TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer

NCT ID: NCT03287674

Last Updated: 2023-03-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-09
• Study Completion Date: 2020-06-01

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. 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

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.

Conditions

Metastatic Ovarian Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Patient group

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.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.

Fludarabine

Intervention Type: DRUG

Fludarabine 25 mg/m2 is administered on day -5 to day -1.

TIL infusion

Intervention Type: BIOLOGICAL

The maximum number of expanded TILs are infused over 30-45 minutes on day 0.

Interleukin-2

Intervention Type: DRUG

Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.

Ipilimumab

Intervention Type: DRUG

One dose of Ipilimumab 3 mg/kg is administered 14 days prior to surgical removal of tumor tissue for TIL expansion.

Nivolumab

Intervention Type: DRUG

Nivolumab 3 mg/kg is administered on day -2 before TIL infusion and every 2 weeks for a total of 4 doses.

Interventions

Cyclophosphamide

Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.

Intervention Type: DRUG

Fludarabine

Fludarabine 25 mg/m2 is administered on day -5 to day -1.

Intervention Type: DRUG

TIL infusion

The maximum number of expanded TILs are infused over 30-45 minutes on day 0.

Intervention Type: BIOLOGICAL

Interleukin-2

Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.

Intervention Type: DRUG

Ipilimumab

One dose of Ipilimumab 3 mg/kg is administered 14 days prior to surgical removal of tumor tissue for TIL expansion.

Intervention Type: DRUG

Nivolumab

Nivolumab 3 mg/kg is administered on day -2 before TIL infusion and every 2 weeks for a total of 4 doses.

Intervention Type: DRUG

Other Intervention Names

Fludarabine phosphate; TILs; IL-2

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Inge Marie Svane

OTHER

Sponsor Role: lead

Responsible Party

Inge Marie Svane

M.D., Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Inge Marie Svane, Prof., M.D.

Role: STUDY_DIRECTOR

Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730

Magnus Pedersen, M.D.

Role: PRINCIPAL_INVESTIGATOR

Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730

Locations

Center for Cancer Immune Therapy Dept. of Hematology/oncology

Copenhagen, , Denmark

Countries

Denmark

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

GY1721

Identifier Type: -

Identifier Source: org_study_id