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

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.

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.