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

Primary Purpose

Ovarian Cancer Recurrent

Status

Unknown status

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Tumor Infiltrating Lymphocytes (TIL)

Interferon Alfa 2A

Carboplatin

Paclitaxel

About this trial

This is an interventional treatment trial for Ovarian Cancer Recurrent

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept 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.

Sites / Locations

Leiden University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Arm Description

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

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.

Outcomes

Primary Outcome Measures

NCI CTC criteria

If a DLT occurs in more than one out of the three patients, the study will be stopped. If < 1 out of 3 patients have a DLT, then three additional patients will be treated. Therefore, a minimum of 3 and a maximum of 6 patients will be treated in both cohorts.

Secondary Outcome Measures

Clinical Response

Clinical response according to RECIST 1.1 criteria and immune response criteria (irRC)

Disease Control rate

Disease control rate (DCR: CR+PR+SD) at 6 months

Progression free survival (PFS)

Progression free survival (PFS) is defined as: the duration from the time of start chemotherapy until first observation of radiologically confirmed progressive disease or death due to any cause, whichever occurred first.

Overall Survival (OS)

Overall Survival (OS) is defined as: the duration from the time of start of chemotherapy until death from any cause.

Full Information

NCT ID

NCT04072263

First Posted

August 27, 2019

Last Updated

March 30, 2021

Sponsor

Leiden University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT04072263

Brief Title

Adoptive T Cell Therapy in Patients With Recurrent Ovarian Cancer

Acronym

OVACURE

Official Title

Adoptive T Cell Therapy in Patients With Recurrent Ovarian Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Unknown status

Study Start Date

August 1, 2018 (Actual)

Primary Completion Date

August 1, 2021 (Anticipated)

Study Completion Date

December 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Leiden University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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).

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ovarian Cancer Recurrent

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

Tumor Infiltrating Lymphocytes (TIL)

Intervention Description

Adoptive cell therapy using Tumor-Infiltrating Lymphocytes (TIL) i.v.

Intervention Type

Drug

Intervention Name(s)

Interferon Alfa 2A

Other Intervention Name(s)

IFNalpha

Intervention Description

Interferon alpha (IFNα) s.c., 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.

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Other Intervention Name(s)

carboplatine

Intervention Description

chemotherapy i.v.

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Other Intervention Name(s)

Taxol

Intervention Description

Chemotherapy i.v.

Primary Outcome Measure Information:

Title

NCI CTC criteria

Description

Time Frame

3 years

Secondary Outcome Measure Information:

Title

Clinical Response

Description

Clinical response according to RECIST 1.1 criteria and immune response criteria (irRC)

Time Frame

3 years

Title

Disease Control rate

Description

Disease control rate (DCR: CR+PR+SD) at 6 months

Time Frame

3 years

Title

Progression free survival (PFS)

Description

Time Frame

3 years

Title

Overall Survival (OS)

Description

Overall Survival (OS) is defined as: the duration from the time of start of chemotherapy until death from any cause.

Time Frame

3 years

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Judith Kroep, MD, PhD

Phone

0031715263464

j.r.kroep@lumc.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Els Verdegaal, PhD

Phone

0031715263464

E.M.E.Verdegaal@lumc.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Judith Kroep, MD, PhD

Organizational Affiliation

Leiden University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Leiden University Medical Center

City

Leiden

State/Province

ZIP/Postal Code

2333ZA

Country

Netherlands

Individual Site Status

Recruiting

12. IPD Sharing Statement

Plan to Share IPD

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Adoptive T Cell Therapy in Patients With Recurrent Ovarian Cancer

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