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MT2007-12 Allogeneic Natural Killer Cells With Rituximab in Patients With CD20 Positive Relapsed Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia. Strategies to Increase Sensitivity of CLL Tumor Cells to Natural Killer Cell-Immune-Mediated Cytolysis

Phase 1/Phase 2
18 Years
Not Enrolling
Leukemia, Lymphoma

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Trial Information

MT2007-12 Allogeneic Natural Killer Cells With Rituximab in Patients With CD20 Positive Relapsed Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia. Strategies to Increase Sensitivity of CLL Tumor Cells to Natural Killer Cell-Immune-Mediated Cytolysis



- To determine if allogeneic natural killer (NK) cells infused following
chemoimmunotherapy can be safely expanded in vivo with aldesleukin.


- To determine if interleukin-15 production at day 0 correlates with NK cells expansion.

- To determine overall response rate at 3 months.

- To determine time to progression and overall survival.

- To characterize the quantitative and qualitative toxicities of this treatment plan.

- To determine the incidence of donor products that do not meet release criteria and the
NK cell numbers infused.

- To correlate clinical response with donor/recipient KIR ligand matching status, FcG
receptor 3A genotype, and NK cells phenotype and function

- To determine pharmacodynamic and pharmacogenomic markers and correlate them with NK
cell expansion and disease response.


- Conditioning regimen: Patients receive rituximab intravenously (IV) over 6-8 hours on
days -8, -1, 6, and 13; fludarabine IV on days -6 to -2; and cyclophosphamide IV on day

- Allogeneic natural killer (NK) cell administration: Patients receive
aldesleukin-activated haploidentical NK cells IV over less than 1 hour on day 0. Within
4 hours after allogeneic NK cell infusion, patients receive aldesleukin subcutaneously
(SC) 3 times a week for 6 doses. Patients also receive filgrastim (G-CSF) SC beginning
on day 14 and continuing until absolute neutrophil count (ANC) is > 2,500/mm³ for 2
consecutive days.

Patients who achieve a complete or partial response at 28 days are eligible for allogeneic
stem cell transplantation. Patients who achieve initial response at 3 months, clinically
benefit from treatment, but subsequently relapse are eligible for retreatment provided all
eligibility criteria are met.

Blood samples are collected periodically for correlative laboratory studies. Patients with
chronic lymphocytic leukemia (CLL) also undergo bone marrow aspiration periodically for
correlative laboratory studies.

After completion of study treatment, patients are followed periodically for up to 1 year.

Inclusion Criteria:

- Patient 18 years or older with a diagnosis of non-Hodgkin Lymphoma or chronic
lymphocytic leukemia (NHL or CLL) and one of the following:

- Progression of NHL following at least 2 prior chemotherapy regimens, (must
contain rituximab for all NHL and fludarabine for follicular NHL) defined as:

- failure to achieve partial remission (PR) with the last chemotherapy

- disease progression within 6 months following last chemotherapy

- Progression of CLL/SLL (small lymphocytic lymphoma) following at least 2 prior
chemotherapy regimens (containing purine analogs ) in stage Rai III or IV or
symptomatic disease.

- Relapsed NHL or CLL following stem cell transplantation for whom the option of
donor lymphocyte infusion is not available or clinically indicated (e.g.
recipients of autologous or umbilical cord blood [UCB] transplants).

- Available related HLA-haploidentical (human leukocyte antigen) natural killer (NK)
cell adult donor by at least Class I serologic typing

- Karnofsky performance status > 60%

- Measurable disease based on modified Response Evaluation Criteria In Solid Tumors

- Have acceptable organ function as defined within 28 days of enrollment:

- Hematologic: platelets ≥ 80,000 x 10^9/L; hemoglobin ≥ 9g/dL, unsupported by
transfusions; absolute neutrophil count (ANC) ≥ 1000 x 10^9/L, unsupported by
granulocyte-colony stimulating factor or granulocyte-macrophage
colony-stimulating factor (G-CSF or GM-CS)F 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 lymphoma who are otherwise eligible

- Renal: glomerular filtration rate (GFR) > 50 ml/min

- Hepatic: alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3 x
upper limit of normal and total bilirubin <3 mg/dl

- Pulmonary function: >50% corrected carbon monoxide diffusing capacity (DLCO)
and Forced Expiratory Volume in the first second (FEV1)

- Cardiac: no symptoms of uncontrolled cardiac disease, left ventricular ejection
fraction >40%

- Off prednisone or other immunosuppressive medications for at least 3 days prior to
Day 0

- 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 informed consent before performance of any study-related procedure
not part of normal medical care.

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 2 weeks prior
to registration to rule out pregnancy. Women of childbearing age must use appropriate
contraceptive method.

- Active central nervous system (CNS) lymphoma/leukemia

- 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 the chest x-ray

- Allergy to rituximab or IL-2

- Human immunodeficiency virus (HIV) and associated non-Hodgkins lymphoma (NHL)

- Active concurrent malignancy (except skin cancer) requiring systemic therapy in the
past 2 years

- Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder

- Positive hepatitis B surface antigen (HBsAg). If Hepatitis B core antibody (HBcAb) is
positive, Hepatitis B deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR)
will be evaluated. Positive anti HBcAb and undetectable viral load does not exclude
the patient.

- Any experimental therapy in the past 30 days

Donor Selection:

- Related donors (sibling, parent, offspring, parent or offspring of an HLA identical
sibling) ≥ age 18 years

- Able and willing to undergo lymphapheresis

- HLA-haploidentical donor/recipient match. If time permits and multiple donors are
available, preference will be given to the Killer-cell Immunoglobulin-like Receptors
(KIR) ligand mismatched donor (as predicted by HLA typing).

- HIV-1, HIV-2 negative, Human T-lymphotropic virus Type I (HTLV-1), HTLV-2 negative,
West Nile virus (WNV) negative, Hepatitis B and C negative

- Adequate organ function defined as:

- Hematologic: CBC/diff/platelet count near normal limits,

- Hepatic: ALT < 2 x upper limit of normal,

- Not pregnant or lactating

- In general good health as determined by the study physician

- Able to give informed consent

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Number of Patients Exhibiting Natural Killer Cell Expansion

Outcome Description:

Successful natural killer (NK) cell expansion will be defined as an absolute circulating donor-derived NK cell count of >100 cells/μl 14 days after infusion with <5% donor T and B cells in the mononuclear population.

Outcome Time Frame:

Day 14

Safety Issue:


Principal Investigator

Veronika Bachanova, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

January 2008

Completion Date:

April 2010

Related Keywords:

  • Leukemia
  • Lymphoma
  • recurrent adult grade III lymphomatoid granulomatosis
  • adult nasal type extranodal NK/T-cell lymphoma
  • Waldenstrom macroglobulinemia
  • recurrent adult Burkitt lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent mantle cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • refractory chronic lymphocytic leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Non-Hodgkin



Masonic Cancer Center, University of Minnesota Minneapolis, Minnesota  55455