Allogeneic Natural Killer Cells in Patients With Recurrent Ovarian Cancer, Fallopian Tube, and Primary Peritoneal Cancer

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00652899
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 17
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy, such as cyclophosphamide and fludarabine, and total-body irradiation before a donor natural killer cell infusion helps stop the growth of tumor cells. It also helps stop the patient's immune system from rejecting the donor's natural killer cells. Aldesleukin may stimulate the natural killer cells to kill ovarian, fallopian tube, or primary peritoneal cancer cells. Treating the donor natural killer cells with aldesleukin may help the natural killer cells kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving laboratory-treated donor natural killer cells together with aldesleukin works when given after cyclophosphamide, fludarabine, and total-body irradiation in treating patients with recurrent and/or metastatic ovarian, fallopian tube, or primary peritoneal cancer.

Condition or Disease	Intervention/Treatment	Phase
Fallopian Tube Cancer; Ovarian Cancer; Peritoneal Cavity Cancer	Biological: Allopurinol; Drug: Cyclophosphamide; Drug: Fludarabine phosphate; Radiation: total-body irradiation; Biological: Allogeneic natural killer cells; Biological: Aldesleukin	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To evaluate the in vivo expansion of an infused allogeneic natural killer (NK) cell product following a preparative regimen comprising cyclophosphamide, fludarabine phosphate, and total-body irradiation in treating patients with recurrent and/or metastatic ovarian, fallopian tube, or primary peritoneal cancer.

Secondary

• To characterize the quantitative and qualitative toxicities of this treatment regimen.

• To estimate disease response (complete or partial response) or clinical benefit (stable disease for > 6 months) as measured by Response Evaluation Criteria in Solid Tumours (RECIST) criteria.

• To estimate time to progression and overall survival.

• To estimate the association between clinical response and donor/recipient KIR ligand matching status.

Tertiary

• To evaluate immune activation of the in vivo expanded haploidentical allogeneic NK cells and its effect on the immune system.

OUTLINE:

• Preparative regimen: Patients receive fludarabine phosphate IV on days 6 to 2 preceding natural killer (NK) cell infusion and cyclophosphamide IV on days 5 and 4 preceding NK cell infusion. Patients also undergo total-body irradiation on day 1 preceding NK cell infusion.

• Allogeneic natural killer (NK) cell administration and aldesleukin: Patients receive aldesleukin-activated haploidentical allogeneic NK cells intravenously (IV) on day 0. Beginning 4-6 hours after allogeneic NK cell infusion, patients receive aldesleukin subcutaneously (SC) 3 times a week for 6 doses.

Patients achieving any initial response (complete or partial response) or a clinical benefit (stable disease for > 6 months) who progress after 6 months may receive 1 re-treatment course as above.

Blood samples are collected at baseline, on days 0, 7, 14, and 28, and then at 2 and 3 months post NK cell infusion for cytokine measurements, immunophenotyping, functional analyses, and testing for persistence of donor cells.

