing reduced intensity transplant.

        -  For patients with ALL or AML, a myeloblative regimen based on current COG standard-of-
           care preparative regimen will also be included.

        -  Donors will undergo 1-3 apheresis sessions for filgrastim mobilized PBSC. This product
           will be T cell and NK cell depleted prior to cryopreservation. NK cells selected from
           the product will be used for ex vivo activation and expansion using KT64.4-BBL
           artificial antigen presenting cells.

        -  A phase 1 cell dose escalation of donor derived NK-DLI will be performed using 3 dose
           levels (1 x 105, 1 x 106 and 1 x 107 NK cells/kg) infused on days 21 more or less 3
           post-PBSCT and a second infusion on day 49 more or less 7 post-PBSCT.

        -  Three patients will be enrolled at each dose level, with the cohort expanded to 6 if
           dose-limiting toxicity occurs. An expanded group of 12 patients will be treated at the
           highest dose level tolerated.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalPre-BMT Prep Regimen with Stem Cell and NK Cell Infusions coupled with Induction therapy

    Eligibility Criteria

            -  INCLUSION CRITERIA: PATIENTS (RECIPIENT)
    
              -  Hematologic Malignancies Diagnoses:
    
                   1. Acute lymphoblastic leukemia (ALL) with a history of bone marrow relapse in
                      clinical remission (CR) #2 or greater, or in CR#1 if prior induction failure; or
                      with an M1 marrow if unable to achieve CR.
    
                   2. Philadelphia chromosome positive ALL patients who;
    
                        1. Have progressed through or relapsed following TKI therapy or conventional
                           myeloablative therapy
    
                           OR
    
                        2. Are ineligible to receive tyrosine kinase inhibitor (TKI) therapy AND
                           myeloablative HSCT
    
                   3. Acute Myelogenous Leukemia (AML) with a history of bone marrow relapse in
                      remission CR #2 or greater; or with an M1 marrow if unable to achieve CR; or in
                      CR#1 if prior induction failure; or any of the following High-Risk categories:
    
                        1. FLT3/ITD+ with high allelic ratio > 0.4 (HR FLT3/ITD+)
    
                           regardless of low risk features.
    
                        2. Presence of monosomy 7, monosomy 5, or del5q, without
    
                           inv(16)/t(16;16) or t(8;21) cytogenetics or NPM or CEBP(alpha)
    
                           mutations.
    
                        3. AML without inv(16)/t(16;16), t(8;21), NPM, CEPB(alpha) mutations, monosomy
                           7, monosomy 5, del5q, or HR FLT3/ITD+,
    
                      but with evidence of residual AML (greater than or equal to 0.1%) at end of
                      Induction I.
    
                   4. Hodgkin s and Non-Hodgkin s Lymphoma with refractory disease or relapse after at
                      least one salvage regimen, or after autologous stem cell transplant
    
                   5. Juvenile Myelocytic Leukemia (JMML) with less than 10% blasts in marrow and
                      blood, who are not eligible for effective standard therapies.
    
              -  Age: 4 to less than or equal to 35 years old at the time of enrollment for solid tumor
                 patients and 4 to less than or equal to 35 years old for hematologic malignancies.
    
              -  All previous cytotoxic chemotherapy must be completed at least 3 weeks prior to study
                 entry. Any prior non-hematologic vital organ toxicity (cardiac, pulmonary, hepatic,
                 renal) of any previous therapy must have resolved to grade 1 or less, unless specified
                 elsewhere in Inclusion Criteria for Patient (Recipient).
    
            EXCEPTIONS:
    
            There is no time restriction in regard to prior intrathecal chemotherapy provided there is
            complete recovery from any acute toxic effects; or
    
            Subjects receiving standard ALL maintenance chemotherapy will not require washout.
    
              -  All previous immunologic or molecularly targeted therapy must be completed at least 1
                 week prior to study entry. Any prior non-hematologic toxicity of any previous therapy
                 must have resolved to grade 1 or less, unless specified elsewhere in Inclusion
                 Criteria for Patient (Recipient).
    
              -  Prior investigational therapy must be completed at least 30 days prior to study entry
    
              -  Patients with prior autologous or allogeneic transplant are eligible. Patients must be
                 greater than 100 days post transplant and have no evidence of active GVHD.
    
