Back to resultsTIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer
Primary Purpose
Metastatic Ovarian Cancer
Status
Completed
Phase
Phase 1
Locations
Denmark
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine
TIL infusion
Interleukin-2
Ipilimumab
Nivolumab
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Ovarian Cancer
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.
Sites / Locations
- Center for Cancer Immune Therapy Dept. of Hematology/oncology
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Patient group
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Treatment Related Immune Responses
Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.
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
Overall Survival
Overall Survival (OS), defined as time from TIL infusion to death
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03287674
Brief Title
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
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
October 9, 2017 (Actual)
Primary Completion Date
June 1, 2020 (Actual)
Study Completion Date
June 1, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Inge Marie Svane
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Ovarian Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Patient group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludarabine phosphate
Intervention Description
Fludarabine 25 mg/m2 is administered on day -5 to day -1.
Intervention Type
Biological
Intervention Name(s)
TIL infusion
Other Intervention Name(s)
TILs
Intervention Description
The maximum number of expanded TILs are infused over 30-45 minutes on day 0.
Intervention Type
Drug
Intervention Name(s)
Interleukin-2
Other Intervention Name(s)
IL-2
Intervention Description
Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Intervention Description
One dose of Ipilimumab 3 mg/kg is administered 14 days prior to surgical removal of tumor tissue for TIL expansion.
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
Nivolumab 3 mg/kg is administered on day -2 before TIL infusion and every 2 weeks for a total of 4 doses.
Primary Outcome Measure Information:
Title
Number of Participants With Reported Adverse Events by Type
Description
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.
Time Frame
Up to 12 months
Secondary Outcome Measure Information:
Title
Treatment Related Immune Responses
Description
Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.
Time Frame
Until protocol end, until 6 months after TIL infusion
Title
Objective Response Rate
Description
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
Time Frame
Assessed up to 12 months after therapy.
Title
Overall Survival
Description
Overall Survival (OS), defined as time from TIL infusion to death
Time Frame
Up to 3 years after TIL infusion
Title
Progression Free Survival
Description
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.
Time Frame
Up to 12 months after TIL infusion
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Inge Marie Svane, Prof., M.D.
Organizational Affiliation
Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Magnus Pedersen, M.D.
Organizational Affiliation
Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
Official's Role
Principal Investigator
Facility Information:
Facility Name
Center for Cancer Immune Therapy Dept. of Hematology/oncology
City
Copenhagen
ZIP/Postal Code
2730
Country
Denmark
12. IPD Sharing Statement
Learn more about this trial
TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer
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