Allogeneic Natural Killer (NK) Cells in Patients With Advanced Metastatic Breast Cancer

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00376805
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 45
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy before a donor natural killer (NK) cell infusion helps stop the growth of tumor cells. It also helps stop the patient's immune system from rejecting the donor's cells. Giving NK cells from a related donor may kill the tumor cells.

PURPOSE: This study furthers the research of previous studies (MT2003-01 and MT2004-25) which were to determine a specific preparatory regimen (cyclophosphamide and fludarabine) could create an environment in which infused NK cells can grow and effectively treat patients with relapsed AML. This study will test the previous regimen in patients with breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total body irradiation; Other: Natural killer cell infusion; Biological: Interleukin-2	Phase 2

Detailed Description

We believe that administration of related allogeneic (donor) natural killer cells along with IL-2, rather than autologous natural killer cells will provide the most effective anticancer therapy in this setting, and wish to test this approach. To do this, we will select a related donor who is partially HLA-matched with the study subject, to increase the likelihood that donor natural killer cells will kill the subject's cancer cells. We will also give chemotherapy drugs to increase the subject's tolerance for the donor natural killer cells. We will test the use of donor natural killer (NK) cell infusions. The immune system has a special way that it sees and identifies cancer cells or foreign agents (like viruses). The subject's own NK cells may not attack their cancer because NK cells see the tumor cells as "self" (a coating on the cell surface identifies a cell as "self" or "non-self"). We have reason to believe that NK cells may not kill cancer cells because NK cells have special receptors that "turn them off" when they encounter cancer cells (by seeing them as "self"). We may be able to get around this problem by using donor NK cells. Finally, subjects will receive a dose of subcutaneous IL-2 3 times a week (for 2 weeks) which has been proven safe in our previous studies to stimulate the natural killer cells.

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: Allogeneic Natural Killer Cells in Patients With Advanced Metastatic Breast Cancer
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Jan 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All Treated Patients All patients with advanced metastatic breast cancer treated with natural killer cells after receiving fludarabine, cyclosphosphamide and total body irradiation.

Drug: Fludarabine; administered intravenously 25 mg/m^2 times 5 doses; Other Names: Fludara ; Drug: Cyclophosphamide; administered intravenously 60 mg/kg days times 2 doses.; Other Names: Endoxan, Cytoxan, Neosar, Procytox ; Radiation: Total body irradiation; 200 cGy (gray) on day -1; Other Names: radiation ; Other: Natural killer cell infusion; Infused cell dose is within the range of 1.5-8.0 x 10^7/kg. Cell counts are based on total cells infused after the activation culture and washing determined on the morning of infusion.; Other Names: NK cells ; Biological: Interleukin-2; administered subcutaneously (10 MU) 3 times per week for 6 doses; Other Names: IL-2

Outcome Measures

Primary Outcome Measures

1. Number of Patients Who Had Expansion of Natural Killer Cells [Day 14]

   Successful Natural Killer (NK) cell expansion is defined as detection of an absolute circulating donor-derived NK cell count of >100 cells/ul of whole blood 14 days after infusion with <5% donor T and B cells in mononuclear population (in metastatic breast cancer patients).

Secondary Outcome Measures

1. Number of Patients by Disease Response [6 Months, 1 Year]

   Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria: Complete Response (CR: Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions of appearance of one or more new lesions of clinical benefit (CB; stable disease for greater than 6 months.

2. Number of Patients Who Died While on Study [Within 100 days, After 100 days]

   Number of patients who died within 100 days and after 100 days of natural killer (NK) treatment with or without total body irradiation.

3. Overall Median Number of Days Patients Alive After Treatment [First Day of Treatment Until Death]

   Calculated median number of days of survival (patients alive days after treatment).

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Diagnosis of metastatic breast cancer that has progressed on or failed at least one salvage chemotherapy regimen for metastatic disease and that meets the following disease specific related criteria:

• Measureable metastatic disease per Response Evaluation Criteria In Solid Tumor (RECIST) - bone only not eligible.

