Adoptive T Cell Therapy in Patients With Recurrent Ovarian Cancer (OVACURE)

Leiden University Medical Center (LUMC)

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Ovarian Cancer Recurrent

Treatments: Drug: Paclitaxel; Drug: Interferon Alfa 2A; Drug: Carboplatin; Biological: Tumor Infiltrating Lymphocytes (TIL)

Study type: Interventional

Funder types: Other

Identifiers

NCT04072263

OVACURE

Details and patient eligibility

About

The clinical benefit of standard treatment for patients with epithelial ovarian cancer (EOC) are poor. Ovarian cancer is a highly immunogenic tumor and good survival is tightly linked to the presence of tumor-infiltrating CD8+ T cells and the absence of immunosuppressive immune cells. This clear correlation between T cell infiltration and disease progression suggests that EOC may be sensitive to adoptive cell therapy by infusion of ex-vivo expanded autologous Tumor Infiltrating Lymphocytes (TIL) provided that immune suppression is reduced. Carboplatin+paclitaxel chemotherapy is directly killing tumor cells but was also shown to alleviate immunosuppression for 2 weeks coinciding with enhanced T-cell immunity, potentially creating a window of opportunity for T-cell based immunotherapy.

In addition, there is evidence that interferon alpha (IFNα) not only may work as a low toxic preconditioning regimens that creates the space required for the infused TIL but that it also supports the TIL by sustaining their persistence and indirectly their function, by upregulation of HLA class I on tumor cells and decreasing the numbers of regulatory T cells. Based on this we hypothesize that a synergistic clinical effect may be obtained when adoptive cell therapy with autologous TIL is administered during treatment with chemotherapy and IFNα. The feasibility and safety of TIL administration is studied in the window of opportunity created by carboplatin-paclitaxel chemotherapy with or without interferon alpha (IFNα). Furthermore, exploratory studies will be performed to analyze and confirm the proposed underlying mechanisms.

Tumor material for TIL production will be collected during first line debulking surgery in case of FIGO stage IIIC/IV disease (pre-OVACURE) or in case of recurrent platinum sensitive disease an extra biopsy can be planned (OVACURE).

Full description

Study the feasibility and safety of TIL administration in the window of opportunity created by carboplatin-paclitaxel chemotherapy with or without interferon alpha (IFNα). Furthermore, exploratory studies will be performed to analyze and confirm the proposed underlying mechanisms.

Intervention:

Cohort 1

• Carboplatin-paclitaxel day1, q3 weeks, 6x, plus
• TIL starting 14 days after the 2nd chemotherapy cycle, q3 weeks, 3x.

Cohort 2

• Carboplatin-paclitaxel day1, q3 weeks, 6x, plus
• TIL starting 14 days after the 2nd chemotherapy cycle, q3 weeks, 3x, plus
• IFNα (3x10e6 U daily) starting one week before the first TIL infusion for 12 weeks in total.

Enrollment: 12 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age ≥ 18 years.
• Histologically proven epithelial ovarian cancer (EOC).
• Recurrent ovarian cancer amenable to carboplatin and paclitaxel chemotherapy. Patient with primary stage III or IV EOC can participate in the pre-OVACURE to collect rest tumor during debulking surgery for TILs preservation, so TILs will be available in case of recurrent disease will develop in the future.
• Presence of measurable progressive disease according to RECIST version 1.1 or elevated CA125 ≥ 2 times the upper normal limit (UNL) within 3 months and confirmed.
• Expected survival of at least 3 months.
• WHO performance status 0-2.
• Within the last 2 weeks prior to study day 0, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified:

Lab Parameter Range Hemoglobin ≥ 6,0 mmol/l Granulocytes ≥ 1,500/µl Lymphocytes ≥ 700/µl Platelets ≥ 100,000/µl Creatinine clearance ≥ 50 min/ml Serum bilirubin ≤ 40 mol/l ASAT and ALAT ≤ 5 times the normal upper limit LDH ≤ 2 times the normal upper limit

• Viral tests:

  • Negative for HIV type 1/2, HTLV and TPHA
  • No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum
  • No antibodies against HCV (hepatitis C virus) in the serum

• Able and willing to give valid written informed consent.

• Prior treatment, including immunotherapy e.g. with anti-PD(L)1, is allowed but systemic therapy and radiotherapy must have been discontinued for at least two weeks before study entry.

• Patients should have disease progression.

Exclusion criteria

• Patients with brain metastases.
• Clinically significant heart disease (NYHA Class III or IV).
• Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or other conditions requiring concurrent medications not allowed during this study.
• Active immunodeficiency disease or autoimmune disease requiring immune suppressive drugs. Vitiligo is not an exclusion criterion.
• Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical or vulva carcinoma.
• Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.
• Lack of availability for follow-up assessments.
• Pregnancy or breastfeeding.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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12 participants in 2 patient groups

Cohort 1

Experimental group

Description:

* Carboplatin-paclitaxel day1, q3 weeks, 6x, plus * Tumor Infiltrating Lymphocytes (TIL) starting 14 days after the 2nd chemotherapy cycle, q3 weeks, 3x.

Treatment:

Drug: Carboplatin

Biological: Tumor Infiltrating Lymphocytes (TIL)

Drug: Paclitaxel

Cohort 2

Experimental group

Description:

* Carboplatin-paclitaxel day1, q3 weeks, 6x, plus * Tumor Infiltrating Lymphocytes (TIL) starting 14 days after the 2nd chemotherapy cycle, q3 weeks, 3x, plus * Interferon Alpha 2A (3x10e6 U daily) starting one week before the first TIL infusion for 12 weeks in total.

Treatment:

Drug: Carboplatin

Drug: Interferon Alfa 2A

Biological: Tumor Infiltrating Lymphocytes (TIL)

Drug: Paclitaxel