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

Inclusion Criteria

- INCLUSION CRITERIA:

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

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).

- 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 10/10 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.

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 10/10 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.