Haploidentical Natural Killer (NK) Cells in Patients With Relapsed or Refractory Neuroblastoma
Condition: Neuroblastoma
MeSH terms: Neuroblastoma
Intervention: Fludarabine; Cyclophosphamide; Natural Killer Cell Infusion; Mesna; Interleukin-2
Intervention description: 25 mg/m^2 By Vein Daily Over 30 minutes Starting 6 days before the NK cell infusion (considered Day -6) and once a day through Day -2.; 60 mg/kg By Vein Daily Over 2 Hours On Days -5 and -4; Natural Killer Cell Infusion on Day 0.; 12 mg/kg By Vein, Over about 15 minutes, Five Times Per Day on Days -5 and -4.; Received under skin three times weekly for 9 total doses following NK Cell Infusion:
For patients weighing 45 kg or more, dose administered is 10 Million units three times weekly for 9 total doses. For patients less than 45 kg, dose administered is 5 Million units/m2 (max dose 10 Million units) three times weekly for 9 total doses.
Intervention MeSH terms: Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Healthy volunteers: No
Keywords: Neuroblastoma; Natural Killer Cell; NK Cell Infusion; Haploidentical Natural Killer (NK) Cells; Fludarabine; Fludarabine Phosphate; Fludara; Cyclophosphamide; Cytoxan; Neosar; Interleukin-2; IL-2; Proleukin; Mesna; Mesnex; Infusion of NK cells; Pediatric NK Cell Infusion; Pediatric Neuroblastoma; Pediatric NK; Pediatric

Summary:

      Primary:

      Evaluate safety, feasibility, persistence, and anti-tumor effect of infused haploidentical
      donor-derived natural killer (NK) cells and low-dose interleukin-2 (IL-2).

      Secondary:

        -  Quantification of cytokine levels;

        -  Assessment of NK cell immunophenotype and function.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Inclusion Criteria: (Must be met within 28 days prior to initiating lymphodepleting
             conditioning regimen) The first two patients enrolled in this protocol, if they have
             undergone a previous autologous transplant, will need to be at least 6 months
             post-transplant and/or have available prior cryopreserved autologous peripheral blood
             stem cells. This criterion safeguards against the possibility that the lymphodepletion
             regimen may lead to prolonged myelosuppression in this patient population.

          2. Evidence of relapse or progression of neuroblastoma after autologous peripheral blood
             stem-cell transplantation or similar aggressive therapy; high risk neuroblastoma that
             is refractory to standard induction therapy.

          3. Measurable disease, with at least one of the following: One or more measurable
             radiographic abnormalities (X-ray, CT, MRI, PET); MIBG (metaiodobenzylguanidine) scan
             with uptake at a minimum of 1 site; Bone marrow with tumor cells seen on routine
             morphology (not by neuron specific enolase (NSE) staining or by immunocytology only).
             If the only bony or soft tissue lesion available for evaluation has been previously
             irradiated, the lesion must either a) have viable neuroblastoma on biopsy at least 4
             weeks after radiation therapy or b) have measurable growth in the lesion after
             radiation.

          4. Donor must be related to the recipient.

          5. Off all systemic chemotherapeutic agents or retinoids for at least 21 days prior to NK
             infusion.

          6. Platelets >/= 50,000 * 10^ 9/L and hemoglobin (Hgb) >/= 9 g/dL, unsupported by
             transfusions in last seven days.

          7. absolute neutrophil count (ANC) >/= 1,000 * 10^ 9/L, unsupported by cytokines in last
             seven days.

          8. Off prednisone or other immunosuppressive medications for at least 3 days prior to
             both the lymphodepleting regimen and the NK infusion (This excludes chronic low dose
             steroids for adrenal replacement which may be continued).

          9. Karnofsky score or Lansky score >/= 60.

         10. Adequate renal function defined as: Serum creatinine (Cr), for adults less than or
             equal to 2 mg/dL, for children less than or equal to 2 mg/dL or less than or equal to
             2 times upper limit of normal (ULN) for age (whichever is less). If these criteria are
             not met, then recipient must have a Cr clearance greater than 60 mL/min/1.73m^2.

         11. Adequate liver function defined as: Total bilirubin </=2 mg/dL and serum glutamate
             pyruvate transaminase (SGPT/Alanine aminotransferase, ALT) </= 2.5 * ULN for age
             (unless Gilbert's disease or abnormal liver function due to primary disease).

         12. Pulmonary symptoms controlled by medication and pulse oximetry greater than or equal
             to 92% room air.

         13. Females of childbearing potential (non childbearing is defined as premenarchal,
             greater than one year post-menopausal or surgically sterilized) must have a negative
             serum pregnancy test obtained within 2 weeks prior to registration and may not be
             breast feeding during the study. All males and females of childbearing potential are
             required to use a form of contraception considered effective and medically acceptable
             by the Investigator during the time of the study.

         14. Donor must meet standard medical eligibility criteria for allogeneic stem cell
             donation and be able and willing to undergo apheresis.

         15. Donor must have infectious disease marker testing [Hepatitis B, Hepatitis C, HIV,
             cytomegalovirus (CMV), Syphilis (RPR), Chagas, human T-cell lymphoma virus (HTLV), and
             West Nile Virus] and complete blood count (CBC), differential and platelet studies
             that meet standard medical eligibility criteria for allogeneic blood stem cell
             donation within 7 days of apheresis.

         16. Donor, if a female of childbearing potential (non-childbearing is defined as
             premenarchal, greater than one year post-menopause or surgically sterilized), must
             have a negative serum pregnancy test obtained within 14 days of apheresis and may not
             be breast feeding.

        Exclusion Criteria:

          1. Exclusion Criteria: These criteria apply to both the start of the lymphodepleting
             regimen and to the NK infusion

          2. Evidence of HIV (human immunodeficiency virus) disease or positive serology for HIV.

          3. Currently requiring supplemental oxygen or on a ventilator.

          4. Currently undergoing dialysis.

          5. New detected cardiac arrhythmia not controlled with medical management within prior 72
             hour period.

          6. Hypotension requiring pressor support within prior 72 hour period.

          7. Uncontrolled infection, daily fever greater than or equal to 39 degrees Celsius or new
             positive culture for bacteria, fungus, or virus within the 72 hours prior to NK-cell
             infusion.

          8. Ascites requiring paracentesis within prior 72 hour period.

          9. Seizure activity, clinically detectable encephalopathy or new focal neurologic
             deficits within prior 72 hour period.

         10. Donor may not have an uncontrolled infection within 7 days of apheresis.