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

ID: NCT03399448
Status: Recruiting
Phase: Phase 1
Start Date: February 01, 2018
First Submitted: December 20, 2017
Last Updated: February 20, 2018
Results: N/A
Sponsors & Collaborators: University of Pennsylvania
Location: United States
Conditions: Multiple Myeloma, Melanoma, Synovial Sarcoma, Myxoid/Round Cell Liposarcoma
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Study Description

Brief Summary

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.

Detailed Description

Condition or disease Intervention/treatment Phase

Melanoma

Multiple Myeloma

Myxoid/Round Cell Liposarcoma

Synovial Sarcoma

Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Other Names
Drug: Cyclophosphamide
Other Names
Drug: Fludarabine
Other Names
Device: NY-ESO-1 expression testing
Other Names
Phase 1

Tracking Information

First Submitted DateDecember 20, 2017
Last Update Posted DateFebruary 20, 2018
Anticipated Start DateFebruary 01, 2018
Anticipated Completion DateJanuary 01, 2033
Anticipated Primary Completion DateJanuary 01, 2033
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Evaluate Manufacturing Feasibility of NYCE T Cells. [Time Frame: 5 years]

    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.

  • 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]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Percentage of patients achieving complete response (CR) before or at Month 6 [Time Frame: 4 years]

  • Overall survival (OS) [Time Frame: 5 years]

  • Duration of remission (DOR) [Time Frame: 5 years]

  • Progression- free survival (PFS) [Time Frame: 5 years]

  • Cause of death (COD) when appropriate [Time Frame: 5 years]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleNY-ESO-1-redirected CRISPR (TCRendo and PD1) Edited T Cells (NYCE T Cells)
Official TitlePhase 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)
Brief Summary

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.

Detailed Description

Study TypeInterventional
Study PhasePhase 1
Estimated Enrollment
18
Allocation
Non-Randomized
Interventional Model
Parallel Assignment
Masking
None (Open Label)
Primary Purpose
Other
Conditions
Melanoma
Multiple Myeloma
Myxoid/Round Cell Liposarcoma
Synovial Sarcoma
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1

Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1 (NYCE T Cells).

Other Names
Drug: Cyclophosphamide

a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Other Names
Drug: Fludarabine

a chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Other Names
Device: NY-ESO-1 expression testing

Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Other Names
Study Groups/Cohorts
Multiple Myeloma (MM)

Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)

Melanoma
Not Recruiting at the UPenn Site

Study Arms
Experimental Melanoma
Not Recruiting at the UPenn Site
Biological : NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1 (NYCE T Cells).

Experimental Melanoma
Not Recruiting at the UPenn Site
Drug : Cyclophosphamide
a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Experimental Melanoma
Not Recruiting at the UPenn Site
Drug : Fludarabine
a chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Experimental Melanoma
Not Recruiting at the UPenn Site
Device : NY-ESO-1 expression testing
Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Experimental Multiple Myeloma (MM)
Device : NY-ESO-1 expression testing
Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Experimental Multiple Myeloma (MM)
Drug : Cyclophosphamide
a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Experimental Multiple Myeloma (MM)
Biological : NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1 (NYCE T Cells).

Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Biological : NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Autologous T cells transduced with a lentiviral vector to express NY-ESO-1 and electroporated with CRISPR guide RNA to disrupt expression of endogenous TCRα, TCRβ and PD-1 (NYCE T Cells).

Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Drug : Cyclophosphamide
a cytotoxic chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Device : NY-ESO-1 expression testing
Testing to determine if NY-ESO-1 is expressed on tumor tissue.

Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Drug : Fludarabine
a chemotherapy agent used for lymphodepletion prior to NYCE T cells.

Arm Intervention/Treatment
Experimental Melanoma
Not Recruiting at the UPenn Site
Biological : NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Experimental Melanoma
Not Recruiting at the UPenn Site
Drug : Cyclophosphamide
Experimental Melanoma
Not Recruiting at the UPenn Site
Drug : Fludarabine
Experimental Melanoma
Not Recruiting at the UPenn Site
Device : NY-ESO-1 expression testing
Experimental Multiple Myeloma (MM)
Device : NY-ESO-1 expression testing
Experimental Multiple Myeloma (MM)
Drug : Cyclophosphamide
Experimental Multiple Myeloma (MM)
Biological : NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Biological : NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1
Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Drug : Cyclophosphamide
Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Device : NY-ESO-1 expression testing
Experimental Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)
Drug : Fludarabine

Recruitment Information

Recruitment Status:Recruiting
Enrollment18
Completion DateJanuary 01, 2033
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.
3. 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 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 enrollment.

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.
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
United States

Administrative Information

NCT Number:NCT03399448
Other Study ID Numbers
UPCC# 25416; IRB #826672
Has Data Monitoring CommitteeYes
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
University of Pennsylvania
Collaborators
Not Available
Investigators
Principal Investigator
Edward Stadtmauer, MD
University of Pennsylvania