Donor Natural Killer Cell Infusion, Rituximab, Aldesleukin, and Chemotherapy in Treating Patients With Relapsed Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia - Full Text View

Sponsor:	Masonic Cancer Center, University of Minnesota
Collaborator:	National Cancer Institute (NCI)
Information provided by:	Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00625729

Purpose

RATIONALE: Aldesleukin may stimulate natural killer cells to kill cancer cells. Treating natural killer cells with aldesleukin in the laboratory may help the natural killer cells kill more cancer cells when they are put back in the body. Giving monoclonal antibodies, such as rituximab, and chemotherapy drugs, such as fludarabine and cyclophosphamide, before a donor natural killer cell infusion helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells.

PURPOSE: This phase I/II trial is studying how well giving rituximab and chemotherapy followed by a donor natural killer cell infusion that has been treated in the laboratory with aldesleukin followed by aldesleukin works in treating patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia.

Condition	Intervention	Phase
Leukemia Lymphoma	Biological: aldesleukin Biological: allogeneic natural killer cells Biological: rituximab Drug: cyclophosphamide Drug: fludarabine phosphate	Phase I Phase II

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

MedlinePlus related topics: Acute Lymphocytic Leukemia Cancer Chronic Lymphocytic Leukemia Leukemia Lymphoma

Drug Information available for: Cyclophosphamide Fludarabine Fludarabine monophosphate Aldesleukin Rituximab

U.S. FDA Resources

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

Primary Outcome Measures:

Number of Patients Exhibiting Natural Killer Cell Expansion [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Number of Patients With Interleukin-15 Production and NK Cell Expansion [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
Correlation of interleukin-15 production at day 0 with natural killer (NK) cells expansion
Number of Patients With Overall Response [ Time Frame: 3 Months ] [ Designated as safety issue: No ]
Overall response (complete remission plus partial remission) rate at 3 months, as defined by International Working Group for non-Hodgkin lymphoma and NCI Working Group guidelines for chronic lymphocytic leukemia
Number of Patients Whose Disease Progressed After Treatment [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
Includes patients (with non-Hodgkin leukemia or chronic lymphocytic leukemia) whose disease progressed after treatment.
Number of Patients With Adequate Natural Killer Cells Infused [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
Incidence of donor products that met release criteria in accordance with FDA regulations (Lot Release Criteria for allogeneic, interleukin-2 (IL-2) activated natural killer (NK) cell products (BB-IND 8847) and the NK cell numbers infused (donor NK cell dose 1.5-8.0 x 10^7/kg).
Number of Patients With Overall Survival [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
Number of patients alive at 6 months after treatment.

Enrollment:	6
Study Start Date:	January 2008
Study Completion Date:	April 2010
Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Treated Patients Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with donor natural killer cells infusion, rituximab, aldesleukin and chemotherapy.	Biological: aldesleukin Day 0-14, 10 million international units, 3 times per week for 6 doses Other Name: IL-2 Biological: allogeneic natural killer cells Day 0 infusion of cells (1.5-8 x 10^7 cells/kg). Other Name: Natural Killer Cells Biological: rituximab Administered Day -8, day -1, day +6 and day +13, intravenously (IV) 357 mg/m^2 Other Name: Rituxan Drug: cyclophosphamide 60 mg/kg intravenous (IV) on Day -5. Other Name: Cytoxan Drug: fludarabine phosphate Day -6 through day -2, 25 mg/m^2 intravenous (IV) Other Name: Fludara

Arms

Assigned Interventions

Experimental: Treated Patients

Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with donor natural killer cells infusion, rituximab, aldesleukin and chemotherapy.

Biological: aldesleukin

Day 0-14, 10 million international units, 3 times per week for 6 doses

Other Name: IL-2

Biological: allogeneic natural killer cells

Day 0 infusion of cells (1.5-8 x 10^7 cells/kg).

Other Name: Natural Killer Cells

Biological: rituximab

Administered Day -8, day -1, day +6 and day +13, intravenously (IV) 357 mg/m^2

Other Name: Rituxan

Drug: cyclophosphamide

60 mg/kg intravenous (IV) on Day -5.

Other Name: Cytoxan

Drug: fludarabine phosphate

Day -6 through day -2, 25 mg/m^2 intravenous (IV)

Other Name: Fludara

Detailed Description:

OBJECTIVES:

Primary

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

Secondary

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.

OUTLINE:

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 -5.
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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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 (RECIST)
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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00625729

Locations

United States, Minnesota
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States, 55455

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Veronika Bachanova, MD

Masonic Cancer Center, University of Minnesota

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Veronika Bachanova, MD, Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00625729 History of Changes
Other Study ID Numbers:	2007LS064, MT2007-12, UMN-0707M13561, P01CA065493
Study First Received:	February 26, 2008
Results First Received:	July 2, 2010
Last Updated:	September 22, 2010
Health Authority:	United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:

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

Additional relevant MeSH terms:

Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine monophosphate
Rituximab

Fludarabine
Aldesleukin
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic

ClinicalTrials.gov processed this record on February 08, 2012