Clinical Trials /

NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells)

NCT03399448

Description:

This is a first-in-human trial proposed to test HLA-A*0201 restricted NY-ESO-1 redirected T cells with edited endogenous T cell receptor and PD-1.

Related Conditions:
  • Melanoma
  • Multiple Myeloma
  • Myxoid Liposarcoma
  • Synovial Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: NY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells)
  • Official Title: Phase 1 Trial of Autologous T Cells Engineered to Express NY-ESO-1 TCR and CRISPR Gene Edited to Eliminate Endogenous TCR and PD-1 (NYCE T Cells)

Clinical Trial IDs

  • ORG STUDY ID: UPCC# 25416; IRB #826672
  • NCT ID: NCT03399448

Conditions

  • Multiple Myeloma
  • Melanoma
  • Synovial Sarcoma
  • Myxoid/Round Cell Liposarcoma

Interventions

DrugSynonymsArms
NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1Multiple Myeloma (MM)
CyclophosphamideMultiple Myeloma (MM)
FludarabineMultiple Myeloma (MM)

Purpose

This is a first-in-human trial proposed to test HLA-A*0201 restricted NY-ESO-1 redirected T cells with edited endogenous T cell receptor and PD-1.

Trial Arms

NameTypeDescriptionInterventions
Multiple Myeloma (MM)Experimental
  • NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
  • Cyclophosphamide
  • Fludarabine
Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)Experimental
  • NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
  • Cyclophosphamide
  • Fludarabine
MelanomaExperimentalNot Recruiting at the UPenn Site
  • NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Inclusion Criteria:

        - 1. Subjects with a confirmed diagnosis of relapsed refractory multiple myeloma (MM),
        melanoma, synovial sarcoma, or myxoid/round cell liposarcoma (MRCL) as follows:

        a. Multiple Myeloma i. Subjects must have a confirmed prior diagnosis of active MM as
        defined by the International Myeloma Working Group (IMWG) criteria.

        ii. Subjects must have relapsed or refractory disease after either one of the following:

          1. At least 3 prior regimens, which must have contained an alkylating agent, proteasome
             inhibitor, and immunomodulatory agent (IMiD) OR

          2. At least 2 prior regimens if "double-refractory" to a proteasome inhibitor and IMiD,
             defined as progression on or within 60 days of treatment with these agents.

        Note: Induction therapy, stem cell transplant, and maintenance therapy, if given
        sequentially without intervening progression, should be considered as 1 "regimen".

        iii. Subjects must be at least 90 days since autologous stem cell transplant, if performed.

        iv. Toxicities from prior therapies, with the exception of alopecia or peripheral
        neuropathy attributable to bortezomib, must have recovered to grade ≤ 2 according to the
        Common Toxicity Criteria (CTCAE) 4.0 criteria or to the subject's prior baseline.

        v. Subjects must have measurable disease per IMWG criteria on study entry, which must
        include at least 1 of the following:

          1. Serum M-spike ≥ 0.5 g/dL*

          2. 24 hour (hr) urine M-spike ≥ 200mg

          3. Involved serum free light chain (FLC) ≥ 50 mg/L with abnormal ratio

          4. Measurable plasmacytoma on exam or imaging

          5. Bone marrow plasma cells ≥ 20%

               -  Note: Patients with IgA myeloma in whom serum protein electrophoresis is deemed
                  unreliable, due to co-migration of normal serum proteins with the paraprotein in
                  the beta region, may be considered eligible as long as total serum IgA level is
                  elevated above normal range.

                  b. Melanoma i. Subjects must have a confirmed prior diagnosis of melanoma. ii.
                  Progressed after at least 2 therapy lines. iii. Subjects with BRAF mutant tumors
                  should have received and progressed through, or are intolerant to, BRAF/MEK
                  inhibitor therapy prior to enrollment iv. Patients must have measurable disease
                  per RECIST 1.1 in order to allow assessment of an anti-tumor response.

                  c. Synovial Sarcoma or Myxoid/Round Cell Liposarcoma (MRCL) i. Subjects must have
                  a confirmed prior diagnosis of synovial sarcoma or MRCL. ii. Patients with proven
                  metastatic disease or surgically inoperable local recurrence that have failed
                  first line treatment.

        iii. Patients must have measurable disease per RECIST 1.1 in order to allow assessment of
        an anti-tumor response.

