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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00625729
• Other study ID #: 2007LS064
• Secondary ID: MT2007-12UMN-070
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: February 26, 2008
• Last updated: December 3, 2017
• Start date: January 2008
• Est. completion date: April 2010

Study information

• Verified date: December 2017
• Source: Masonic Cancer Center, University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: April 2010
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

Biological:
• aldesleukin
Day 0-14, 10 million international units, 3 times per week for 6 doses
• allogeneic natural killer cells
Day 0 infusion of cells (1.5-8 x 10^7 cells/kg).
• rituximab
Administered Day -8, day -1, day +6 and day +13, intravenously (IV) 357 mg/m^2

Drug:
• cyclophosphamide
60 mg/kg intravenous (IV) on Day -5.
• fludarabine phosphate
Day -6 through day -2, 25 mg/m^2 intravenous (IV)

Locations

Country	Name	City	State
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients Exhibiting Natural Killer Cell Expansion	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.	Day 14
Secondary	Number of Patients With Interleukin-15 Production and NK Cell Expansion	Correlation of interleukin-15 production at day 0 with natural killer (NK) cells expansion	Day 0
Secondary	Number of Patients With Overall Response	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	3 Months
Secondary	Number of Patients Whose Disease Progressed After Treatment	Includes patients (with non-Hodgkin leukemia or chronic lymphocytic leukemia) whose disease progressed after treatment.	6 Months
Secondary	Number of Patients With Adequate Natural Killer Cells Infused	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).	Day 0
Secondary	Number of Patients With Overall Survival	Number of patients alive at 6 months after treatment.	6 Months