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

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00625729
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 27
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma	Biological: aldesleukin; Biological: allogeneic natural killer cells; Biological: rituximab; Drug: cyclophosphamide; Drug: fludarabine phosphate	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

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 Names: IL-2 ; Biological: allogeneic natural killer cells; Day 0 infusion of cells (1.5-8 x 10^7 cells/kg).; Other Names: Natural Killer Cells ; Biological: rituximab; Administered Day -8, day -1, day +6 and day +13, intravenously (IV) 357 mg/m^2; Other Names: Rituxan ; Drug: cyclophosphamide; 60 mg/kg intravenous (IV) on Day -5.; Other Names: Cytoxan ; Drug: fludarabine phosphate; Day -6 through day -2, 25 mg/m^2 intravenous (IV); Other Names: Fludara

Outcome Measures

Primary Outcome Measures

1. Number of Patients Exhibiting Natural Killer Cell Expansion [Day 14]

   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

1. Number of Patients With Interleukin-15 Production and NK Cell Expansion [Day 0]

   Correlation of interleukin-15 production at day 0 with natural killer (NK) cells expansion

2. Number of Patients With Overall Response [3 Months]

   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. Number of Patients Whose Disease Progressed After Treatment [6 Months]

   Includes patients (with non-Hodgkin leukemia or chronic lymphocytic leukemia) whose disease progressed after treatment.

4. Number of Patients With Adequate Natural Killer Cells Infused [Day 0]

   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).

5. Number of Patients With Overall Survival [6 Months]

   Number of patients alive at 6 months after treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00625729
• Other Study ID Numbers: 2007LS064; MT2007-12; UMN-0707M13561; P01CA065493
• First Posted: Feb 28, 2008
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• 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: Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Aldesleukin; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate

Study Results

Participant Flow

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 83.3%
>=65 years	1 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.2 (13.6)
Sex: Female, Male (Count of Participants)
Female	4 66.7%
Male	2 33.3%
Region of Enrollment (participants) [Number]
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Exhibiting Natural Killer Cell Expansion
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.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Measure Participants	6
Number [Participants]	0 0%

2. Secondary Outcome

Title	Number of Patients With Interleukin-15 Production and NK Cell Expansion
Description	Correlation of interleukin-15 production at day 0 with natural killer (NK) cells expansion
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

Correlation of interleukin-15 with Natural Killer Cell expansion cannot be calculated because there was no Natural Killer Cell expansion.

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Measure Participants	6
Number [Participants]	0 0%

3. Secondary Outcome

Title	Number of Patients With Overall Response
Description	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
Time Frame	3 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Measure Participants	6
Number [Participants]	4 66.7%

4. Secondary Outcome

Title	Number of Patients Whose Disease Progressed After Treatment
Description	Includes patients (with non-Hodgkin leukemia or chronic lymphocytic leukemia) whose disease progressed after treatment.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

Only patients who responded to treatment included in the analysis.

Arm/Group Title	Responder Patients
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with donor natural killer cells infusion, rituximab, aldesleukin and chemotherapy who had a response to treatment (clinical response or partial response).
Measure Participants	4
Number [Participants]	2 33.3%

5. Secondary Outcome

Title	Number of Patients With Adequate Natural Killer Cells Infused
Description	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).
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Measure Participants	6
Number [Participants]	6 100%

6. Secondary Outcome

Title	Number of Patients With Overall Survival
Description	Number of patients alive at 6 months after treatment.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
Measure Participants	6
Number [Participants]	3 50%

Adverse Events

Time Frame	Serious adverse events were collected after start of chemotherapy treatment (Day -1) through date of death (all within 6 months).
Adverse Event Reporting Description	Stopping Rules for excess toxicity: Any non-hematologic grade 4 toxicity except for fevers alone Grade III/IV GvHD or GvHD requiring more than 7 days of therapy Hematologic toxicity: prolonged neutropenia defined as an absolute neutrophil count of less than 500 on day +35. Prolonged anemia or thrombocytopenia will not constitute toxicity.
Arm/Group Title	Patients Treated With Natural Killer Cells
Arm/Group Description	Patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with 1 dose donor natural killer cells infusion, 4 doses rituximab, 6 doses aldesleukin and 5 doses fludarabine and 1 dose cyclosphosphamide.
All Cause Mortality
	Patients Treated With Natural Killer Cells
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Patients Treated With Natural Killer Cells
	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)
Blood and lymphatic system disorders
Neutrophils/granulocytes (ANC/AGC)	1/6 (16.7%)	1
Cardiac disorders
Cardiac Arrhythmia	1/6 (16.7%)	1
General disorders
Death - Disease Progression NOS	3/6 (50%)	3
Infections and infestations
Infection	2/6 (33.3%)	2
Respiratory, thoracic and mediastinal disorders
Pulmonary - obstruction/stenosis of airway	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Patients Treated With Natural Killer Cells
	Affected / at Risk (%)	# Events
Total	0/6 (0%)

Limitations/Caveats

Study was terminated early due to lack of NK expansion and failure to meet primary outcome.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.