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Genetically Engineered Cells (NY-ESO-1 TCR Engineered T Cells and HSCs) After Melphalan Conditioning Regimen in Treating Patients With Recurrent or Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

NCT03691376

Description:

This phase I trial studies the best dose and side effects of NY-ESO-1 T cell receptor (TCR) engineered T cells and how well they work with NY-ESO-1 TCR engineered hematopoietic stem cells (HSCs) after melphalan conditioning regimen in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent) or does not respond to treatment (refractory). The melphalan conditioning chemotherapy makes room in the patient's bone marrow for new blood cells and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR T cells and stem cells after the conditioning chemotherapy is intended to replace the immune system with new immune cells that have been redirected to attack and kill the cancer cells and thereby improve immune system function against cancer. Giving NY-ESO-1 TCR engineered T cells and HSCs after melphalan may work better in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Genetically Engineered Cells (NY-ESO-1 TCR Engineered T Cells and HSCs) After Melphalan Conditioning Regimen in Treating Patients With Recurrent or Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
  • Official Title: A Phase I, Open Label Study Evaluating the Safety and Efficacy of Adoptive Transfer of Autologous NY-ESO-1 CD8-TCR Engineered T Cells and NY-ESO-1 CD4-TCR Engineered Hematopoietic Stem Cells (HSC) After a Myeloablative Conditioning Regimen, With Administration of IL-2 in Patients With Recurrent or Treatment Refractory Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Clinical Trial IDs

  • ORG STUDY ID: i 287616
  • SECONDARY ID: NCI-2018-01758
  • SECONDARY ID: i 287616
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT03691376

Conditions

  • Platinum-Resistant Fallopian Tube Carcinoma
  • Platinum-Resistant Ovarian Carcinoma
  • Platinum-Resistant Primary Peritoneal Carcinoma
  • Platinum-Sensitive Fallopian Tube Carcinoma
  • Platinum-Sensitive Ovarian Carcinoma
  • Platinum-Sensitive Primary Peritoneal Carcinoma
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • Refractory Fallopian Tube Carcinoma
  • Refractory Ovarian Carcinoma
  • Refractory Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, recombinant human interleukin-2Treatment (autologous NY-ESO-1 engineered T and HSC)
Autologous NY-ESO-1-specific CD8-positive T LymphocytesTreatment (autologous NY-ESO-1 engineered T and HSC)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (autologous NY-ESO-1 engineered T and HSC)

Purpose

This phase I trial studies the best dose and side effects of NY-ESO-1 T cell receptor (TCR) engineered T cells and how well they work with NY-ESO-1 TCR engineered hematopoietic stem cells (HSCs) after melphalan conditioning regimen in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent) or does not respond to treatment (refractory). The melphalan conditioning chemotherapy makes room in the patient's bone marrow for new blood cells and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR T cells and stem cells after the conditioning chemotherapy is intended to replace the immune system with new immune cells that have been redirected to attack and kill the cancer cells and thereby improve immune system function against cancer. Giving NY-ESO-1 TCR engineered T cells and HSCs after melphalan may work better in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and feasibility of intravenous infusion of autologous peripheral
      blood mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) that have been
      genetically modified ex vivo to express NY-ESO-1 TCR, following a myeloablative conditioning
      regimen.

      Ia. Assessment of toxicities using Common Toxicity Criteria (CTC) and definition of a maximum
      tolerated dose (MTD).

      SECONDARY OBJECTIVES:

      I. TCR engineered hematopoietic stem cell (HSC) engraftment. II. Functional assays for TCR
      transgenic cells. III. Progression-free survival (PFS) (compare with the duration of the PFS
      in the last treatment regimen).

      IV. Durable tumor response in at least 30% of the patients defined as immune-related complete
      response (irCR) or immune-related partial response (irPR) by immune-related Response
      Evaluation Criteria in Solid Tumors (irRECIST) criteria at 6 months.

      V. Long-term persistence of TCR transgenic cells (regardless of cell origin) as evidenced by
      > 5% of CD3 lymphocytes being NY-ESO-1 specific by major histocompatibility complex (MHC)
      tetramer assay at 3 and 6 months.

      VI. Discrimination of TCR transgenic cells resulting from retrovirally-transduced mature
      lymphocytes and lentivirally-transduced HSCs and their phenotyping.

      VII. Long term monitoring for replication competent retrovirus and lentivirus. VIII. Analysis
      of viral insertion sites in long term persisting NY-ESO-1 TCR clones: absence of a clonal
      expansion of TCR transgenic cells with a particular transgene insertion site (defined as a
      clone comprising > 20% of all PBSC-derived gene-marked cells).

      IX. Gut microbiota pre and post treatment to evaluate the role of microbiota on the
      therapeutic efficacy of the proposed therapy.