              -  Performance status: ECOG 0, 1 or 2, or for children less than or equal to 10 years of
                 age, Lansky greater than or equal to 60. Life expectancy greater than 3 months.
    
              -  Availability of HLA-matched (5-6/6 antigen or 8/8 allele) related or unrelated donor.
    
              -  Cardiac function: Left ventricular ejection fraction greater than or equal to 45% by
                 MUGA or ECHO, fractional shortening greater than or equal to 28% by ECHO.
    
              -  Pulmonary function: DLCO >= 40% of the expected value corrected for alveolar volume
                 and hgb for reduced intensity transplant and DLCO >=55% for myeloablative regimen. For
                 children who are unable to cooperate for PFTs, the criterion is: No evidence of
                 dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen
                 therapy.
    
              -  Liver function: Serum total bilirubin less than 2 mg/dl, serum AST and ALT less than
                 or equal to 2.5 times upper limit of normal. Patients with Gilbert syndrome are
                 excluded from the requirement of a normal bilirubin. (Gilbert syndrome is found in
                 3-10% of the general population, and is characterized by mild, chronic unconjugated
                 hyperbilirubinemia in the absence of liver disease or overt hemolysis).
    
              -  Renal function: Age-adjusted normal serum creatinine according to the following, or a
                 creatinine clearance greater than or equal to 60 ml/min/1.73 m(2):
    
                   -  For age (years) of less than or equal to 5, a Maximum serum creatinine (mg/dl) of
                      0.8
    
                   -  For age (years) of greater than 5 but less than or equal to 10, a Maximum serum
                      creatinine (mg/dl) of 1.0
    
                   -  For age (years) of greater than 10 but less than or equal to 15, a Maximum serum
                      creatinine (mg/dl) of 1.2
    
                   -  For age (years) of greater than 15, a Maximum serum creatinine (mg/dl) of 1.5
    
              -  Marrow function: ANC must be greater than 750/mm(3) (unless due to underlying disease
                 in which case there is no grade restriction), platelet count must be greater than or
                 equal to 75,000/mm(3) (not achieved by transfusion) unless due to underlying disease
                 in which case there is no grade restriction). Lymphopenia, CD4 lymphopenia,
                 leukopenia, and anemia will not render patients ineligible.
    
              -  Ability to give informed consent. For patients less than 18 years of age their legal
                 guardian must give informed consent. Pediatric patients will be included in
                 age-appropriate discussion in order to obtain verbal assent.
    
                   -  Durable power of attorney form completed (patients greater than or equal to 18
                      years of age only).
    
                   -  Female patients (and when relevant their male partners) must be willing to
                      practice birth control (including abstinence) during and for two months after
                      treatment, if of childbearing potential.
    
            EXCLUSION CRITERIA: PATIENT (RECIPIENT)
    
              -  Uncontrolled infection.
    
              -  Active CNS malignancy as defined by:
    
                   1. Solid Tumors: History of untreated CNS tumor involvement. Extradural masses which
                      have not invaded the brain parenchyma or parameningeal tumors without evidence
                      for leptomeningeal spread will not render the patient ineligible. Patients with
                      previous CNS tumor involvement are eligible IF the CNS tumor(s) has been treated
                      and has been stable or resolving for at least 6 months; and if the patient does
                      not currently require steroids.
    
                   2. Lymphoma: tumor mass on CT scan or leptomeningeal disease
    
                   3. Leukemia: CNS 2 or CNS 3 classification.
    
              -  Lactating or pregnant females (due to risk to fetus or newborn).
    
              -  HIV positive (due to unacceptable risk associated with severe immune suppression).
    
              -  Hepatitis B surface antigen (HBsAg) positive or hepatitis C antibody positive with
                 elevated liver transaminases. All patients with chronic active hepatitis (including
                 those on treatment) are ineligible.
    
              -  Patients who require systemic corticosteroid or other immunosuppressive therapy.
                 Immunosuppressive therapy must be stopped at least 28 days prior to protocol C1D1.
                 Topical agents and/or inhaled corticosteroids are permitted.
    
              -  High risk of inability to comply with transplant protocol, or inability to give
                 appropriate informed consent in the estimation of the PI, social work, psychiatry, or
                 the stem cell transplant team.
    
