Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

All Conditions

Rare Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Fallopian Tube Neoplasms

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Fallopian Tube Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Nivolumab

Ipilimumab

Relatlimab

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antimetabolites

At Step 1, 6 patients will be treated without Ipilimumab pre tumor harvest. If feasible and tolerable, as defined by no additional SAE/SAR compared to the previously completed pilot studies at CCIT-DK, the trial will move to Step 2.

Depending on the safety and feasibility on step 2, 6 more patients can be included at step 1.

At Step 2, 6 patients will be included. Ipilimumab 3 mg/kg will be administered 2-6 weeks pre tumor harvest.

If no additional SAE/SAR compared to the previous completed pilot study at CCIT-DK is observed additional 6 patients can be included at Step 2. If on the other hand Step 2is not found safe additional 6 patients can be included at Step 1

Ipilimumab 3 mg/kg is administered 2-6 weeks before surgical removement of the tumor. The medicine is administered i.v. over 30 minutes.

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

Cyclophosphamid

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

Fludarabine Phosphate

Tumor-infiltrating lymphocytes grown ex-vivo from resected from cancer tissue and reapplied to the patient via an intravenous infusion. The maximum number of expanded TILs are infused over 30-45 minutes on day 0.

Tumor Infiltrating Lymphocytes infusion

Nivolumab 240 mg i.v. is administered on day -2 and every 2 weeks for a total of 4 doses. The medicine is administered over 30 minutes.

Relatlimab 80 mg i.v. is administered on day -2 and every 2 weeks for a total of 4 doses. The medicine is administered over 60 minutes.

Inge Marie Svane, Prof, M.D.

Tine J Monberg, M.D.

Tine J Monberg, MD

Inge Marie Svane, Prof., M.D.

Although immunotherapy has revolutionized the treatment of many cancers, ovarian cancer patients have not yet benefitted from the advances.

In two consecutive pilot trials at National Center for Cancer Immune Therapy (CCIT-DK), is has been have shown that adoptive cell therapy (ACT) with TILs for patients with advanced ovarian cancer (OC) is feasible and tolerable. In the most recent of these trials ACT was combined with a CTLA-4 inhibitor, Ipilimumab and a PD1-inhibitor, Nivolumab. Only transient clinical responses where observed.

Between 90-100 % of infused T-cells in our previous ovarian cancer ACT trial expressed LAG-3. The interaction between LAG-3 on T-cells and MHC-II on tumor cells inhibits T-cell function.

In this study adding the LAG-3 antibody Relatlimab to the ACT-regimen described above may therefore well unleash T-cell antitumor efficacy by blocking the known LAG-3-MHC-II interaction.

With this study the aim is to demonstrate that adding the lag-3-inhibitor Relatlimab to the above treatment regimen is feasible and tolerable. The study will elucidate whether the combination Relatlimab-Nivolumab leads to objective responses and improves progression free survival (PFS).

Rationale T-cell therapy is an experimental personalized immunotherapy where TILs are isolated from the patient's own tumor tissue, expanded in vitro to billions of cells and then administered to the individual patient with the purpose of eliminating the remaining cancer cells. Lymphodepleting chemotherapy with cyclophosphamide and fludarabine phosphate is administered to the patient before TIL infusion to reduce the number of irrelevant immune cells.

In two consecutive pilot trials at National Center for Cancer Immune Therapy (CCIT-DK), it has been shown that adoptive cell therapy (ACT) with TILs for patients with advanced ovarian cancer (OC) is feasible and tolerable. In the most recent of these trials ACT was combined with a CTLA-4 inhibitor, Ipilimumab and a PD1-inhibitor, Nivolumab.

Between 90-100% of infused T-cells in these previous ovarian cancer ACT trial expressed LAG-3. The interaction between LAG-3 on T-cells and MHC-II on tumor cells inhibits T-cell function.

In this phase I/II study 18 patients with advanced ovarian -, fallopian tube-, and primary peritoneal cancer will be included. Included patients undergo surgical removal of tumor tissue for tumor-infiltrating lymphocyte (TIL) manufacturing. Lymphodepleting chemotherapy is administered prior to TIL infusion. Hereafter the patients are treated with the programmed cell death protein 1 (PD-1) antibody Nivolumab and the anti-lymphocyte activation gene 3 (anti-LAG-3) antibody Relatlimab. The study will be devided into 3 steps.

* Step One (6 subjects): Patients are treated without prior administration of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody Ipilimumab pre-tumor harvest.
* Step Two (6 subjects): If Step One proves feasible and tolerable patients in Step Two will receive one dose of Ipilimumab pre-tumor harvest.
* Step Three (6 subjects): Patients are treated either with or without prior Ipilimumab pre-tumor harvest depending on the tolerability data from Step Two.

All patients are treated with lymphodepleting chemotherapy for 7 days followed by infusion of TILs. For safety reasons no IL-2- will be administered in this study

The aim of this study is to demonstrate that ACT and a combination of Relatlimab-Nivolumab does not increase the toxicity compared to the same treatment regimen including Nivolumab monotherapy. The study will elucidate whether the combination Relatlimab-Nivolumab lead to objective responses and improves progression free survival (PFS). It is anticipated that combining Relatlimab and Nivolumab with Adoptive T cell therapy (ACT) for advanced OC is safe and feasible. Further, it is hypothesized that the combination will lead to improved immunity in tumor and blood as well as improved antitumor efficacy.

Objectives

* To evaluate the tolerability and safety of the treatment
* To characterize antitumor immune responses and clinical efficacy

18 patients are included in 3 steps, containing 6 patients each.

Step 1: 6 patients will be included. Ipilimumab wil not be administered pre-tumor harvest. If feasible and tolerable, as defined by no additional SAE/SAR compared to the previously completed pilot studies at CCIT-DK, the trial will move to Step 2

Step 2: 6 patients will be included. Ipilimumab will be administered once 2-6 weeks before tumor resection.

Step 3: If no additional SAE/SAR, compared to the previous completed study at CCIT-DK, is observed additional 6 patients can be included at Step Two. If on the other hand Step 2 is not found safe, additional 6 patients can be included at Step 1

T-cell Therapy in Combination With Nivolumab, Relatlimab and Ipilimumab for Patients With Metastatic Ovarian Cancer

T-cell Therapy in Combination With Nivolumab, Relatlimab and Ipilimumab for Patients With Advanced Ovarian-, Fallopian Tube- and Primary Peritoneal Cancer

Number of patients excluded due to treatment related safety issues compared to the number of patients enrolled in the study

Fraction of patients experiencing grade III or worse adverse events

Number of patients excluded due to feasibility issues compared to the number of patients enrolled in the study

Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) assessed by CT scan.

Spots Global Cancer Trial Database for tumor infiltrating lymphocytes infusion