      OUTLINE: This is a dose-escalation study of autologous NY-ESO-1-specific CD8-positive T
      lymphocytes.

      Patients receive melphalan intravenously (IV) over 30 minutes on day -1. Patients then
      receive autologous NY-ESO-1 CD4-TCR CD34+ HSC IV on day 0 and autologous NY-ESO-1-specific
      CD8-positive T lymphocytes IV between days 7 and 21. Patients also receive aldesleukin
      subcutaneously (SC) twice daily (BID) for 14 days on the following day after the T cell
      infusion (between days 8 and 22).

      After completion of study treatment, patients are followed up every 6 months for 5 years,
      then annually for up to 15 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (autologous NY-ESO-1 engineered T and HSC)ExperimentalPatients receive melphalan IV over 30 minutes on day -1. Patients then receive autologous NY-ESO-1 CD4-TCR CD34+ HSC IV on day 0 and autologous NY-ESO-1-specific CD8-positive T lymphocytes IV between days 7 and 21. Patients also receive aldesleukin SC BID for 14 days on the following day after the T cell infusion (between days 8 and 22).
  • Aldesleukin
  • Autologous NY-ESO-1-specific CD8-positive T Lymphocytes
  • Melphalan

Eligibility Criteria

        Inclusion Criteria:

          -  Must have a diagnosis of platinum-sensitive or platinum-resistant recurrent or
             refractory epithelial ovarian, primary peritoneal or fallopian tube carcinoma and have
             progressed, relapsed, or recurred through at least one or more prior lines of
             standard-of-care therapies. For platinum sensitive patients, the standard of care
             therapies include additional platinum-containing regimens and bevacizumab

          -  Have been informed of other treatment options

          -  Must be HLA- A*02.1 and HLA-DP*04 positive. Retesting is not required for patients who
             have previous documented positivity

          -  Patient's tumor must be positive by histological or molecular assay for NY-ESO-1

          -  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 Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1

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

          -  Since the study drug may affect pregnancy since it targets proteins present during
             development, women of childbearing potential are requested to use acceptable methods
             of birth control for the duration of the study and until persistence of the study drug
             is no longer detected in the patient by polymerase chain reaction (PCR). 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 >= 1.5 x 10^9/L

          -  Platelets >= 100 x 10^9/L

          -  Total bilirubin within normal institutional limits

          -  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 upper limit of normal (ULN); if creatinine level > 2 x ULN, then
             creatinine clearance must be > 60 mL/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

          -  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

        Exclusion Criteria:

          -  Patients may not be receiving any other investigational agents

          -  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

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to 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 and topical steroids are not
                  exclusionary. If subjects are prescribed a brief course of oral corticosteroids,
                  the use should be limited to less than 7 days. Use of steroids before apheresis
                  and immune assessment blood draws should be discouraged as it will affect white
                  blood cell function

          -  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 chemo-conditioning used and the unknown risks associated
             with viral replication

               -  Positive serology for HIV

               -  Active hepatitis B infection as determined by 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 reverse
                  transcriptase (RT) PCR or branched deoxyribonucleic 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 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 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 if 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 (FEV1)/forced vital capacity (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
Time Frame:Up to 9 months post infusion
Safety Issue:
Description:The frequency of toxicities will be tabulated by grade across all dose levels and cycles.

Secondary Outcome Measures

Measure:Change in Immunological parameters associated with T cell persistence
Time Frame:Baseline up to 15 years
Safety Issue:
Description:
Measure:Tumor response rates to treatment
Time Frame:Up to 15 years
Safety Issue:
Description:Based on the immune-related Response Evaluation Criteria in Solid Tumors criteria.
Measure:Progression-free survival
Time Frame:From start of the treatment until the first occurrence of confirmed progression, assessed up to 15 years
Safety Issue:
Description:Will calculate the median progression free survival and the corresponding 95% confidence interval.
Measure:Overall survival
Time Frame:From start of the treatment until death, assessed up to 15 years
Safety Issue:
Description:
Measure:Duration of response
Time Frame:Up to 15 years
Safety Issue:
Description:
Measure:Appearance of target antigen/major histocompatibility complex loss variants upon disease recurrence
Time Frame:Up to 15 years
Safety Issue:
Description:NY-ESO-1 expression will be evaluated by quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) and/or immunohistochemistry. HLA-A*0201 and -DP*04 expression on samples will be evaluated by immunohistochemistry.
Measure:Assessment of bioactivity
Time Frame:Baseline up to 15 years
Safety Issue:
Description:measure pre and post treatment percentage of selective migration into the tumor sites
Measure:Assessment of Immunological parameters associated with functionality
Time Frame:Baseline up to 15 years
Safety Issue:
Description:

Details

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

Last Updated

March 6, 2020