After completion of study treatment, patients are followed periodically for at least 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MT2007-19R: WCC #53 Allogeneic Natural Killer Cells in Patients With Recurrent Ovarian Cancer, Fallopian Tube, and Primary Peritoneal Cancer
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Total Body Irradiation This group includes patients that received all chemotherapy, infusion of natural killer (NK) cells and total body irradiation per protocol. 1. Allopurinol 300 mg by mouth daily (unless known allergy) before beginning chemotherapy and continuing through day 14 post NK cell infusion. 2. Cyclophosphamide 60 mg/m^2 on Days 4 and 5 preceding NK cell infusion. 3. Fludarabine phosphate 25 mg/m^2 on Days 6 through 2 preceding NK cell infusion. 4. Radiation: total-body irradiation 200 cGy Day 1 preceding NK cell infusion. 5. Allogeneic natural killer cells- Given day 0 - dose of 1.5-8.0 * 10^7/kg. 6. Aldesleukin 10 million units 3 times/week for a total of 6 doses beginning Day 0.	Biological: Allopurinol; All patients are to receive allopurinol 300 mg PO daily (unless known allergy) before beginning chemotherapy and continuing through day 14 post natural killer cell infusion.; Other Names: Zyloprim ; Drug: Cyclophosphamide; 60 mg/m^2 on Days 4 and 5 preceding natural killer cell infusion.; Other Names: Cytoxan ; Drug: Fludarabine phosphate; 25 mg/m^2 on Days 6 through 2 preceding natural killer cell infusion.; Other Names: Fludarabine ; Radiation: total-body irradiation; 200 cGy Day 1 preceding natural killer cell infusion.; Other Names: TBI ; Biological: Allogeneic natural killer cells; Given day 0 - dose of 1.5-8.0 * 10^7/kg; Other Names: related donor haploidentical allogenic cell infusion ; Biological: Aldesleukin; 10 MU 3 times/week for a total of 6 doses beginning Day 0; Other Names: IL-2 Interleukin-2
Experimental: No Total Body Irradiation This group includes patients that received chemotherapy and infusion of natural killer cells, but did not receive total body irradiation. 1. Allopurinol 300 mg by mouth daily (unless known allergy) before beginning chemotherapy and continuing through day 14 post NK cell infusion. 2. Cyclophosphamide 60 mg/m^2 on Days 4 and 5 preceding NK cell infusion. 3. Fludarabine phosphate 25 mg/m^2 on Days 6 through 2 preceding NK cell infusion. 4. Allogeneic natural killer cells- Given day 0 - dose of 1.5-8.0 * 10^7/kg. 5. Aldesleukin 10 million units 3 times/week for a total of 6 doses beginning Day 0.	Biological: Allopurinol; All patients are to receive allopurinol 300 mg PO daily (unless known allergy) before beginning chemotherapy and continuing through day 14 post natural killer cell infusion.; Other Names: Zyloprim ; Drug: Cyclophosphamide; 60 mg/m^2 on Days 4 and 5 preceding natural killer cell infusion.; Other Names: Cytoxan ; Drug: Fludarabine phosphate; 25 mg/m^2 on Days 6 through 2 preceding natural killer cell infusion.; Other Names: Fludarabine ; Biological: Allogeneic natural killer cells; Given day 0 - dose of 1.5-8.0 * 10^7/kg; Other Names: related donor haploidentical allogenic cell infusion ; Biological: Aldesleukin; 10 MU 3 times/week for a total of 6 doses beginning Day 0; Other Names: IL-2 Interleukin-2

Outcome Measures

Primary Outcome Measures

1. Number of Patients With In Vivo Expansion of Infused Allogeneic Natural Killer (NK) Cell Product [Day 12-14]

   Detection of an absolute donor derived cell count of > or = 100 cells/mL after NK cell infusion.

Secondary Outcome Measures

1. Number of Patients Per Disease Response [1 Month After Natural Killer Cell Infusion (Day 30)]

   Response Evaluation Criteria in Solid Tumors (RECIST) criteria: Complete Response (CR)-Disappearance of all target lesions (TL); Partial Response (PR)-< or = 30% decrease in the sum of the longest diameter (LD) of TL, reference baseline sum LD; Stable Disease (SD)-Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference the smallest sum LD since the treatment started; Progressive Disease (PD)- < or = 20% increase in the sum of the LD of TL, reference the smallest sum LD recorded since treatment started or appearance of < or = 1 new lesion.

2. Median Number of Days to Progression [From date of first treatment to disease progression]

   Median number of days from first date of treatment to date of disease progression (appearance of new metastatic lesions or objective tumor progression). Defined by computated tomography (CT) imaging based on Response Evaluation Criteria In Solid Tumors (RECIST): Progressive Disease (PD) > or = 20% increase in sum of all target or any new lesions.

3. Median Overall Survival Number of Days Patients Alive After Treatment [From first date on-study (treatment) to date of death]

   Median number of days patients alive from date of treatment to date of death or date of last follow-up if censored.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of recurrent ovarian cancer, fallopian tube, or primary peritoneal cancer who meets the following criteria:

• Measurable disease (≥ 1 cm) per Response Evaluation Criteria for Solid Tumors (RECIST)

• patients with bone as their only site of metastatic disease will not be eligible

• Progression on or failure to respond to at least 2 salvage chemotherapy regimens (2 regimens given for disease recurrence) for recurrent/metastatic ovarian, fallopian tube, or primary peritoneal cancer

• If history of brain metastases, stable for at least 3 months after treatment - A brain computed tomography (CT) scan will only be required in subjects with known brain metastases at the time of enrollment or in subjects with new clinical signs or symptoms suggestive of brain metastases.

• Available related HLA-haploidentical natural killer (NK) cell donor (by at least class I serologic typing). If biologic parents or siblings are available, can proceed with work-up of subject prior to return of human leukocyte antigen (HLA) typing results.

