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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

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ClinicalTrials.gov Identifier: NCT01287104
Recruitment Status : Completed
First Posted : February 1, 2011
Last Update Posted : August 16, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief 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 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.

Condition or disease Intervention/treatment Phase
Leukemia Lymphoma Biological: NK Cell Infusion Biological: Stem Cell Infusion Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : January 29, 2011
Actual Primary Completion Date : June 28, 2018
Actual Study Completion Date : June 28, 2018


Arm Intervention/treatment
Experimental: 1
Pre-BMT Prep Regimen with Stem Cell and NK Cell Infusions coupled with Induction therapy
Biological: NK Cell Infusion
Post-transplant Day 21 (plus-minus 3 days): (1 x 105, 1 x 106 or 1 x 107) NK cells/kg by IV infusion. Followed by a second NK cell infusion of the same cell dose, on Day 49 plus-minus 7 days.

Biological: Stem Cell Infusion
Transplant Day 0: >4 x 106/kg CD34+ stem cells by IV infusion Filgrastim, 5 microgram/kg per day SQ from day 0 until ANC >5000/microliters x2




Primary Outcome Measures :
  1. Feasibility & Toxicity [ Time Frame: 1 Year ]
    Number of patients receiving 2 doses of NK cell infusions (within 56 days of HSCT) and the number of AEs, UPs

  2. Efficacy [ Time Frame: 1 Year ]
    Number of patients at the highest NK dose level with sustained donor lymphoid engraftment


Secondary Outcome Measures :
  1. Incidence of cGVHD in allogeneic PBSCT followed by NK-DLI [ Time Frame: 3 years ]
    number of occurrences of cGVHD

  2. Compare disease-free and overall survival [ Time Frame: 3 years ]
    Number of AEs, UPs

  3. Incidence of viral infection and/or reactivation in allogeneic PBSCT followed by NK-DLI [ Time Frame: 3 years ]
    Number of occurrences of viral infection and/or reactivation in allogeneic PBSCT followed by NK-DLI

  4. Correlate post-transplant cell numbers with select immunologic parameters [ Time Frame: 3 years ]
    The correlated post-transplant cell numbers with select immunologic parameters

  5. Impact of KIR expression and KIR reactivity on PFS [ Time Frame: 3 years ]
    Presence or absence of KIR genes and number of AEs, UPs, or deaths



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01287104


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Nirali N Shah, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01287104     History of Changes
Other Study ID Numbers: 110073
11-C-0073
First Posted: February 1, 2011    Key Record Dates
Last Update Posted: August 16, 2018
Last Verified: August 13, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Leukemia/Lymphoma
Hematologic Malignacies
Leukemia
Lymphoma
Ewing Sarcoma
Rhabdomyosarcoma
Neuroblastoma
Healthy Donor

Additional relevant MeSH terms:
Lymphoma
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases