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TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT03287674
Recruitment Status : Active, not recruiting
First Posted : September 19, 2017
Last Update Posted : August 1, 2018
Sponsor:
Information provided by (Responsible Party):
Inge Marie Svane, Herlev Hospital

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.


Condition or disease Intervention/treatment Phase
Metastatic Ovarian Cancer Drug: Cyclophosphamide Drug: Fludarabine Biological: TIL infusion Drug: Interleukin-2 Drug: Ipilimumab Drug: Nivolumab Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: T-cell Therapy in Combination With Checkpoint Inhibitors for Patients With Advanced Ovarian-, Fallopian Tube- and Primary Peritoneal Cancer
Actual Study Start Date : October 9, 2017
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer

Arm Intervention/treatment
Experimental: 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.

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

Drug: Fludarabine
Fludarabine 25 mg/m2 is administered on day -5 to day -1.
Other Name: Fludarabine phosphate

Biological: TIL infusion
The maximum number of expanded TILs are infused over 30-45 minutes on day 0.
Other Name: TILs

Drug: Interleukin-2
Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.
Other Name: IL-2

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

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




Primary Outcome Measures :
  1. Number and type of reported adverse events [ Time Frame: Up to 12 months ]
    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 :
  1. Treatment related immune responses [ Time Frame: Until progression, assessed up to 60 months. ]
    To evaluate the immunological impact of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer, mainly by flow cytometry.

  2. Objective response rate [ Time Frame: Until progression, assessed up to 60 months. ]
    Clinical responses will be evaluated by RECIST 1.1.

  3. Overall Survival [ Time Frame: Until progression, assessed up to 60 months. ]
    Overall Survival (OS), defined as time from treatment initiation to death, will be described

  4. Progression free survival [ Time Frame: Until progression, relapse or death, assessed up to 60 months. ]
    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



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03287674


Locations
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Denmark
Center for Cancer Immune Therapy Dept. of Hematology/oncology
Copenhagen, Denmark, 2730
Sponsors and Collaborators
Inge Marie Svane
Investigators
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Study Director: Inge Marie Svane, Prof., M.D. Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
Principal Investigator: Magnus Pedersen, M.D. Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730

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Responsible Party: Inge Marie Svane, M.D., Professor, Herlev Hospital
ClinicalTrials.gov Identifier: NCT03287674     History of Changes
Other Study ID Numbers: GY1721
First Posted: September 19, 2017    Key Record Dates
Last Update Posted: August 1, 2018
Last Verified: July 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Vidarabine
Cyclophosphamide
Nivolumab
Fludarabine
Fludarabine phosphate
Ipilimumab
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents