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

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

Eligibility Criteria:
Inclusion Criteria:

1. Histological proven advanced ovarian-, fallopian tube or primary peritoneal cancer with the possibility of surgical removal of tumor tissue of \> 1 cm3. All histologies can be included.
2. Progressive or recurrent resistant disease after platin-based chemotherapy (platinum resistant) or progressive or recurrent disease after second line or additional chemotherapy.
3. Age: 18 - 75 years.
4. ECOG performance status of ≤1 (Appendix 2).
5. Life expectancy of \> 6 months.
6. At least one measurable parameter in accordance with RECIST 1.1 -criteria.
7. LVEF assessment with documented LVEF ≥50% by either TTE or MUGA (TTE preferred test) within 6 months from first study drug administration
8. No significant toxicities or side effects (CTC ≤ 1) from previous treatments, except sensory- and motoric neuropathy (CTC ≤ 2) and/or alopecia (CTC ≤ 2).
9. Sufficient organ function, including:

   * Absolute neutrophil count (ANC) ≥ 1.500 /µl
   * Leucocyte count ≥ lower normal limit
   * Platelets ≥ 100.000 /µl and \<700.000 /µl
   * Hemoglobin ≥ 6,0 mmol/l (regardless of prior transfusion)
   * S-creatinine \< 140
   * S-bilirubin ≤ 1,5 times upper normal limit
   * ASAT/ALAT ≤ 2,5 times upper normal limit
   * Alkaline phosphatase ≤ 5 times upper normal limit
   * Lactate dehydrogenase ≤ 5 times upper normal limit
   * Sufficient coagulation: APPT\<40 and INR\<1,5
10. Signed statement of consent after receiving oral and written study information
11. Willingness to participate in the planned controls and capable of handling toxicities.
12. Age and Reproductive Status: Females, ages ≥18 years, inclusive

    * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[hCG\]) within 24 hours prior to the start of study treatment.Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception. This applies from inclusion in the study and for the duration of treatment with Ipilimumab, Relatlimab and Nivolumab plus 5 half-lives of study treatment plus 30 days (duration of ovulatory cycle) for a total of 24 weeks post-treatment completion. The following are considered safe methods of contraception:
    * Hormonal anticonception (birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch)
    * Intrauterine device
    * Surgical sterilization
    * Surgical sterilization of male partner with verification of no sperm after the procedure
    * Menopause (for more than 12 months)

Exclusion Criteria:

Patients will be excluded if they meet one of the criteria's listed below

1. A history of prior malignancies. Patients treated for another malignancy can participate if they are without signs of disease for a minimum of 3 years after treatment.
2. Known hypersensitivity to one of the active drugs or one or more of the excipients.
3. Severe medical conditions, such as severe asthma/COLD, significant cardiac disease, poorly regulated insulin dependent diabetes mellitus among others.
4. Creatinine clearance \< 70 ml/min (1).
5. Acute/chronic infection with HIV, hepatitis, syphilis among others.
6. Severe allergies or previous anaphylactic reactions.
7. Active autoimmune disease, such as autoimmune neutropenia/thrombocytopenia or hemolytic anemia, systemic lupus erythematosis, Sjögren's syndrome, sclerodermia, myasthenia gravis, Goodpasteur's disease, Addison's disease, Hashimotos thyroiditis, active Graves disease.
8. Subjects with history of myocarditis, regardless of etiology
9. Troponin T (TnT) or I (TnI) \> 2x institutional upper limit of normal (ULN) is excluded. ii) between \> 1 to 2 x ULN will be permitted if a repeat assessment remains ≤ 2 x ULN and participant undergoes a cardiac evaluation and is cleared by a cardiologist or cardio-oncologist
10. Prior treatment with LAG-3 targeted agents.
11. Pregnant women and women breastfeeding.
12. Simultaneous treatment with systemic immunosuppressive drugs (including prednisolone, methotrexate among others) (2).
13. Simultaneous treatment with other experimental drugs. Based on clinical judgement antihormonal treatment can be accepted.
14. Simultaneous treatment with other systemic anti-cancer treatments.
15. Patients with active and uncontrollable hypercalcemia

(1)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.

(2)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.