          -  2. Provides written, informed consent.

          -  3. Subjects ≥ 18 years of age.

          -  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          -  5. Documented NY-ESO-1 and/or LAGE-1 expression on tumor tissue.

          -  6. HLA-A*201 positive

          -  7. Subjects of reproductive potential must agree to use acceptable birth control
             methods, as described in protocol Section 4.3.

          -  8. Adequate vital organ function as defined by:

               1. Serum creatinine ≤ 2.5 or estimated creatinine clearance ≥30 ml/min and not
                  dialysis-dependent.

               2. Absolute neutrophil count ≥1000/μl and platelet count ≥50,000/μl (≥30,000/μl if
                  bone marrow plasma cells are ≥50% of cellularity for MM patients).

               3. Serum glutamic oxaloacetic transaminase (SGOT) ≤ 3x the upper limit of normal and
                  total bilirubin ≤ 2.0 mg/dl (except for patients in whom hyperbilirubinemia is
                  attributed to Gilbert's syndrome).

               4. Left ventricular ejection fraction (LVEF) ≥ 45%. LVEF assessment must have been
                  performed within 8 weeks of eligibility confirmation by physician-investigator.

        Exclusion Criteria:

          -  1. Pregnant or nursing (lactating) women.

          -  2. Have inadequate venous access for or contraindications to leukapheresis.

          -  3. Have any active and uncontrolled infection.

          -  4. Active hepatitis B or hepatitis C

          -  5. Human immunodeficiency virus (HIV) infection.

          -  6. Any uncontrolled medical or psychiatric disorder that would preclude participation
             as outlined.

          -  7. New York Heart Association (NYHA) Class III or IV heart failure, unstable angina,
             or a history of recent (within 6 months) myocardial infarction or sustained (>30
             seconds) ventricular tachyarrhythmias.

          -  8. Received prior gene therapy or gene-modified cellular immunotherapy. Subject may
             have received, however, non-gene-modified autologous T-cells in association with an
             anti-myeloma vaccine (e.g., hTERT or MAGEA3) or vaccination against infectious agents
             (e.g., influenza or pneumococcus) as was performed on our previous studies.

          -  9. Active auto-immune disease, including connective tissue disease, uveitis,
             sarcoidosis, inflammatory bowel disease, or multiple sclerosis, or have a history of
             severe (as judged by the principal investigator) autoimmune disease requiring
             prolonged immunosuppressive therapy.

          -  10. Prior allogeneic stem cell transplant.

          -  11. Prior or active central nervous system (CNS) involvement (e.g. leptomeningeal
             disease, parenchymal masses) with myeloma. Screening for this (e.g. with lumbar
             puncture) is not required unless suspicious symptoms or radiographic findings are
             present. Subjects with calvarial disease that extends intracranially and involves the
             dura will be excluded, even if cerebrospinal fluid (CSF) is negative for myeloma.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine safety profile of a single infusion of NYCE T cells by monitoring the frequency and severity of adverse events assessed by the National Cancer Institute (NCI) - Common Toxicity Criteria (v4.03)
Time Frame:5 years
Safety Issue:
Description:Evaluate the percentage of manufacturing products that do not meet release criteria for vector transduction efficiency, gene disruption T cell product purity, viability, sterility or due to tumor contamination.

Secondary Outcome Measures

Measure:Percentage of patients achieving complete response (CR) before or at Month 6
Time Frame:4 years
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:5 years
Safety Issue:
Description:
Measure:Duration of remission (DOR)
Time Frame:5 years
Safety Issue:
Description:
Measure:Progression- free survival (PFS)
Time Frame:5 years
Safety Issue:
Description:
Measure:Cause of death (COD) when appropriate
Time Frame:5 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Pennsylvania

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