Clinical Trials /

Genetically Modified T Cells and Decitabine in Treating Patients With Recurrent or Refractory Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

NCT03017131

Description:

This phase I trial studies the side effects of genetically modified T cells and decitabine in treating patients with recurrent or refractory epithelial or non-epithelial ovarian, primary peritoneal, or fallopian tube cancer that has come back or has not responded to previous treatments. White blood cells called T cells are collected via a process called leukapheresis, genetically modified to recognize and attack tumor cells, then given back to the patient. Decitabine may induce and increase the amount of the target protein NY-ESO-1 available on the surface of tumor cells. Giving genetically modified T cells and decitabine may kill more tumor cells.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Malignant Ovarian Germ Cell Tumor
  • Ovarian Carcinoma
  • Ovarian Granulosa Cell Tumor
  • Ovarian Sarcoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Genetically Modified T Cells and Decitabine in Treating Patients With Recurrent or Refractory Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
  • Official Title: A Phase I Open Label Clinical Trial Evaluating the Safety and Efficacy of Adoptive Transfer of NY-ESO-1 TCR Engineered Autologous T Cells in Combination With Decitabine in Patients With Recurrent or Treatment Refractory Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: i 283616
  • SECONDARY ID: NCI-2016-01477
  • SECONDARY ID: i 283616
  • SECONDARY ID: P30CA016056
  • SECONDARY ID: P50CA159981
  • NCT ID: NCT03017131

Conditions

  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2Treatment (decitabine, genetically modified T cells)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (decitabine, genetically modified T cells)
Decitabine5-Aza-2'-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (decitabine, genetically modified T cells)
Genetically Engineered NY-ESO-1-specific T LymphocytesTreatment (decitabine, genetically modified T cells)

Purpose

This phase I trial studies the side effects of genetically modified T cells and decitabine in treating patients with recurrent or refractory epithelial or non-epithelial ovarian, primary peritoneal, or fallopian tube cancer that has come back or has not responded to previous treatments. White blood cells called T cells are collected via a process called leukapheresis, genetically modified to recognize and attack tumor cells, then given back to the patient. Decitabine may induce and increase the amount of the target protein NY-ESO-1 available on the surface of tumor cells. Giving genetically modified T cells and decitabine may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of the autologous NY-ESO-1 redirected T cell
      therapy in combination with decitabine and low-dose IL-2 in patients with treatment
      refractory or recurrent epithelial or non-epithelial ovarian, primary peritoneal or fallopian
      tube carcinoma.

      SECONDARY OBJECTIVES:

      I. To evaluate the persistence of genetically modified cells in the peripheral blood, and at
      tumor sites.

      II. To examine the effect of the treatment on tumor as measured by objective tumor response
      and progression free survival, both assessed by immune-related Response Evaluation Criteria
      in Solid Tumors (irRECIST).

      III. To assess the occurrence of target antigen and/or major histocompatibality complex (MHC)
      loss variants upon disease recurrence.

      TERTIARY OBJECTIVES:

      I. To evaluate the post treatment phenotype and functionality of genetically modified T cells
      isolated from peripheral blood and from tumor sites.

      II. To assess changes in immunoscore, Tregs, Myeloid cell subsets, and antigen spreading in
      peripheral blood and tumor site.

      III. To assess the influence of demographic and disease molecular characteristics on
      treatment outcomes of complete response (CR) and overall survival (OS).

      OUTLINE:

      COURSE 1: Patients receive decitabine IV daily over 1 hour on days -8 to Day -6,
      cyclophosphamide IV over 2 hours on days -4 and -3, and genetically engineered
      NY-ESO-1-specific T lymphocytes IV and intraperitoneally (IP) on day 0. Followed by low-dose
      IL-2 for 2 weeks from Day 1 to Day 14..

      After completion of study treatment, patients are followed up monthly at 3-9 months, every 6
      months for 4 years, and then annually for up to 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (decitabine, genetically modified T cells)ExperimentalCOURSE 1: Patients receive decitabine IV daily over 1 hour on days -8 to -6, cyclophosphamide IV over 2 hours on days -4 and -3, and genetically engineered NY-ESO-1-specific T lymphocytes IV and IP on day 0. Patients also receive aldesleukin SC BID on days 1-14..
  • Aldesleukin
  • Cyclophosphamide
  • Decitabine
  • Genetically Engineered NY-ESO-1-specific T Lymphocytes

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with recurrent or refractory epithelial or non-epithelial ovarian, primary
             peritoneal or fallopian tube carcinoma who have received platinum containing
             chemotherapy and either has platinum refractory or resistant disease, or if plantinum
             sensitive disease, have received >= 2 lines of chemotherapy. Subjects may have
             received PARP inhibitators , bevacizumab or immunotherapy. Non-epithelial tumors of
             the ovary include sarcomas, granulosa cell tumors and malignant germ cell tumors
             including chiriocarcinoma

          -  Have been informed of other treatment options

          -  Must be HLA- A*02;01 positive; retesting is not required for patients who have
             previous documented HLA-A*02;01 positivity

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Life expectancy of > 4 months

          -  At least 4 weeks from prior chemotherapy, radiotherapy or immunotherapy, or prior
             investigational agents

