Penostatin, Rituximab and Ontak and Allogeneic Natural Killer (NK) Cells for Refractory Lymphoid Malignancies
Condition: Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia
MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Rituximab; Interleukin-2; Natural killer cells; Cyclophosphamide; Methylprednisolone; Fludarabine
Intervention description: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK); subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule.; administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion); 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine.; 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion.; 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through day -2).
Intervention MeSH terms: Methylprednisolone; Cyclophosphamide; Rituximab; Fludarabine; Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Healthy volunteers: No
Keywords: related HLA-haploidentical donor

Summary:

      In this study the investigators investigate a cell therapy strategy that could harness
      allogeneic effectors that can potentially mediate anti-lymphoma effect. The investigators
      have designed a novel lymphodepleting conditioning regimen followed by infusion of
      donor-derived natural killer (NK) cells and interleukin-2 (IL-2) for patients with refractory
      lymphoid malignancies.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients of any age with diagnosis of:

               -  Relapsed/refractory lymphoma (B cell non-Hodgkin) who have lack of objective
                  response to at least two prior chemotherapy regimens

               -  Relapsed chronic lymphocytic leukemia with high risk features: lack of objective
                  response or relapse within 6 months following nucleoside-analogue based
                  chemotherapy regimen or patients with 17p deletion CLL who lacked objective
                  response to at least 1 preceding chemotherapy regimen

          -  Available related HLA haploidentical NK cell donor by at least Class I serologic
             typing at the A&B locus (age 12-75 years)

          -  Karnofsky > 70% for patients 16 years and older and Lansky play score > 50 for
             patients under 16 years of age

          -  Measurable disease based on modified Response Evaluation Criteria in Solid Tumors
             (RECIST)

          -  Have acceptable organ function as defined within 28 days of enrollment:

               -  Hematologic: platelets ≥ 80,000 x 10^9/L; hemoglobin ≥ 9 g/dL, unsupported by
                  transfusions within 7 days; absolute neutrophile count (ANC) ≥ 1000 x 10^9/L,
                  unsupported by Granulocyte colony-stimulating factor (G-CSF) or
                  Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) for 10 days or Neulasta
                  for 21 days - the hematologic requirements are waived for patients with
                  inadequate counts due to known bone marrow involvement by disease who are
                  otherwise eligible

               -  Renal: calculated glomerular filtration rate (GFR) > 50 ml/min

               -  Hepatic: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5
                  x upper limit of normal and total bilirubin ≤3 mg/dl - hepatic requirements are
                  waived for patients with known disease involvement in the liver if otherwise
                  eligible

               -  Pulmonary function: >40% corrected Carbon Monoxide Diffusing Capacity (DLCO) and
                  Forced expiratory volume in one second (FEV1) (oxygen saturation [>92%] can be
                  used in child where pulmonary function tests (PFT's) cannot be obtained)

               -  Cardiac: no symptoms of uncontrolled cardiac disease, left ventricular ejection
                  fraction ≥ 40%

          -  Able to be off prednisone or other immunosuppressive medications for at least 3 day
             prior to Day 0 (excluding denileukin diftitox pre-medications)

          -  Sexually active women of childbearing potential must agree to use adequate
             contraception (diaphragm, birth control pills, injections, intrauterine device [IUD],
             surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration
             of treatment.

          -  Voluntary written consent

        Exclusion Criteria:

          -  Pregnant or lactating. The agents used in this study may be teratogenic to a fetus and
             there is no information on the excretion of agents into breast milk. All females of
             childbearing potential must have a blood test or urine study within 14 days prior to
             enrollment to rule out pregnancy. Women of childbearing age must use appropriate
             contraceptive method.

          -  Active central nervous system (CNS) lymphoma/leukemia - Patients with prior CNS
             involvement are eligible provided that it has been treated and is in remission.

          -  Active serious infection (pulmonary infiltrates or lesions are allowed only after the
             appropriate diagnostic testing is negative for infection or appropriate therapy was
             initiated for probable infection)

          -  Pleural effusion large enough to be detectable on chest x-ray (CXR)

          -  Evidence of human immunodeficiency virus (HIV) infection or known HIV positive
             serology

          -  Active concurrent malignancy (except skin cancer)

          -  Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder

          -  Positive HBsAg. If HBcAb is positive, Hepatitis B DNA by PCR will be evaluated.
             Positive anti HBcAb with an undetectable viral load does not exclude the patient.

          -  Any investigational therapy in the past 30 days

          -  Patients following allogeneic stem cell transplantation are eligible in the absence of
             graft versus host disease and are off immunosuppression for at least 30 days

          -  Known allergy to any of the study agents