• Age 18 years or older

• Gynecology Oncology Group (GOG) performance status 0 or 1

• Adequate organ function as determined by the following criteria within 14 days of study enrollment:

• Bone marrow: platelets ≥ 80,000 x 10^{9/L and hemoglobin ≥ 9g/dL, unsupported by transfusions; absolute neutrophil count (ANC) ≥ 1000 x 10}9/L, unsupported by granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF)

• Renal function: creatinine (Cr) ≤ 2.0 mg/dL

• Liver function: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase < 5 times upper limit of institutional normal

• Cardiac: Left ventricular ejection fraction >40%

• Pulmonary function: > 50% corrected Carbon Monoxide Diffusing Capacity (DLCO) and Forced expiratory volume in one second (FEV1), if presence of pleural effusion due to metastatic disease >40% corrected DLCO and FEV1 acceptable.

• Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to Day 0

• Voluntary written informed consent signed 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 14 days prior to registration to rule out pregnancy.

• Active infection - subjects must be afebrile, off antibiotics, and with no uninvestigated radiologic lesions (infiltrates or lesions with negative cultures or biopsies are allowed).

Human anti-mouse antibody (HAMA) monitoring: All subjects will be questioned about prior exposure to antibody therapy (including OKT3, Rituximab, Trastuzumab, etc). Responses will be recorded and reported to the FDA as part of the annual report. For subjects with no prior antibody therapy exposure, no further action will be taken. For subjects who have received previous antibody therapies 10 ml of serum (red top tube) will be drawn before starting therapy and banked per section 8.1. The presence of HAMA will not exclude a patient from the study.

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

• Principal Investigator: Melissa A. Geller, 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: NCT00652899
• Other Study ID Numbers: 2007LS138; UMN-MT2007-19R; UMN-WCC-53; UMN-0712M23462
• First Posted: Apr 4, 2008
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: recurrent ovarian epithelial cancer; recurrent ovarian germ cell tumor; stage IV ovarian epithelial cancer; stage IV ovarian germ cell tumor; fallopian tube cancer; peritoneal cavity cancer
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Vidarabine; Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2; Allopurinol

Study Results

Participant Flow

Pre-assignment Detail	Two patients did not receive all of study treatment per protocol.

Arm/Group Title	All Patients Enrolled
Arm/Group Description	This group includes all patients consented to participate in this study.
Period Title: Overall Study
STARTED	14
COMPLETED	12
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	All Patients Enrolled
Arm/Group Description	This group includes all patients consented to participate in this study.
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (5.19)
Sex: Female, Male (Count of Participants)
Female	14 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With In Vivo Expansion of Infused Allogeneic Natural Killer (NK) Cell Product
Description	Detection of an absolute donor derived cell count of > or = 100 cells/mL after NK cell infusion.
Time Frame	Day 12-14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ovarian/Fallopian Tube/Peritoneal Cancer Patients
Arm/Group Description	This group includes patients with recurrent ovarian, fallopian tube or primary peritoneal cancer who received at least one dose of chemotherapy (cyclophosphamide 60 mg/m^2 and fludarabine 25 mg/m^2 for 2 doses, and aldesleukin 10 million units for 6 doses), infusion of natural killer cells (1.5-8.0 * 10^7 kg) and/or total body irradiation per protocol (200 Gy on Day 1 preceding natural killer cell infusion).
Measure Participants	12
Number [Patients]	0

2. Secondary Outcome

Title	Number of Patients Per Disease Response
Description	Response Evaluation Criteria in Solid Tumors (RECIST) criteria: Complete Response (CR)-Disappearance of all target lesions (TL); Partial Response (PR)-< or = 30% decrease in the sum of the longest diameter (LD) of TL, reference baseline sum LD; Stable Disease (SD)-Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference the smallest sum LD since the treatment started; Progressive Disease (PD)- < or = 20% increase in the sum of the LD of TL, reference the smallest sum LD recorded since treatment started or appearance of < or = 1 new lesion.
Time Frame	1 Month After Natural Killer Cell Infusion (Day 30)

Outcome Measure Data

Analysis Population Description

Includes 12 patients that completed treatment per protocol criteria.

Arm/Group Title	No Total Body Irradiation	Total Body Irradiation
Arm/Group Description	This group includes patients with recurrent ovarian, fallopian tube or primary peritoneal cancer who received at least one dose of chemotherapy (cyclophosphamide 60 mg/m^2 and fludarabine 25 mg/m^2 for 2 doses, and aldesleukin 10 million units for 6 doses), infusion of natural killer cells (1.5-8.0 * 10^7 kg) and no total body irradiation.	This group includes patients with recurrent ovarian, fallopian tube or primary peritoneal cancer who received at least one dose of chemotherapy (cyclophosphamide 60 mg/m^2 and fludarabine 25 mg/m^2 for 2 doses, and aldesleukin 10 million units for 6 doses), infusion of natural killer cells (1.5-8.0 * 10^7 kg) and total body irradiation (200 Gy on Day 1 preceding natural killer cell infusion).
Measure Participants	7	5
Complete Response	0	0
Partial Response	2	1
Stable Disease	4	4
Progressive Disease	1	0

