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Penostatin, Rituximab and Ontak and Allogeneic Natural Killer (NK) Cells for Refractory Lymphoid Malignancies

This study has been completed.
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota Identifier:
First received: August 12, 2010
Last updated: January 21, 2016
Last verified: January 2016
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.

Condition Intervention Phase
Non-Hodgkin Lymphoma
Chronic Lymphocytic Leukemia
Drug: Rituximab
Biological: Interleukin-2
Biological: Natural killer cells
Drug: Cyclophosphamide
Drug: Methylprednisolone
Drug: Fludarabine
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Lymphodepleting Chemotherapy With Rituximab and Allogeneic Natural Killer Cells for Patients With Refractory Lymphoid Malignancies (MT2009-15)

Resource links provided by NLM:

Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Objective Response Rate [ Time Frame: Month 2 Post Infusion ]
    The proportion of patients with an objective response rate (Partial Response +Complete Response) at 2 months post haploidentical NK cell infusion in patient with refractory/relapsed NHL or chronic lymphocytic leukemia (CLL).

Secondary Outcome Measures:
  • Serious Adverse Events [ Time Frame: Day 1 through Month 12 ]
    Number of serious adverse events that occur during study. Adverse event collection for the purposes of this study will focus on targeted adverse events and unexpected adverse events at specific time points in relation to the NK cell infusion and post infusion IL2 injections.

  • Time to Disease Progression [ Time Frame: Day 1 through Month 12 ]
    Cumulative incidence will be used to determine time to disease progression.

  • Patients with Expansion of NK Cells [ Time Frame: Day 14 ]
    Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells.

Enrollment: 32
Study Start Date: August 2010
Study Completion Date: August 2015
Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Patients Receiving NK Cell Infusion
Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL
Drug: Rituximab
375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK)
Other Names:
  • Rituxan
  • MabThera
Biological: Interleukin-2
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.
Other Name: IL-2
Biological: Natural killer cells
administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion)
Other Name: NK cells
Drug: Cyclophosphamide
60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine.
Other Name: Cytoxan
Drug: Methylprednisolone
1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion.
Other Name: Medrol
Drug: Fludarabine
25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through day -2).
Other Name: Fludara

Detailed Description:

This is a single center phase II trial designated to expand donor NK cells and induce remissions in patients with refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) using chemotherapy followed by haploidentical NK cells and IL2.

Primary Objective is to evaluate the objective response rate (PR+CR) at 2 months post haploidentical NK cell infusion in patients with refractory Non Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

Secondary Objective is to 1) evaluate the safety and tolerability of lymphodepleting chemotherapy, rituximab, and methylprednisone as determined by incidence of serious adverse events; 2) evaluate in vivo expansion of allogeneic donor NK cells at day 14; 3) determine time to progression

Exploratory Objective is to 1) correlate clinical response with frequencies of peripheral blood T reg cells after chemotherapy; 2) correlate clinical response with donor KIR-B-content score determined by genotype; 3) monitor phenotypic and functional characteristics of natural killer cells and regulatory T cells in vivo; 4) correlate clinical response with donor FcR polymorphism.

  • Pre-NK cell infusion chemotherapeutic regimen consist of 1) Rituximab 375mg/m2 IV weekly x 4, start day -7; 2) Fludarabine 25 mg/m2 IV day -6 through day -2; 3) Cyclophosphamide 60mg/kg IV day -5; 4) Methylprednisolone 1 mg/kg day -2 through day +9.
  • NK cell infusion using IL2 activated donor NK cells 1.5 to 8 x 107 cells/kg IV day 0
  • IL2 SC 9 million IU every other day x 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

Accrual Goal: Up to 17 patients will be enrolled


Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
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Please refer to this study by its identifier: NCT01181258

United States, Minnesota
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Principal Investigator: Veronika Bachanova, MD Masonic Cancer Center, University of Minnesota
  More Information

Responsible Party: Masonic Cancer Center, University of Minnesota Identifier: NCT01181258     History of Changes
Other Study ID Numbers: 2009LS083
MT2009-15 ( Other Identifier: Blood and Marrow Transplantation Program )
1002M77545 ( Other Identifier: IRB, University of Minnesota )
Study First Received: August 12, 2010
Last Updated: January 21, 2016

Keywords provided by Masonic Cancer Center, University of Minnesota:
related HLA-haploidentical donor

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Fludarabine phosphate
Methylprednisolone Hemisuccinate
Prednisolone acetate
Methylprednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents processed this record on April 24, 2017