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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03017131
Recruitment Status : Recruiting
First Posted : January 11, 2017
Last Update Posted : March 2, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Biological: Aldesleukin Drug: Cyclophosphamide Drug: Decitabine Biological: Genetically Engineered NY-ESO-1-specific T Lymphocytes Other: Laboratory Biomarker Analysis Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 8, 2017
Estimated Primary Completion Date : December 8, 2020
Estimated Study Completion Date : December 8, 2021


Arm Intervention/treatment
Experimental: Treatment (decitabine, genetically modified T cells)
COURSE 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..
Biological: Aldesleukin
Given SC
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2

Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-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- 138719

Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2'-deoxycytidine
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Biological: Genetically Engineered NY-ESO-1-specific T Lymphocytes
Given IV and IP

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. 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 ]
    The frequency of toxicities will be tabulated by grade across all dose levels and cycles.


Secondary Outcome Measures :
  1. Appearance of target antigen/major histocompatibility complex loss variants upon disease recurrence [ Time Frame: Up to 15 years ]
    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.

  2. Clinical response rates [ Time Frame: Up to 15 years ]
    Percentage of complete and partial responses and the corresponding 95% confidence interval will be calculated.

  3. Duration of response [ Time Frame: Up to 15 years ]
    Will be observed.

  4. Immunological parameters associated with T cell persistence, bioactivity and functionality [ Time Frame: Up to 15 years ]
    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.

  5. Overall survival [ Time Frame: Up to 15 years ]
    Will be observed.

  6. Progression free survival [ Time Frame: Up to 15 years ]
    The median progression free survival and the corresponding 95% confidence interval will be calculated.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03017131


Locations
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United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Roswell Park    877-275-7724    ASKRPCI@roswellpark.org   
Principal Investigator: Kunle Odunsi         
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Kunle Odunsi Roswell Park Cancer Institute

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Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT03017131    
Other Study ID Numbers: i 283616
NCI-2016-01477 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
i 283616 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
P50CA159981 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2017    Key Record Dates
Last Update Posted: March 2, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Aldesleukin
Cyclophosphamide
Decitabine
Interleukin-2
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Enzyme Inhibitors
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents