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
Study type: Interventional
Phase: Phase 1

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.
    

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. Natural killer (NK) mediated killing appears to confer improved outcomes
           after HSCT for patients with acute myelogenous leukemia (AML) and acute lymphoblastic
           leukemia (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 antigen-presenting cells (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 human leukocyte antigen (HLA)-matched T cell depleted
           (TCD) peripheral blood stem cell transplant (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 acute graft versus host disease (aGVHD) (less than
           25% incidence of grade III or grade IV).

      Eligibility

      -Patients 4-35 years with hematologic malignancies (e.g., ALL, AML, Chronic Myelogenous
      Leukemia (CML), Hodgkins Lymphoma (HD), Non-Hodgkins Lymphoma (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 myeloablative regimen based on current Children's
           Oncology Group (COG) standard-of- care preparative regimen will also be included.

        -  Donors will undergo 1-3 apheresis sessions for filgrastim mobilized peripheral blood
           stem cells (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 10(5), 1 x 10(6) and 1 x 10(7) 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.
    

Intervention name(s): Natural Killer (NK) Cell Infusion; Stem Cell Infusion
Intervention type(s): Biological; Biological
Intervention description(s): 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
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Leukemia/Lymphoma; Hematologic Malignancies; Leukemia; Lymphoma; Ewing Sarcoma; Rhabdomyosarcoma; Neuroblastoma; Healthy Donor