Clinical trial NCT03287674: TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer
Official title: T-cell Therapy in Combination With Checkpoint Inhibitors for Patients With Advanced Ovarian-, Fallopian Tube- and Primary Peritoneal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Ovarian Cancer
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
First posted: 2017-09-19
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Reported Adverse Events by Type
timeFrame: Up to 12 months
Secondary outcomes:
measure: Treatment Related Immune Responses
timeFrame: Until protocol end, until 6 months after TIL infusion
measure: Objective Response Rate
timeFrame: Assessed up to 12 months after therapy.
measure: Overall Survival
timeFrame: Up to 3 years after TIL infusion
measure: Progression Free Survival
timeFrame: Up to 12 months after TIL infusion
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Center for Cancer Immune Therapy Dept. of Hematology/oncology
Study officials:
affiliation: Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
name: Inge Marie Svane, Prof., M.D.
role: STUDY_DIRECTOR
affiliation: Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
name: Magnus Pedersen, M.D.
role: PRINCIPAL_INVESTIGATOR
References: