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

Information source: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Leukemia; Lymphoma

Intervention: aldesleukin (Biological); allogeneic natural killer cells (Biological); rituximab (Biological); cyclophosphamide (Drug); fludarabine phosphate (Drug)

Phase: Phase 1/Phase 2

Status: Terminated

Sponsored by: Masonic Cancer Center, University of Minnesota

Official(s) and/or principal investigator(s):
Veronika Bachanova, MD, Principal Investigator, Affiliation: Masonic Cancer Center, University of Minnesota


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.

Clinical Details

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

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

Primary outcome: Number of Patients Exhibiting Natural Killer Cell Expansion

Secondary outcome:

Number of Patients With Interleukin-15 Production and NK Cell Expansion

Number of Patients With Overall Response

Number of Patients Whose Disease Progressed After Treatment

Number of Patients With Adequate Natural Killer Cells Infused

Number of Patients With Overall Survival

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.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


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

Locations and Contacts

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

Starting date: January 2008
Last updated: November 6, 2012

Page last updated: August 23, 2015

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