TIL Therapy for Metastatic Renal Cell Carcinoma

Phase 1

Completed

Conditions: Metastatic Renal Cell Carcinoma

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

Registration Number: NCT02926053

Lead Sponsor: Inge Marie Svane

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Patient group	Interleukin-2	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).
Patient group	Surgical removal of tumor tissue for T cell production	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).
Patient group	TIL infusion	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).
Patient group	Cyclophosphamide	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).
Patient group	Fludarabine	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).

Primary Outcome Measures

Name	Time	Method
Number of Patients in Which the Treatment Was Tolerable	0-24 weeks	Determine the safety of the administration of TIL therapy including lymphodepleting chemotherapy and Interleukin-2 for patients with metastatic renal cell cancer. This will be assessed clinically by whether the patients are able to receive treatment as described in the protocol.

Secondary Outcome Measures

Name	Time	Method
Number of Infusion Products With Detectable in Vitro Anti-tumor Responses	Up to 12 months	In vitro anti-tumor responses will be measured by cytokine production in a flow-cytometry based assed after co-culture of tumor-infiltrating lymphocytes from the infusion product with autologous tumor cells (from tumor digest and/or autologous tumor cell lines).
Objective Response Rate	Up to 12 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR