Clinical Trials /

Gene-Modified T Cells With or Without Decitabine in Treating Patients With Advanced Malignancies Expressing NY-ESO-1

NCT02650986

Description:

This phase I/IIa trial studies the side effects and best dose of gene-modified T cells when given with or without decitabine, and to see how well they work in treating patients with malignancies expressing cancer-testis antigens 1 (NY-ESO-1) gene that have spread to other places in the body (advanced). A T cell is a type of immune cell that can recognize and kill abnormal cells of the body. Placing a modified gene for NY-ESO-1 into the patients' T cells in the laboratory and then giving them back to the patient may help the body build an immune response to kill tumor cells that express NY-ESO-1. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving gene-modified T cells with or without decitabine works better in treating patients with malignancies expressing NY-ESO-1.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
  • Synovial Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Gene-Modified T Cells With or Without Decitabine in Treating Patients With Advanced Malignancies Expressing NY-ESO-1
  • Official Title: A Phase I/IIa Study of TGFß Blockade in TCR-Engineered T-Cell Cancer Immunotherapy in Patients With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: I 258514
  • SECONDARY ID: NCI-2015-02080
  • SECONDARY ID: I 258514
  • SECONDARY ID: P30CA016056
  • SECONDARY ID: R01CA164333
  • NCT ID: NCT02650986

Conditions

  • Advanced Fallopian Tube Carcinoma
  • Advanced Malignant Solid Neoplasm
  • Advanced Melanoma
  • Advanced Ovarian Carcinoma
  • Advanced Primary Peritoneal Carcinoma
  • Advanced Synovial Sarcoma
  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Metastatic Fallopian Tube Carcinoma
  • Metastatic Melanoma
  • Metastatic Ovarian Carcinoma
  • Metastatic Primary Peritoneal Carcinoma
  • Metastatic Synovial Sarcoma
  • Pathologic Stage III Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIA Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIB Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IIID Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Platinum-Resistant Fallopian Tube Carcinoma
  • Platinum-Resistant Ovarian Carcinoma
  • Platinum-Resistant Primary Peritoneal Carcinoma
  • Stage III Fallopian Tube Cancer AJCC v8
  • Stage III Ovarian Cancer AJCC v8
  • Stage III Primary Peritoneal Cancer AJCC v8
  • Stage IIIA Fallopian Tube Cancer AJCC v8
  • Stage IIIA Ovarian Cancer AJCC v8
  • Stage IIIA Primary Peritoneal Cancer AJCC v8
  • Stage IIIA1 Fallopian Tube Cancer AJCC v8
  • Stage IIIA1 Ovarian Cancer AJCC v8
  • Stage IIIA2 Fallopian Tube Cancer AJCC v8
  • Stage IIIA2 Ovarian Cancer AJCC v8
  • Stage IIIB Fallopian Tube Cancer AJCC v8
  • Stage IIIB Ovarian Cancer AJCC v8
  • Stage IIIB Primary Peritoneal Cancer AJCC v8
  • Stage IIIC Fallopian Tube Cancer AJCC v8
  • Stage IIIC Ovarian Cancer AJCC v8
  • Stage IIIC Primary Peritoneal Cancer AJCC v8
  • Stage IV Fallopian Tube Cancer AJCC v8
  • Stage IV Ovarian Cancer AJCC v8
  • Stage IV Primary Peritoneal Cancer AJCC v8
  • Stage IVA Fallopian Tube Cancer AJCC v8
  • Stage IVA Ovarian Cancer AJCC v8
  • Stage IVA Primary Peritoneal Cancer AJCC v8
  • Stage IVB Fallopian Tube Cancer AJCC v8
  • Stage IVB Ovarian Cancer AJCC v8
  • Stage IVB Primary Peritoneal Cancer AJCC v8
  • Unresectable Melanoma
  • Unresectable Ovarian Carcinoma
  • Unresectable Synovial Sarcoma

Interventions

DrugSynonymsArms
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, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Cohort I (cyclophosphamide, TCR/dnTGFbetaRII)
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineCohort II (decitabine, cyclophosphamide, TCR/dnTGFbetaRII)
TGFbDNRII-transduced Autologous Tumor Infiltrating LymphocytesTGFbDNRII-transduced Autologous TILsCohort I (cyclophosphamide, TCR/dnTGFbetaRII)

Purpose

This phase I/IIa trial studies the side effects and best dose of gene-modified T cells when given with or without decitabine, and to see how well they work in treating patients with malignancies expressing cancer-testis antigens 1 (NY-ESO-1) gene that have spread to other places in the body (advanced). A T cell is a type of immune cell that can recognize and kill abnormal cells of the body. Placing a modified gene for NY-ESO-1 into the patients' T cells in the laboratory and then giving them back to the patient may help the body build an immune response to kill tumor cells that express NY-ESO-1. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving gene-modified T cells with or without decitabine works better in treating patients with malignancies expressing NY-ESO-1.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the safety and feasibility of adoptive transfer of TGFbDNRII-transduced
      autologous tumor infiltrating lymphocytes (autologous NY-ESO-1 TCR/dnTGFbetaRII transgenic T
      cells).

      SECONDARY OBJECTIVES:

      I. NY-ESO-1 TCR/ dnTGFbetaRII transgenic T cell persistence by analyzing serial peripheral
      blood samples for the presence of T cells with the NY-ESO-1 TCR by tetramer analysis.

      II. To study T cell differentiation that correlates with higher anti-tumor responses.

      III. To test the hypothesis that NY-ESO-1 TCR/dnTGFbetaRII will constitute in cells more
      efficient in inducing tumor regression.

      IV. Determine objective tumor responses by immune-related Response Evaluation Criteria in
      Solid Tumors (irRECIST) 1.1.

      EXPLORATORY OBJECTIVE:

      I. To evaluate the role of microbiota on the therapeutic efficacy of the proposed therapy.

      OUTLINE: This is a phase I, dose-escalation study of NY-ESO-1 TCR/TGFbDNRII-transduced TILs
      followed by a phase IIa study. Participants are assigned 1 to 2 cohorts.

      COHORT I: Patients undergo leukapheresis on day -6, and receive cyclophosphamide
      intravenously (IV) over 2 hours on days -5 and -4. Patients then receive TGFbDNRII-transduced
      autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who
      showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous
      tumor infiltrating lymphocytes infusion at any time after progression is confirmed.

      COHORT II: Patients undergo leukapheresis on day -6 and receive decitabine IV over 1 hour on
      days -6 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients then receive
      TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0.
      Eligible patients who showed initial response/disease control, may receive a second
      TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after
      progression is confirmed.

      After completion of study treatment, patients are followed up at weeks 1-4, 6, 8, and 12, at
      6 and 9 months, every 6 months for 5 years, and then yearly for 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (cyclophosphamide, TCR/dnTGFbetaRII)ExperimentalPatients undergo leukapheresis on day -6 and receive cyclophosphamide IV over 2 hours on days -5 and -4. Patients then receive TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after progression is confirmed.
  • Cyclophosphamide
  • TGFbDNRII-transduced Autologous Tumor Infiltrating Lymphocytes
Cohort II (decitabine, cyclophosphamide, TCR/dnTGFbetaRII)ExperimentalPatients undergo leukapheresis on day -6 and receive decitabine IV over 1 hour on days -6 to -4 and cyclophosphamide IV over 2 hours on days -3 and -2. Patients then receive TGFbDNRII-transduced autologous tumor infiltrating lymphocytes IV over 15 minutes on day 0. Eligible patients who showed initial response/disease control, may receive a second TGFbDNRII-transduced autologous tumor infiltrating lymphocytes infusion at any time after progression is confirmed.
  • Cyclophosphamide
  • Decitabine
  • TGFbDNRII-transduced Autologous Tumor Infiltrating Lymphocytes

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with solid tumors as described below:

               -  Inoperable or metastatic (advanced) melanoma:

                    -  Has received, is intolerant, or refused a CTLA-4 inhibitor (ipilimumab) or a
                       PD-1 inhibitor (nivolumab or pembrolizumab) as monotherapy and/or a
                       combination of ipilimumab and nivolumab

                    -  Has received or is intolerant of a BRAF inhibitor or the combination of BRAF
                       and MEK inhibitors for BRAFv600 mutant melanoma and a PD-1 inhibitor as
                       monotherapy or in combination

               -  Inoperable or metastatic (advanced) ovarian, primary peritoneal or fallopian tube
                  carcinoma:

                    -  Has received platinum containing chemotherapy and has platinum refractory or
                       resistant disease that has progressed on second line therapy

                    -  If platinum sensitive disease, should have received >= 2 lines of
                       chemotherapy

                    -  May have received PARP inhibitors, bevacizumab or other targeted VEGF
                       inhibitor therapy

               -  Inoperable or metastatic (advanced) synovial sarcoma:

                    -  Should have received and progressed on >= two lines of systemic therapy

               -  Subjects with other histologies:

                    -  Must have previously received two lines of systemic standard care (or
                       effective salvage chemotherapy regimens) for metastatic disease, if known to
                       be effective for that disease, and have been deemed either non-responders
                       (progressive disease) or have recurred

          -  For cohorts 1, 2 and 3 only: Patient's tumor must be positive by histological or
             molecular assay for NY-ESO-1, according to the screening algorithm; historical results
             may be used

               -  For cohort 4, NY-ESO-1 results will be noted but NY-ESO-1 positivity is not
                  required for eligibility

          -  Human leukocyte antigen (HLA)-A*0201 (HLA-A2.1) positivity by molecular subtyping
             (blood test or buccal swab, historical documentation acceptable)

          -  Age >= 18 years old, (Cohort 4: Age >= 12 years old)

          -  Life expectancy greater than 3 months assessed by a study physician

          -  Have been informed of other treatment options

          -  A minimum of one measurable lesion defined as:

               -  Meeting the criteria for measurable disease according to irRECIST criteria

               -  For patients with skin metastases, lesions selected as non-completely biopsied
                  target lesion(s) that can be accurately measured and recorded by color
                  photography with a ruler to document the size of the target lesion(s)

          -  No restriction based on prior treatments but at least 4 weeks from prior
             immunotherapy, or prior investigational agents. Note: Patients who have suffered
             >grade 2 irAEs during previous checkpoint inhibitor therapy should be excluded.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  Must have adequate venous access for apheresis

          -  Women of childbearing potential and men must agree to use effective methods of birth
             control for the duration of the study and 6 months after; 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: >= 3,000/mcl

          -  Absolute neutrophil count: >= 1,000/mcl

          -  Platelets: >= 100,000/mcl

          -  Total bilirubin: =< 1.5 upper limit of normal (ULN)

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

          -  Creatinine: =< 2 X ULN; if creatinine > 2 X ULN, creatinine clearance must be > 60
             ml/min

          -  Must be willing and able to accept the leukapheresis procedure

          -  At screening, must have tissue available for NY-ESO-1 testing (if not previously
             performed) or be willing and able to undergo a fresh tissue biopsy

          -  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

          -  Participant must agree to and arrange for a caregiver (age >= 18 years old) available
             24 hours a day/ 7 days a week and arrange for lodging within 45 minutes drive to
             Roswell Park and transportation for a period of time after discharge from the
             hospital; the exact amount of time will depend on the individual status as determined
             by the treating physician

          -  ELIGIBILITY CRITERIA FOR A SECOND TRANSGENIC T CELL INFUSION

        Subjects in whom disease control was observed after the T cell infusion may be eligible for
        a second transgenic T cell infusion if the subject meets the following criteria:

          -  Patient attained confirmed disease control (either complete remission [CR], partial
             remission [PR] or stable disease [SD]) after the first transgenic T cell infusion

          -  Patient still meets the eligibility criteria above

          -  A second T cell infusion is discussed and the patient agrees to receive it

          -  Either cryopreserved extra cells from the first T cell product is available or
             cryopreserved autologous peripheral blood mononuclear cell (PBMC) is available for the
             manufacture of a second transgenic T cell product

        Exclusion Criteria:

          -  Previously known hypersensitivity to any of the agents used in this study

          -  Currently receiving any other investigational agents. Note: Patients who have suffered
             >grade 2 irAEs during previous checkpoint inhibitor therapy should be excluded.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements; electrocardiogram (EKG) will be done at screening; cardiac stress
             test will be done as clinically indicated, the specific test to be chosen at the
             discretion of the treating physician.

          -  History of severe autoimmune disease requiring steroids or other immunosuppressive
             treatments

          -  History of inflammatory bowel disease, celiac disease, or other chronic
             gastrointestinal conditions associated with diarrhea or bleeding, which in the
             investigator's opinion would place the patient at an increased risk for adverse effect
             or current acute colitis of any origin; treated cases with no active disease are
             eligible

          -  Potential requirement for systemic corticosteroids or concurrent immunosuppressive
             drugs based on prior history or received systemic steroids within the last 4 weeks
             prior to enrollment (inhaled or topical steroids at standard doses or isolated use of
             steroids as premedication for medical procedures to minimize allergic reaction [e.g.
             computed tomography (CT) scan dye] are allowed)

          -  Known active infection with human immunodeficiency virus (HIV), hepatitis B, hepatitis
             C or cytomegalovirus (CMV)

          -  Known cases of clinically active brain metastases (brain magnetic resonance imaging
             [MRI] as clinically indicated); prior evidence of brain metastasis successfully
             treated with surgery or radiation therapy will not be exclusion for participation as
             long as they are deemed under control at the time of study enrollment

          -  Dementia or significantly altered mental status that would prohibit the understanding
             or rendering of compliance with the requirements of this protocol even with caregiver
             support

          -  Pregnancy or breast-feeding; female patients must be surgically sterile or be
             postmenopausal for two years, or must agree to use effective contraception during the
             period of treatment and 6 months after; all female patients with reproductive
             potential must have a negative pregnancy test (serum/urine) within 48 hours from
             starting the conditioning chemotherapy

          -  Lack of availability of a patient for immunological and clinical follow-up assessment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity
Time Frame:Up to 30 days
Safety Issue:
Description:Will be assessed using Common Toxicity Criteria. Patients will be monitored by medical histories, physical examinations, ophthalmologic exams, and blood studies to detect potential toxicities from the treatment.

Secondary Outcome Measures

Measure:Expression of the NY-ESO-1 T cell receptor (TCR) transgenic protein in peripheral blood mononuclear cells (PBMC)
Time Frame:Up to 15 years
Safety Issue:
Description:TCR and vector presence will be quantitated in PBMC samples, obtained before adoptive transfer and at weeks 1, 2, 4, 8, and 12 after transgenic cell adoptive transfer. Thereafter, sampling will be every 3 months during the first year, and then every 6 to 12 months per schedule of procedures and observations.
Measure:Replication competent retrovirus (RCR)
Time Frame:Up to 1 year
Safety Issue:
Description:Will be assessed in blood by polymerase chain reaction (PCR).
Measure:Tumor response (complete and partial response)
Time Frame:Up to 90 days after TCR transgenic PBMC adoptive transfer
Safety Issue:
Description:Will be determined by immune-related Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Response assessment will be performed by comparing standard computed tomography imaging scans and photographs of target lesions from baseline.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Roswell Park Cancer Institute

Last Updated

April 23, 2021