Allogeneic Natural Killer (NK) Cells for Ovarian, Fallopian Tube, Peritoneal and Metastatic Breast Cancer

Study Overview
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Brief Summary
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This is a single center phase II trial designed to optimize a clinical platform of lymphodepleting chemotherapy and T-cell suppression to promote the persistence, function, and expansion of allogeneic natural killer (NK) cells in patients with recurrent ovarian, fallopian tube, primary peritoneal cancer and advanced metastatic breast cancer.

Detailed Description
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The donor NK cells are infused on day 0, after a non-myeloablative preparative regimen of cyclophosphamide and fludarabine plus a cyclosporine A (CsA) based immunosuppressive therapy. Subcutaneous interleukin-2 (IL-2) is started the evening of the NK infusion and continued three times a week for 6 doses total. Up to 4 sequential immunosuppressive platforms will be tested (Arms 1 and 2 are currently closed) to identify a platform where patients have the potential for successful NK cell expansion (defined as an absolute circulating donor derived NK cell count of > 100 cells/μl 14 days after NK cell infusion). Once a clinical platform is determined, the platform will be expanded to a total of 18 patients. The primary goal of this extended phase is to obtain preliminary efficacy information. Follow-up for disease response is for 1 year from the NK cell infusion, with the possibility of re-treatment for patients who experience at least a clinical benefit who progress after 6 months.

Official Title
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Lymphodepleting Chemotherapy and T-Cell Suppression Followed By Allogeneic Natural Killer Cells and IL-2 in Patients With Recurrent Ovarian, Fallopian Tube, Primary Peritoneal Cancer and Advanced Metastatic Breast Cancer (MT2009-30)

