TIL Therapy for Metastatic Renal Cell Carcinoma

Study Overview
=================
Brief Summary
-----------------
Adoptive T cell therapy (ACT) 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 activation and proliferation in vivo. Recent studies suggest, that TIL therapy works in other cancers than Metastatic Melanoma, including Renal Cell Carcinoma. In this study TIL therapy is administered to patients with metastatic Renal Cell Carcinoma.

Detailed Description
-----------------
Adoptive T cell therapy (ACT) 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 activation and proliferation in vivo. Objectives: To evaluate safety and feasibility when treating patients with metastatic renal cell carcinoma 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, pulmonary function test, Cr-EDTA clearance, MUGA scan 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 administration with high-dose bolus IL-2 every eight hour for up to 5 days (maximum of 15 doses). The patients will followed until progression or up to 5 years.

Official Title
-----------------
T Cell Therapy for Patients With Metastatic Renal Cell Carcinoma

Conditions
-----------------
Metastatic Renal Cell Carcinoma

Intervention / Treatment
-----------------
* Procedure: Surgical removal of tumor tissue for T cell production
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: TIL infusion
* Drug: Interleukin-2


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological proven mRCC with the possibility of surgical removal of tumor tissue of > 1 cm3. Histology must include a clear cell component with or without a sarcomatoid dedifferentiation. Metastatic disease irrespective of number of previous treatment lines. Treatment naïve pt's can be included. ECOG performance status of ≤1. IMDC prognostic group 'Favorable' or 'Intermediary'. Life expectancy of > 6 months. At least one measurable parameter after surgery in accordance with RECIST 1.1 -criteria's. No significant toxicities or side effects (CTC ≤ 1) from previous treatments. Normal ejection fraction (EF) measured by a multigated acquisition (MUGA) scan. Crom EDTA clearance >40 ml/min. Adequate renal, hepatic and hematological function. LDH ≤ 5 times upper normal limit as a measure of tumor burden. Women in the fertile age must use effective contraception. Likewise, men included in the study, as well as their partners, must use effective contraception. This applies from inclusion and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered safe contraceptives. Able to comprehend the information given and willing to sign informed consent. Willingness to participate in the planned controls. Exclusion Criteria: A history of prior malignancies, except curatively treated non-melanoma skin cancer and CIS of the cervix uteri. Patients treated for another malignancy can participate if they are without signs of disease for a minimum of 3 years after treatment. Patients with cerebral metastases. Patients with widespread bone or bone only metastases. Severe allergies, history of anaphylaxis or known allergies to the administered drugs. Severe medical conditions or psychiatric comorbidity. Acute/chronic infection with HIV, hepatitis, tuberculosis among others. Severe and active autoimmune disease. Pregnant women and women breastfeeding. Simultaneous treatment with systemic immunosuppressive drugs (including prednisolone, methotrexate among others). Simultaneous treatment with other experimental drugs. Simultaneous treatment with other systemic anti-cancer treatments. Patients with active and uncontrollable hypercalcaemia.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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. Surgical removal of tumor tissue for T cell production, which takes 4-6 weeks, is performed initially. All patients are hospitalized during treatment (one week in advance of the T cell product being ready and for approximately 3 weeks in total) and receive treatment only once. 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 as high-dose i.v. bolus every eight hour starting approximately 6 hours after TIL infusion and for up to 5 days (maximum of 15 doses). | Procedure: Surgical removal of tumor tissue for T cell production<br>* Surgical removal of > 1 cm3 tumor tissue chosen with regards to high rate of success and to minimize the general risks involved in a surgical procedure.<br>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. Maximum dose of 50 mg per administration.<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 high-dose bolus infusions (600.000 IU/kg) over a 15 minute period every 8 hours and continuing for up to 5 days (maximum of 15 doses).<br>* Other names: Proleukin;|

What is the study measuring?
-----------------
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 Renal Cell Carcinoma. | 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 |