3. Secondary Outcome

Title	Median Number of Days to Progression
Description	Median number of days from first date of treatment to date of disease progression (appearance of new metastatic lesions or objective tumor progression). Defined by computated tomography (CT) imaging based on Response Evaluation Criteria In Solid Tumors (RECIST): Progressive Disease (PD) > or = 20% increase in sum of all target or any new lesions.
Time Frame	From date of first treatment to disease progression

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	No Total Body Irradiation	Total Body Irradiation
Arm/Group Description	This group includes patients with recurrent ovarian, fallopian tube or primary peritoneal cancer who received at least one dose of chemotherapy (cyclophosphamide 60 mg/m^2 and fludarabine 25 mg/m^2 for 2 doses, and aldesleukin 10 million units for 6 doses), infusion of natural killer cells (1.5-8.0 * 10^7 kg) and no total body irradiation.	This group includes patients with recurrent ovarian, fallopian tube or primary peritoneal cancer who received at least one dose of chemotherapy (cyclophosphamide 60 mg/m^2 and fludarabine 25 mg/m^2 for 2 doses, and aldesleukin 10 million units for 6 doses), infusion of natural killer cells (1.5-8.0 * 10^7 kg) and total body irradiation (200 Gy on Day 1 preceding natural killer cell infusion).
Measure Participants	7	5
Median (95% Confidence Interval) [Days]	107	90

4. Secondary Outcome

Title	Median Overall Survival Number of Days Patients Alive After Treatment
Description	Median number of days patients alive from date of treatment to date of death or date of last follow-up if censored.
Time Frame	From first date on-study (treatment) to date of death

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Total Body Irradiation	No Total Body Irradiation
Arm/Group Description	This group includes patients that received chemotherapy, infusion of natural killer cells and total body irradiation per protocol.	This group includes patients that received chemotherapy, infusion of natural killer cells and no total body irradiation per protocol.
Measure Participants	5	7
Median (95% Confidence Interval) [Days]	171.5	291

Adverse Events

Time Frame	Serious adverse events were monitored through the follow-up period; death was followed for up to 2 years after Day 1 treatment.
Adverse Event Reporting Description	Adverse event collection for the purposes of this study focused on targeted adverse events and unexpected adverse events at specific time points in relation to the NK cell infusion and post infusion IL-2 injections.
Arm/Group Title	All Patients Enrolled
Arm/Group Description	This group includes all patients consented to participate in this study.
All Cause Mortality
	All Patients Enrolled
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients Enrolled
	Affected / at Risk (%)	# Events
Total	9/14 (64.3%)
Blood and lymphatic system disorders
Hemolysis	1/14 (7.1%)	1
Cardiac disorders
Left ventricular systolic dysfunction	1/14 (7.1%)	1
Gastrointestinal disorders
Pain - abdomen NOS	1/14 (7.1%)	1
General disorders
Constitutional symptoms	1/14 (7.1%)	2
Death - disease progression NOS	5/14 (35.7%)	5
Tumor lysis syndrome	1/14 (7.1%)	1
Infections and infestations
Infection	1/14 (7.1%)	1
Infection - febrile neutropenia	1/14 (7.1%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/14 (7.1%)	1
Hypoxia	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	All Patients Enrolled
	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)
Blood and lymphatic system disorders
Edema	6/14 (42.9%)	29
Positive blood culture with fever	2/14 (14.3%)	5
Hemolysis	1/14 (7.1%)	1
Cardiac disorders
Hypertension	1/14 (7.1%)	8
Gastrointestinal disorders
Vomiting	11/14 (78.6%)	30
Nausea	12/14 (85.7%)	80
General disorders
Fever	12/14 (85.7%)	42
Chills	12/14 (85.7%)	44
Fatigue	13/14 (92.9%)	115
Musculoskeletal and connective tissue disorders
Myalgia	9/14 (64.3%)	28
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/14 (42.9%)	23
Pneumonia	3/14 (21.4%)	17
Cough	5/14 (35.7%)	18
Skin and subcutaneous tissue disorders
Injection Site Reaction	11/14 (78.6%)	58
Rash	11/14 (78.6%)	45
Sweats	10/14 (71.4%)	27

Limitations/Caveats

Endpoint for association of clinical benefit response with donor/recipient KIR ligand matching status is not evaluable due to 0 complete responders. Correlative laboratory objectives are irrelevant due to ineffectiveness of study regimen.

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.