          -  Must have measurable disease as defined by irRECIST

          -  Must have adequate venous access for apheresis; (pheresis catheter placement for cell
             collection is allowed)

          -  Women of childbearing potential in agreement to use acceptable birth control methods
             for the duration of the study and until persistence of the study drug is no longer
             detected in the peripheral blood; this may be a period of several years; methods for
             acceptable birth control include: condoms, diaphragm or cervical cap with spermicide,
             intrauterine device, and hormonal contraception; it is recommended that a combination
             of two methods be used

          -  Leukocytes >= 3 x 10^9/L

          -  Absolute neutrophil count >= 1 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin within normal institutional limits

          -  Aspartate Aminotransferases (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal

          -  Creatinine level = 2X< upper limit of normal (ULN): if creatinine > 2XULN, creatinine
             clearance must be > 60ml/min

          -  Patient must understand the investigational nature of this study and sign an
             Independent Ethics Committee/Institutional Review Board approved written informed
             consent form prior to receiving any study related procedure

        Exclusion Criteria:

          -  Patients receiving any other investigational agents

          -  Patients with active brain metastases should be excluded from this clinical trial;
             patients with prior history of brain metastasis who have undergone local therapy
             (i.e., metastasectomy and/or radiation) and show no evidence of local recurrence or
             progression over the past 6 months are eligible. Brain MRI as clinically indicated
             only

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cyclophosphamide, decitabine or other agents used in the study

          -  Prior malignancy (except non melanoma skin cancer) within 3 years

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g.,
             interleukin 2, interferon alpha or gamma, granulocyte colony stimulating factors,
             etc.) within 30 days prior to study entry

               -  NOTE: recent or current use of inhaled steroids is not exclusionary; if subjects
                  are prescribed a brief course of oral corticosteroids, the use should be limited
                  to less than 7 days

          -  Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV),
             hepatitis C virus (HCV), or cytomegalovirus (CMV) as defined below, due to the
             immunosuppressive effects of cyclophosphamide used and the unknown risks associated
             with viral replication

               -  Positive serology for HIV

               -  Active hepatitis B infection as determined by a positive test for hepatitis B
                  surface antigen (Ag)

               -  Active hepatitis C; patients will be screened for HCV antibody; if the HCV
                  antibody is positive, a screening HCV ribonucleic acid (RNA) by any real time
                  polymerase chain reaction (RT PCR) or branched deoxyribose nucleic acid (bDNA)
                  assay must be performed at screening by a local laboratory with a Clinical
                  Laboratory Improvement Act (CLIA) certification or its equivalent; eligibility
                  will be determined based on a negative screening value; the test is not required
                  if documentation of a negative result of a HCV RNA test performed within 60 days
                  prior to screening is provided

               -  Serology (CMV immunoglobulin G [IgG]) positive for active CMV

          -  Received any previous gene therapy using an integrating vector within 6 months

          -  Pregnancy or breast-feeding

          -  Lack of availability of a patient for immunological and clinical follow up assessment

          -  Evidence or history of significant cardiac disease (including evidence or history of
             significant cardiac disease (including myocardial infarction [MI] in the past 6
             months, significant cardiac arrhythmia, stage III or IV congestive heart failure
             [CHF]); cardiac stress test will be done as clinically indicated; (the specific test
             to be chosen at the discretion of the principal investigator [PI])

          -  Patients with pulmonary function test abnormalities as evidenced by a forced
             expiratory volume in 1 second to forced vital capacity ratio measurement (FEV1/FVC) <
             70% of predicted for normality will be excluded
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events version 4
Time Frame:Up to 28 days post infusion
Safety Issue:
Description:The frequency of toxicities will be tabulated by grade across all dose levels and cycles.

Secondary Outcome Measures

Measure:Appearance of target antigen/major histocompatibility complex loss variants upon disease recurrence
Time Frame:Up to 15 years
Safety Issue:
Description:Will be evaluated by quantifying expression of targeted antigens/major histocompatibility complex alleles (NY-ESO-1/human leukocyte antigen-A*02) in tumor samples obtained on disease recurrence if available, and comparing those values to the pretreatment (diagnosis) samples. NY-ESO-1 expression will be evaluated by quantitative real time polymerase chain reaction immunohistochemistry. Human leukocyte antigen-A*0201 expression on samples will be evaluated by immunohistochemistry.
Measure:Clinical response rates
Time Frame:Up to 15 years
Safety Issue:
Description:Percentage of complete and partial responses and the corresponding 95% confidence interval will be calculated.
Measure:Duration of response
Time Frame:Up to 15 years
Safety Issue:
Description:Will be observed.
Measure:Immunological parameters associated with T cell persistence, bioactivity and functionality
Time Frame:Up to 15 years
Safety Issue:
Description:Will measure the pre- and post-treatment percentage of transgenic T cells in the peripheral blood, selective migration into the tumor sites, the ex-vivo immune functionality and phenotype of these cells, the modulation of cytokine milieu in serum post treatment as compared to baseline as well as the development of an expanded patient immune response against tumor via epitope spreading.
Measure:Overall survival
Time Frame:Up to 15 years
Safety Issue:
Description:Will be observed.
Measure:Progression free survival
Time Frame:Up to 15 years
Safety Issue:
Description:The median progression free survival and the corresponding 95% confidence interval will be calculated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

December 5, 2019