Conditions
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Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Cyclosporine
* Biological: Natural killer cells
* Drug: IL-2
* Drug: Methylprednisolone
* Drug: Methylprednisolone
* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of recurrent ovarian cancer, fallopian tube, or primary peritoneal cancer that has failed or progressed after at least 2 prior salvage chemotherapy regimens (directed at recurrent/metastatic disease). OR Diagnosis of metastatic breast cancer (female or male) that has progressed on or failed at least one salvage chemotherapy regimen for metastatic disease and that meets the following disease specific related criteria: If estrogen receptor or progesterone receptor positive must have progressed on prior hormonal therapy and/or if HER2-neu positive must have progressed on trastuzumab, lapatinib, or similar agent Women with a history of both cancers are eligible for this study provided that they currently meet eligibility for one of the diseases. Women who have had another malignancy and have been disease free for at least 3 year, or with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible. Measurable disease per disease specific Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 - patients with bone as their only site of disease will not be eligible. If history of brain metastases must be 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 clinical signs or symptoms suggestive of brain metastases. Available related HLA-haploidentical natural killer (NK) cell donor (by at least class I serologic typing at the A&B locus) Age 18 years or older Karnofsky performance status > or = 50% Adequate organ function as determined by the following criteria within 14 days of study enrollment Bone marrow: platelets > or = 80,000 x 10^9/L and hemoglobin > or = 9 g/dL, unsupported by transfusions; absolute neutrophil count (ANC) > or = 1000 x 10^9/L, unsupported by growth colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) Renal function: creatinine (Cr) < or = 2.0 mg/dL Liver function: Aspartate aminotransferase (AST), Alanine transaminase (ALT), total bilirubin, alkaline phosphatase < 5 times upper limit of institutional normal (ULN) Cardiac: Left ventricular ejection fraction >40% (within 28 days of treatment start) 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 is acceptable (within 28 days of treatment start) Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to Day 0 At least 14 days must lapse between last prior anti-cancer treatment and 1st day of preparative regimen Voluntary written informed consent Exclusion Criteria: Pregnant or nursing - 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. Participants of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy and agree to use adequate birth control during study treatment Active infection - subjects must be afebrile, off antibiotics, and with no uninvestigated radiologic lesions (infiltrates or lesions with negative cultures or biopsies) are allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: CsA<br>Patients receiving Cyclosporine (CsA) and Natural Killer (NK) cells infusion (created from donor lymphapheresis) after preparative regimen of Fludarabine and Cyclophosphamide. Interleukin-2 (IL-2) 6 million units 3 times a week x 6 doses given post NK cell infusion. | Drug: Fludarabine<br>* Administered intravenously, 25 mg/m^2, days -6 through -2 (5 days).<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Administered intravenously, 60 mg/kg, days -5 and -4.<br>* Other names: Cytoxan;Drug: Cyclosporine<br>* Administered intravenously, CsA 1.5 mg/kg for target dose range of 150-250 ng/mL day -3 through day +14<br>* Other names: CsA;Biological: Natural killer cells<br>* Administered by infusion over less than 1 hour, no more than 8.0 x 10^7 cells/kg will be given.<br>Drug: IL-2<br>* Will be given subcutaneously at 9 million units 3 times a week for a total of 6 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 5 million units/m^2 3 times per week for 6 doses).<br>* Other names: Interleukin-2;Drug: Interleukin-2<br>* Will be given subcutaneously at million units 3 times a week for a total of 3 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 3 million units/m^2 3 times per week for 6 doses).<br>* Other names: IL-2;|
| Experimental: Arm 2: CsA plus Methylprednisolone (10mg)<br>Patients receiving Cyclosporine (CsA), methylprednisolone and natural killer cells (NK) infusion (created from donor lymphapheresis) after preparative regimen of Fludarabine and Cyclophosphamide. Interleukin-2 (IL-2) 6 million units 3 times a week x 6 doses given post NK cell infusion. | Drug: Fludarabine<br>* Administered intravenously, 25 mg/m^2, days -6 through -2 (5 days).<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Administered intravenously, 60 mg/kg, days -5 and -4.<br>* Other names: Cytoxan;Drug: Cyclosporine<br>* Administered intravenously, CsA 1.5 mg/kg for target dose range of 150-250 ng/mL day -3 through day +14<br>* Other names: CsA;Biological: Natural killer cells<br>* Administered by infusion over less than 1 hour, no more than 8.0 x 10^7 cells/kg will be given.<br>Drug: IL-2<br>* Will be given subcutaneously at 9 million units 3 times a week for a total of 6 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 5 million units/m^2 3 times per week for 6 doses).<br>* Other names: Interleukin-2;Drug: Methylprednisolone<br>* Administered intravenously (IV) 10 mg/kg Days -2 to +4 and 1 mg/kg Days +5 to +9<br>* Other names: Medrol;Drug: Methylprednisolone<br>* Administered intravenously (IV) 1 mg/kg Days -2 to +9<br>* Other names: Medrol;Drug: Interleukin-2<br>* Will be given subcutaneously at million units 3 times a week for a total of 3 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 3 million units/m^2 3 times per week for 6 doses).<br>* Other names: IL-2;|
| Experimental: Arm 3: CsA plus Methylprednisolone (1 mg)<br>Patients receiving Cyclosporine (CsA), methylprednisolone and natural killer (NK) cells infusion (created from donor lymphapheresis) after preparative regimen of Fludarabine and Cyclophosphamide. Interleukin-2 (IL-2) 6 million units 3 times a week x 6 doses given post NK cell infusion. | Drug: Fludarabine<br>* Administered intravenously, 25 mg/m^2, days -6 through -2 (5 days).<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Administered intravenously, 60 mg/kg, days -5 and -4.<br>* Other names: Cytoxan;Drug: Cyclosporine<br>* Administered intravenously, CsA 1.5 mg/kg for target dose range of 150-250 ng/mL day -3 through day +14<br>* Other names: CsA;Biological: Natural killer cells<br>* Administered by infusion over less than 1 hour, no more than 8.0 x 10^7 cells/kg will be given.<br>Drug: IL-2<br>* Will be given subcutaneously at 9 million units 3 times a week for a total of 6 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 5 million units/m^2 3 times per week for 6 doses).<br>* Other names: Interleukin-2;Drug: Methylprednisolone<br>* Administered intravenously (IV) 10 mg/kg Days -2 to +4 and 1 mg/kg Days +5 to +9<br>* Other names: Medrol;Drug: Methylprednisolone<br>* Administered intravenously (IV) 1 mg/kg Days -2 to +9<br>* Other names: Medrol;Drug: Interleukin-2<br>* Will be given subcutaneously at million units 3 times a week for a total of 3 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 3 million units/m^2 3 times per week for 6 doses).<br>* Other names: IL-2;|
| Experimental: Arm 4: CsA minus Methylprednisolone<br>Patients receiving Cyclosporine (CsA), no methylprednisolone, eliminating IL-2 doses 4-6 and receiving Natural Killer (NK) cells infusion (created from donor lymphapheresis) after preparative regimen of Fludarabine and Cyclophosphamide. Interleukin-2 (IL-2) 6 million units 3 times a week x 3 doses given post NK cell infusion. | Drug: Fludarabine<br>* Administered intravenously, 25 mg/m^2, days -6 through -2 (5 days).<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Administered intravenously, 60 mg/kg, days -5 and -4.<br>* Other names: Cytoxan;Drug: Cyclosporine<br>* Administered intravenously, CsA 1.5 mg/kg for target dose range of 150-250 ng/mL day -3 through day +14<br>* Other names: CsA;Biological: Natural killer cells<br>* Administered by infusion over less than 1 hour, no more than 8.0 x 10^7 cells/kg will be given.<br>Drug: Interleukin-2<br>* Will be given subcutaneously at million units 3 times a week for a total of 3 doses, beginning 4 hours after NK cell infusion. (For patients weighing less than 45 kilograms, will be given at 3 million units/m^2 3 times per week for 6 doses).<br>* Other names: IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response includes Complete Response (CR), Partial Response (PR), and Stable Disease (SD) as defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v.1.1) for target lesions and assessed by CT or MRI. Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease. | Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression | Time from study entry until progressive disease or data collection cutoff. | 1 Year | 
| Number of Participants With Progressive Disease at One Year |  | 1 Year | 
| Overall Survival | Number of participants alive at 1 year. | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent ovarian cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cancer, refractory ovarian cancer, refractory fallopian tube cancer, refractory peritoneal cancer, metastatic breast cancer