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

Phase 1

Terminated

• Conditions: Myxoid/Round Cell Liposarcoma; Multiple Myeloma; Melanoma; Synovial Sarcoma
• Interventions: Biological: NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1; Drug: Cyclophosphamide; Drug: Fludarabine; Device: NY-ESO-1 expression testing

• Registration Number: NCT03399448
• Lead Sponsor: University of Pennsylvania

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

Not available

Study Timeline

• Study First Submitted: 2017-12-20
• Study First Submitted QC: 2018-01-08
• Study First Posted: 2018-01-16
• Study Start: 2018-09-05
• Primary Completion: 2020-02-29
• Status Verified: 2020-10
• Study Completion: 2020-10-09
• Last Update Submitted: 2023-06-20
• Last Update Posted: 2023-06-22

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 3

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.

3. Adequate vital organ function as defined by:

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

5. 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).

6. 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).

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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)	5 years
Evaluate Manufacturing Feasibility of NYCE T Cells.	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.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	5 years
Progression- free survival (PFS)	5 years
Duration of remission (DOR)	5 years
Percentage of patients achieving complete response (CR) before or at Month 6	6 months
Cause of death (COD) when appropriate	5 years

Trial Locations

Locations (1)

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States