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
Condition: Leukemia; Lymphoma
MeSH terms: Lymphoma; Leukemia
Intervention: Natural Killer (NK) Cell Infusion; Stem Cell Infusion
Intervention description: Post-transplant Day 21 (plus-minus 3 days): (1 x 10(5), 1 x 10(6) or 1 x 10(7) natural killer (NK) cells/kg by intravenous (IV) infusion. Followed by a second NK cell infusion of the same cell dose, on Day 49 plus-minus 7 days.; Transplant Day 0: >4 x 10(6)/kg cluster of differentiation 34 (CD34)+ stem cells by IV infusion Filgrastim, 5 microgram/kg per day subcutaneous (SQ) from day 0 until absolute neutrophil count (ANC) >5000/microliters x2
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 34.0
Sex: All
Minimum age: 4 Years
Maximum age: 35 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Leukemia/Lymphoma; Hematologic Malignancies; Leukemia; Lymphoma; Ewing Sarcoma; Rhabdomyosarcoma; Neuroblastoma; Healthy Donor

Summary:

      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 patients 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 donors 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
           human leukocyte antigen (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.
    

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 tyrosine kinase inhibitor
                       (TKI) therapy or conventional myeloablative therapy

                       OR

                    2. Are ineligible to receive tyrosine kinase inhibitor (TKI) therapy AND
                       myeloablative hematopoietic stem cell transplant (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. Fms-related tyrosine kinase 3 (FLT3)/internal tandem duplication (ITD)+ with
                       high allelic ratio > 0.4 (high allelic ration (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. Acute myelogenous leukemia (AML) without inv(16)/t(16;16), t(8;21),
                       nucleophosmin (NPM), CCAAT/enhancer binding protein (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 acute lymphoblastic leukemia (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 graft versus host
             disease (GVHD).

          -  Performance status: Eastern Cooperative Oncology Group (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 human leukocyte antigen (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
             multi-gated acquisition scan (MUGA) or echocardiogram (ECHO), fractional shortening
             greater than or equal to 28% by ECHO.

          -  Pulmonary function: Diffusing capacity of the lungs for carbon monoxide (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 pulmonary function tests (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 aspartate
             aminotransferase (AST) and alanine aminotransferase (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: Absolute neutrophil count (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, cluster of differentiation 4 (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 central nervous system (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 computed tomography (CT) scan or leptomeningeal disease

               3. Leukemia: CNS 2 or CNS 3 classification.

          -  Lactating or pregnant females (due to risk to fetus or newborn).

          -  Human immunodeficiency virus (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 cycle 1,
             day 1 (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 principal investigator (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 patients 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 National Institutes of Health
             (NIH)/Clinical Center (CC) Department of Transfusion Medicine (DTM) criteria and, in
             the case of an unrelated donor, the National Marrow Donor Program (NMDP) standards and
             Food and Drug Administration (FDA) 21 Code of Federal Regulations (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 (Hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (less
             than100,000/microliters).

          -  Identical twins will be excluded; the lack of Major histocompatibility complex Major
             histocompatibility complex (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.