              -  Fanconi Anemia
    
              -  Clinically significant systemic illness (e.g. serious active infections or significant
                 cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the
                 PI would likely compromise the patient s ability to tolerate protocol therapy or
                 significantly increase the risk of complications.
    
            INCLUSION CRITERIA: DONOR
    
              -  Weight greater than or equal to 15 kilograms and for unrelated donors, greater than or
                 equal to 18 years.
    
              -  HLA-matched related or unrelated allogeneic donors. Genotypically identical twins may
                 serve as stem cell donors. Related donors must be 5 or 6/6 antigen matched. Unrelated
                 donors must be 8/8 allele matched.
    
              -  For donors less than 18 years of age, he/she must be the oldest suitable donor, their
                 legal guardian must give informed consent, the donor must give verbal assent, and
                 he/she must be cleared by social work and a mental health specialist to participate.
    
              -  For donors greater than or equal to 18 years of age, ability to give informed consent.
    
              -  Adequate peripheral venous access for apheresis or consent to use a temporary central
                 venous catheter for apheresis.
    
              -  Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine
                 (DTM) criteria and, in the case of an unrelated donor, the National Marrow Donor
                 Program (NMDP) standards and FDA 21 CFR 1271.
    
            EXCLUSION CRITERIA: DONOR
    
              -  History of medical illness that in the estimation of the PI or DTM/NMDP physician
                 poses prohibitive risk to donation including, but not limited to, stroke, hypertension
                 that is not controlled with medication, or heart disease. Individuals with symptomatic
                 angina or a history of coronary bypass grafting or angioplasty will not be eligible.
    
              -  Anemia (Hb less than 11 gm/dl) or thrombocytopenia (less than100,000/microliters).
    
              -  Identical twins will be excluded; the lack of MHC incompatibility will alter the
                 toxicity profile in such a way as to make the results uninterpretable.
    
              -  Breast feeding or pregnant females. Donors of childbearing potential must use an
                 effective method of contraception during the time they are receiving filgrastim. The
                 effects of cytokine administration on a fetus are unknown and may be potentially
                 harmful. The effects upon breast milk are also unknown and may potentially be harmful
                 to the infant.
    
              -  High risk of inability to comply with protocol requirements as determined by the
                 principal investigator and donor center team.
    
              -  Positive screening test for transfusion-transmissible infection in accordance with DTM
                 or NMDP donation standards, including HIV-positive, hepatitis B surface antigen
                 (HBsAg) positive or hepatitis C antibody positive.
          
    Maximum Eligible Age:35 Years
    Minimum Eligible Age:4 Years
    Eligible Gender:All
    Healthy Volunteers:Accepts Healthy Volunteers

    Primary Outcome Measures

    Measure:Feasibility & Toxicity
    Time Frame:1 Year
    Safety Issue:
    Description:Number of patients receiving 2 doses of NK cell infusions (within 56 days of HSCT) and the number of AEs, UPs

    Secondary Outcome Measures

    Measure:Incidence of cGVHD in allogeneic PBSCT followed by NK-DLI
    Time Frame:3 years
    Safety Issue:
    Description:number of occurrences of cGVHD
    Measure:Compare disease-free and overall survival
    Time Frame:3 years
    Safety Issue:
    Description:Number of AEs, UPs
    Measure:Incidence of viral infection and/or reactivation in allogeneic PBSCT followed by NK-DLI
    Time Frame:3 years
    Safety Issue:
    Description:Number of occurrences of viral infection and/or reactivation in allogeneic PBSCT followed by NK-DLI
    Measure:Correlate post-transplant cell numbers with select immunologic parameters
    Time Frame:3 years
    Safety Issue:
    Description:The correlated post-transplant cell numbers with select immunologic parameters
    Measure:Impact of KIR expression and KIR reactivity on PFS
    Time Frame:3 years
    Safety Issue:
    Description:Presence or absence of KIR genes and number of AEs, UPs, or deaths

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Completed
    Lead Sponsor:National Cancer Institute (NCI)

    Trial Keywords

    • Leukemia/Lymphoma
    • Hematologic Malignacies
    • Leukemia
    • Lymphoma
    • Ewing Sarcoma
    • Rhabdomyosarcoma
    • Neuroblastoma
    • Healthy Donor

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