• Disease progression while receiving prior therapy with a hormonal agent (if estrogen/progesterone receptor-positive) and/or trastuzumab (Herceptin®) (if HER2-neu positive)

• Brain metastases allowed provided they are stable for ≥ 3 months after prior treatment

• Related HLA-haploidentical natural killer cell donor available (by ≥ class I serologic typing)

• Male or female

• Performance status 50-100%

• Platelet count ≥ 80,000/mm³ (unsupported by transfusions)

• Hemoglobin ≥ 9 g/dL (unsupported by transfusions)

• Absolute neutrophil count ≥ 1,000/mm³ (unsupported by sargramostim [GM-CSF] or filgrastim [G-CSF])

• Creatinine ≤ 2.0 mg/dL

• Liver function tests < 5 times normal

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• LVEF > 40%*

• Pulmonary function > 50%* (DLCO corrected AND FEV_1)

• No active infection (i.e., afebrile, off antibiotics, and no uninvestigated radiologic lesions)

Exclusion Criteria:

• At least 3 days since prior prednisone or other immunosuppressive medications

• No other concurrent therapy for cancer

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Study Chair: Jeffrey Miller, MD, Masonic Cancer Center, University of Minnesota
• Principal Investigator: Sarah Cooley, 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: NCT00376805
• Other Study ID Numbers: UMN-2005LS033; UMN-0505M70037; UMN-MT2005-08; NCT00167193
• First Posted: Sep 15, 2006
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: stage IV breast cancer; male breast cancer; recurrent breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Cyclophosphamide; Fludarabine; Interleukin-2

Study Results

Participant Flow

Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.1 (7.7)
Sex: Female, Male (Count of Participants)
Female	6 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Who Had Expansion of Natural Killer Cells
Description	Successful Natural Killer (NK) cell expansion is defined as detection of an absolute circulating donor-derived NK cell count of >100 cells/ul of whole blood 14 days after infusion with <5% donor T and B cells in mononuclear population (in metastatic breast cancer patients).
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
Measure Participants	6
Number [Participants]	0 0%

2. Secondary Outcome

Title	Number of Patients by Disease Response
Description	Defined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria: Complete Response (CR: Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions of appearance of one or more new lesions of clinical benefit (CB; stable disease for greater than 6 months.
Time Frame	6 Months, 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
Measure Participants	6
Stable Disease	4 66.7%
Progressive Disease	2 33.3%

3. Secondary Outcome

Title	Number of Patients Who Died While on Study
Description	Number of patients who died within 100 days and after 100 days of natural killer (NK) treatment with or without total body irradiation.
Time Frame	Within 100 days, After 100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
Measure Participants	6
Died within 100 days	1 16.7%
Died after 100 days	5 83.3%

4. Secondary Outcome

Title	Overall Median Number of Days Patients Alive After Treatment
Description	Calculated median number of days of survival (patients alive days after treatment).
Time Frame	First Day of Treatment Until Death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
Measure Participants	6
Median (95% Confidence Interval) [Days]	124

Adverse Events

Time Frame	All adverse events were collected up to patients' death (within 1 year of treatment).
Arm/Group Title	NK Cells With or Without Total Body Irradiation
Arm/Group Description	Patients receiving natural killer cell infusion, fludarabine and cyclosphosphamide preparatory regimen, and with or without total body irradiation for treatment of metastatic breast cancer.
All Cause Mortality
	NK Cells With or Without Total Body Irradiation
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	NK Cells With or Without Total Body Irradiation
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Bone marrow cellularity	1/6 (16.7%)	1
Febrile neutropenia	1/6 (16.7%)	1
Neutropenia	1/6 (16.7%)	1
Passenger lymphocyte syndrome	1/6 (16.7%)	1
General disorders
Death - disease progression NOS	3/6 (50%)	3
Death due to progressive disease	3/6 (50%)	3
Other (Not Including Serious) Adverse Events
	NK Cells With or Without Total Body Irradiation
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Edema	4/6 (66.7%)	22
Hemolytic anemia	1/6 (16.7%)	1
Cardiac disorders
Hypertension	2/6 (33.3%)	12
Hypotension	1/6 (16.7%)	2
Cardiac function LVEF	1/6 (16.7%)	3
Gastrointestinal disorders
Vomiting	4/6 (66.7%)	6
Nausea	4/6 (66.7%)	11
General disorders
Fever	6/6 (100%)	26
Chills	6/6 (100%)	19
Fatigue	6/6 (100%)	46
Musculoskeletal and connective tissue disorders
Myalgia	4/6 (66.7%)	16
Nervous system disorders
Anxiety	1/6 (16.7%)	3
Renal and urinary disorders
Hematuria	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/6 (16.7%)	11
Hypoxia	1/6 (16.7%)	6
Pneumonitis	3/6 (50%)	15
Cough	2/6 (33.3%)	3
Pleural effusion	1/6 (16.7%)	10
Skin and subcutaneous tissue disorders
Injection Site Reaction	6/6 (100%)	26
Rash	5/6 (83.3%)	30
Sweats	4/6 (66.7%)	16

Limitations/Caveats

[Not Specified]

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.