Intraperitoneal Infusion of ex Vivo-cultured Allogeneic NK Cells in Recurrent Ovarian Carcinoma Patients

Study Overview
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Brief Summary
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This study investigates an innovative treatment for recurrent ovarian cancer exploiting ex vivo-generated allogeneic natural killer (NK) cells with or without preceding non-myeloablative conditioning chemotherapy.

Detailed Description
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This study investigates an innovative treatment for recurrent ovarian cancer exploiting ex vivo-generated allogeneic natural killer (NK) cells with or without preceding non-myeloablative conditioning chemotherapy. This study is a phase I safety and feasibility study in a series of 12 patients who are suffering from recurrent ovarian, fallopian tube or primary peritoneal cancer. Prior to NK cell infusion, a laparoscopy is performed to place a catheter in the peritoneal cavity. The first cohort of three patients will receive an intraperitoneal infusion of allogeneic UCB-NK cells generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB unit without a preparative regimen. In the second group of three patients the same UCB-NK cell dosage will be given with a preparative regimen of four days non-myeloablative immunosuppressive conditioning regimen with cyclophosphamide and fludarabine (CyFlu). If no severe toxicity is seen in these 6 patients, an extension cohort of 6 patients will be included to answer the secondary objective.

Official Title
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Intraperitoneal Infusion of ex Vivo-cultured Allogeneic NK Cells in Recurrent Ovarian Carcinoma Patients (a Phase I Study)

Conditions
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Recurrent Ovarian Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Primary Peritoneal Carcinoma

Intervention / Treatment
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* Biological: UCB-NK cells
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients suffering from their second recurrence of ovarian, fallopian tube or primary peritoneal cancer, with an elevated serum level of CA-125 on two successive time points with 28 days in between, reaching a value of more than 2 times nadir and above 35 U/ml without gastrointestinal symptoms. Able to undergo laparoscopic IP port placement and IP treatment administration Adequate organ function Age 18 years or older Age under 76 years. Karnofsky performance status >70% (see appendix 2) Life expectancy > 6 months At least 28 days after last anti cancer treatment, before start of preparative regimen Written informed consent Availability of a partially HLA-matched UCB unit Exclusion Criteria: Patients on immunosuppressive drugs Patients with active infections (viral, bacterial or fungal) that requires specific therapy. Acute anti-infectious therapy must have been completed within 14 days prior to study treatment Laparoscopic adhesion score >4 out of 9. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease (appendix 4) Severe pulmonary dysfunction (CTCAE III-IV) (appendix 4) Severe renal dysfunction (MDRD<50) (appendix 4) Severe hepatic dysfunction (serum bilirubin or transaminases > 3 times normal level) (appendix 4) Severe neurological or psychiatric disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: Parallel Assignment
Interventional Model Description: This study is a phase I safety and feasibility study in a series of 12 patients who are suffering from recurrent ovarian, fallopian tube or primary peritoneal cancer. The first cohort of three patients will receive an intraperitoneal infusion of allogeneic UCB-NK cells generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB unit without a preparative regimen. In the second group of three patients the same UCB-NK cell dosage will be given with a preparative regimen of four days non-myeloablative immunosuppressive conditioning regimen with cyclophosphamide and fludarabine (CyFlu). If no severe toxicity is seen in these 6 patients, an extension cohort of 6 patients will be included to answer the secondary objective.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NK-cells without preparative regimen<br>NK-cells without preparative regimen | Biological: UCB-NK cells<br>* Intraperitoneal allogeneic UCB-NK cells infusion<br>|
| Experimental: NK-cells with preparative regimen<br>NK-cells with preparative regimen | Biological: UCB-NK cells<br>* Intraperitoneal allogeneic UCB-NK cells infusion<br>Drug: Chemotherapy<br>* Cyclofosfamide/fludarabine treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events | Incidence of treatment emergent adverse events (following CTCAE criteria) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| in vivo lifespan of the infused UCB-NK cells | determination of NK cell percentage in blood and peritoneal fluid | 28 days | 
| in vivo expansion of the infused UCB-NK cells | determination of NK cell percentage in peritoneal fluid and blood | 28 days | 
| Measurement of in vitro cytolytic activity of infused NK cells | in CFSE base killing assays a percentage of dead cells (K562 cells) will be measured. | 28 days | 
| the effect of NK cell infusion on measurable disease | CA-125 testing in blood (in E/mL) | 6 months | 
| the effect of NK cell infusion on measurable disease | CT-scan (measurement of visible leasions in cm) | 6 months |