TIL Therapy for Metastatic Ovarian Cancer

Study Overview
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Brief Summary
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Adoptive T cell therapy with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. The TILs are isolated from patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 is administered to support T cell acitivation and proliferation in vivo. Recent studies suggest, that TIL therapy works in other cancers than Metastatic Melanoma, including Ovarian Cancer. In this study TIL therapy is administered to patients with metastatic Ovarian Cancer.

Detailed Description
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Adoptive T cell therapy with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. The TILs are isolated from patients own tumor tissue followed by in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After TIL infusion Interleukin-2 is administered to support T cell acitivation and proliferation in vivo. Objectives: To evaluate safety and feasibility when treating patients with metastatic ovarian cancer with ACT with TILs. To evaluate treatment related immune responses To evaluate clinical efficacy Design: Patients will be screened with a physical exam, medical history, blood samples and ECG. Patients will undergo surgery to harvest tumor material for TIL production. Patients is admitted day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day 0 patients receive TIL infusion and shortly after starts IL-2 infusion continually following the decrescendo regimen. The patients will followed until progression or up to 5 years

Official Title
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T Cell Therapy for Patients With Metastatic Ovarian Cancer

Conditions
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Metastatic Ovarian Cancer

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: TIL infusion
* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed high grade serous adenokarcinoma ovarian cancer metastasis available for surgical resection (more than 1 cm3) and residual measurable disease after resection Progression/reccurence of ovarian cancer after 1. line platin based chemotherapy or progression/reccurence after 2. line or additional chemotherapy ECOG performance status 0-1 Life expectancy > 6 months No significant toxicity from prior treatments, except sensoric- and motoric neuropathia and/or alopecia Adequate renal, hepatic and hematological function Women of childbearing potentil (WOCBP) must be using an effective method of contraception during treatment and for at least 6 months after completion of treatment Able to comprehend the information given and willing to sign informed consent Exclusion Criteria: Other malignancies, unless followed for ≥ 5 years with no sign of disease Severe allergies, history of anaphylaxis or known allergies to the administered drugs. Serious medical or psychiatric comorbidity Creatinine clearance < 70 ml/min Acute or chronic infection with e.g. HIV, hepatitis, tuberculosis Severe and active autoimmune disease Pregnant and nursing women Need for immunosuppressive treatment, e.g. corticosteroids or methotrexate Concomitant treatment with other experimental drugs Patients with uncontrolled hypercalcemia Less than four weeks since prior systemic antineoplastic treatment at the time of treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient group<br>All patients receive the same treatment. Alle patients are hospitalized during treatment (approximately 3 weeks) and receive treatment only once. Stem Cells are harvested a minimum of 3 weeks before treatment for potential later use if the patients are having difficulties recovering from the lymphodepleting chemotherapy. The patients are admitted to hospital day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 5. Interleukin-2 is administered in an i.v. continous decrescendo regimen starting approximately 6 hours after TIL infusion with a duration of approximately 5 days. Stem Cells can be administered after treatment if needed. | Drug: Cyclophosphamide<br>* Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.<br>* Other names: Cyclophospamide;Drug: Fludarabine<br>* Fludarabine 25 mg/m2 is administered on day -5 to day -1.<br>* Other names: Fludara;Biological: TIL infusion<br>* The maximum number of expanded TILs are infused over 30-45 minutes on day 0.<br>* Other names: T Cell infusion;Drug: Interleukin-2<br>* Interleukin-2 is administered as a continous i.v. infusion in a decrescendo regimen (18 MIU/m3 IL-2 over 6 hours, 18 MIU/m2 IL-2 over 12 hours, 18 MIU/m2 IL-2 over 24 hours followed by 4,5 MIU/m2 IL-2 over another 24 hours for three days).<br>* Other names: Proleukin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and type of reported adverse events | Determine the safety of the administration of TIL therapy including lymphodepleting chemotherapy and Interleukin-2 for patients with metastatic Ovarian Cancer by reporting adverse events according to CTCAE v. 4.0. | 0-24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related immune responses | To evaluate the immunological impact of TIL therapy for patients with metastatic Ovarian Cancer | Up to 12 months | 
| Objective response rate | Clinical responses will be evaluated by RECIST 1.1. | Up to 12 months | 
| Overall Survival | Overall Survival (OS), defined as time from treatment initiation to death, will be described with use of Kaplan Meier curve. | Up to 12 months | 
| Progression free survival | Progression free survival (PFS), defined as the time from treatment initiation to disease progression, relapse or death due to any cause, which ever comes first, will be described with Kaplan Meier curve. | Up to 12 months |