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
Leukemia - Lymphoma
Conditions: official terms
Conditions: Keywords
Leukemia/Lymphoma, Hematologic Malignacies, Leukemia, Lymphoma, Ewing Sarcoma, Rhabdomyosarcoma, Neuroblastoma, Healthy Donor
Study Type
Study Phase
Phase 1
Study Design
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Name: NK Cell Infusion Type: Biological
Name: Stem Cell Infusion Type: Biological
Overall Status

- 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.


- 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.


- 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.


- 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

- 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.


-Primary objectives are 1) 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; and 2) 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).

-Secondary objectives will assess DFS and OS of patients treated on this study, the incidence of cGVHD and viral infection, and evaluate biologic correlates of NK expansion and NK activity.


-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.


- 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.
Criteria for eligibility
Healthy Volunteers: Accepts Healthy Volunteers
Maximum Age: 35 Years
Minimum Age: 4 Years
Gender: Both

Patient (Recipient):

-Solid Tumor Diagnoses: bone or soft tissue sarcoma (Ewing Sarcoma, Rhabdomyosarcoma, Desmoplastic Small Round Cell Tumor); Neuroblastoma (NB); who have high risk disease with progressive or recurrent disease after receiving effective front line therapy as defined below.

a) Patients with EWS, or RMS must fit into one of the following categories:

i. Patients who present at the time of initial diagnosis with bone or bone marrow metastases may be enrolled after completion of standard front-line therapy. Standard front line therapy for rhabdomyosarcoma should include vincristine and cyclophosphamide, plus actinomycin D and/or adriamycin. For patients with Ewing s sarcoma, standard front line therapy should include vincristine, cyclophosphamide, adriamycin, ifosfamide and etoposide.

ii. Patients with recurrence of tumor at any site less than one year after completing standard front-line therapy or with a second or subsequent recurrence at any time after completing standard frontline therapy.

iii. Patients with progression or persistence of disease while receiving standard front-line chemotherapy.

b) The following patients with DSRCT are eligible after receiving front line standard therapy, which is defined as surgery (debulking or complete resection, if deemed resectable) and a regimen containing at least vincristine, cyclophosphamide, and adriamycin.

1. unresectable disease

2. metastatic tumor (abdominal and extra-abdominal disease)

3. progressive or persistent while receiving standard therapy

4. recurrence within one year of completing therapy

c) Patients with neuroblastoma must be categorized as High-Risk and must be ineligible or have failed (relapsed following or progression through) all available standard therapies defined as:

1. Standard upfront multiagent chemotherapy.

2. Resection of the primary tumor if resectable and/or local radiotherapy

3. Myeloablative chemotherapy and stem cell rescue (i.e., bone marrow and/or peripheral blood stem cell transplantation), with post-transplant Oral 13-cis-retinoic acid and Chimeric anti-GD2 antibody ch14.18 combined with granulocytemacrophage colony stimulating factor (GMCSF), interleukin-2 (IL 2) in conjunction with retinoic acid.

d) Patients must have no evidence of measureable disease (NED) or

must have minimal residual disease, which can be rendered NED

with localized therapies before transplant.

e) Patients who have previously received high-dose chemotherapy

with autologous stem cell rescue are eligible for this trial.

- 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


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)


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).

- 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).

- 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 greater than or equal to 40% of the expected value corrected for alveolar volume and hgb.

- 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.


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.



-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.



- 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.
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Status: Recruiting
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office - (888) NCI-1937
Start Date
January 2011
Completion Date
October 2018
National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page