TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer

Study Overview
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Brief Summary
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Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. Recently, the investigators have completed a pilot study treating 6 patients with metastatic ovarian cancer. 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 activation and proliferation in vivo. The investigators recent pilot study has shown TIL therapy in patients with metastatic ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where observed and therefore the investigators plan to combine TIL therapy with checkpoint inhibitors to potentially increase the clinical effect.

Detailed Description
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Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved impressive clinical results with durable complete responses in patients with metastatic melanoma. Recently, the investigators have completed a pilot study treating 6 patients with metastatic ovarian cancer. 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 activation and proliferation in vivo. The investigators recent pilot study has shown TIL therapy in patients with metastatic ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where observed and therefore the investigators plan to combine TIL therapy with checkpoint inhibitors to potentially increase the clinical effect. Objectives: To evaluate safety and feasibility when treating patients with metastatic ovarian cancer with ACT with TILs in combination with checkpoint inhibitors. 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 be treated with one dose of Ipilimumab 14 days before undergoing surgery to harvest tumor material for TIL production. Patients is admitted on day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day -2 patients will start treatment with Nivolumab every 2 weeks for a total of 4 doses to increase the activity of the infused TIL product. On day 0 patients receive TIL infusion and shortly after starts IL-2 stimulation with a daily subcutaneous dose for a total of 14 days.The patients will followed until progression or up to 5 years.

Official Title
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T-cell Therapy in Combination With Checkpoint Inhibitors for Patients With Advanced Ovarian-, Fallopian Tube- and Primary Peritoneal 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
* Drug: Ipilimumab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Only patients within the Danish healthcare system are eligible for enrollment. Inclusion Criteria: Histological proven advanced ovarian-, fallopian tube or primary peritoneal cancer with the possibility of surgical removal of tumor tissue of > 1 cm3. Progressive or recurrent resistant disease after platin-based chemotherapy (platinum resistant) or progressive or recurrent disease after second line or additional chemotherapy. Age: 18 - 70 years. ECOG performance status of ≤1 (Appendix 2). Life expectancy of > 6 months. At least one measurable parameter in accordance with RECIST 1.1 -criteria's. No significant toxicities or side effects from previous treatments, except sensoric- and motoric neuropathy and/or alopecia Sufficient renal, hepatic and hematological function Men and women in the fertile age must use effective contraception. This applies from inclusion and until 6 months after 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 Known hypersensitivity to one of the active drugs or one or more of the excipients. Severe medical or psychiatric conditions Creatinine clearance < 70 ml/min. In selected cases it can be decided to include a patient with a GFR < 70 ml/min with the use of a reduced dose of chemotherapy. Acute/chronic infection with HIV, hepatitis, syphilis among others. Severe allergies or previous anaphylactic reactions. Active autoimmune disease Pregnant women and women breastfeeding. Need for immunosuppressive treatment e.g. corticosteroids or methotrexate. In selected cases a systemic dose of ≤10 mg prednisolone or a transient planned treatment that can be stopped before TIL therapy can be tolerated. Simultaneous treatment with other experimental drugs. Simultaneous treatment with other systemic anti-cancer treatments. Patients with active and uncontrollable hypercalcaemia.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
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. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks. The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses. The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13. Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days. | Drug: Cyclophosphamide<br>* Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.<br>Drug: Fludarabine<br>* Fludarabine 25 mg/m2 is administered on day -5 to day -1.<br>* Other names: Fludarabine phosphate;Biological: TIL infusion<br>* The maximum number of expanded TILs are infused over 30-45 minutes on day 0.<br>* Other names: TILs;Drug: Interleukin-2<br>* Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.<br>* Other names: IL-2;Drug: Ipilimumab<br>* One dose of Ipilimumab 3 mg/kg is administered 14 days prior to surgical removal of tumor tissue for TIL expansion.<br>Drug: Nivolumab<br>* Nivolumab 3 mg/kg is administered on day -2 before TIL infusion and every 2 weeks for a total of 4 doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Reported Adverse Events by Type | Determine the safety of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer by reporting adverse events according to CTCAE v. 4.0. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Related Immune Responses | Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry. | Until protocol end, until 6 months after TIL infusion | 
| Objective Response Rate | Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CAT scan: Complete Response (CR) Disappearance of all target lesions (sum of all taget lesions=0) Partial Response (PR) >=30% decrease (vs baseline) of sum of all target lesions dimension Progressive Disease (PD) new lesions or >=20% increase (vs smallest sum of target lesions or nadir) Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD | Assessed up to 12 months after therapy. | 
| Overall Survival | Overall Survival (OS), defined as time from TIL infusion to death | Up to 3 years after TIL infusion | 
| Progression Free Survival | Progression free survival (PFS): Time from TIL infusion to disease progression, relapse or death due to any cause, which ever comes first, will be used as an event. | Up to 12 months after TIL infusion |