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

NCT03399448 | Terminated Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: UPCC# 25416; IRB #826672
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  5 years

Secondary Outcomes (5)

• Percentage of patients achieving complete response (CR) before or at Month 6

  6 months

• Overall survival (OS)

  5 years

• Duration of remission (DOR)

  5 years

• Progression- free survival (PFS)

  5 years

• Cause of death (COD) when appropriate

  5 years

Study Arms (3)

Multiple Myeloma (MM)

EXPERIMENTAL

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

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

EXPERIMENTAL

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

Melanoma

EXPERIMENTAL

Not Recruiting at the UPenn Site

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

Interventions

NY-ESO-1 redirected autologous T cells with CRISPR edited endogenous TCR and PD-1 BIOLOGICAL

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).

Melanoma; Multiple Myeloma (MM); Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)

Cyclophosphamide DRUG

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

Melanoma; Multiple Myeloma (MM); Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)

Fludarabine DRUG

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

Melanoma; Multiple Myeloma (MM); Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)

NY-ESO-1 expression testing DEVICE

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

Melanoma; Multiple Myeloma (MM); Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCL)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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:
• At least 3 prior regimens, which must have contained an alkylating agent, proteasome inhibitor, and immunomodulatory agent (IMiD) OR
• 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:
• Serum M-spike ≥ 0.5 g/dL\*
• hour (hr) urine M-spike ≥ 200mg
• Involved serum free light chain (FLC) ≥ 50 mg/L with abnormal ratio
• Measurable plasmacytoma on exam or imaging
• 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.

You may not qualify if:

• \. Pregnant or nursing (lactating) women.
• \. Have inadequate venous access for or contraindications to leukapheresis.
• \. Have any active and uncontrolled infection.
• \. Active hepatitis B or hepatitis C
• \. Human immunodeficiency virus (HIV) infection.
• \. Any uncontrolled medical or psychiatric disorder that would preclude participation as outlined.
• \. 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.
• \. 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.
• \. 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.
• \. Prior allogeneic stem cell transplant.
• \. 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.

Sponsors & Collaborators

• University of Pennsylvania: lead
• Parker Institute for Cancer Immunotherapy: collaborator
• Gilead Sciences: collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (3)

• Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL, Lancaster E, Mangan PA, Kulikovskaya I, Gupta M, Chen F, Tian L, Gonzalez VE, Xu J, Jung IY, Melenhorst JJ, Plesa G, Shea J, Matlawski T, Cervini A, Gaymon AL, Desjardins S, Lamontagne A, Salas-Mckee J, Fesnak A, Siegel DL, Levine BL, Jadlowsky JK, Young RM, Chew A, Hwang WT, Hexner EO, Carreno BM, Nobles CL, Bushman FD, Parker KR, Qi Y, Satpathy AT, Chang HY, Zhao Y, Lacey SF, June CH. CRISPR-engineered T cells in patients with refractory cancer. Science. 2020 Feb 28;367(6481):eaba7365. doi: 10.1126/science.aba7365. Epub 2020 Feb 6.

  PMID: 32029687 RESULT

• Tsuchida CA, Brandes N, Bueno R, Trinidad M, Mazumder T, Yu B, Hwang B, Chang C, Liu J, Sun Y, Hopkins CR, Parker KR, Qi Y, Hofman L, Satpathy AT, Stadtmauer EA, Cate JHD, Eyquem J, Fraietta JA, June CH, Chang HY, Ye CJ, Doudna JA. Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells. Cell. 2023 Oct 12;186(21):4567-4582.e20. doi: 10.1016/j.cell.2023.08.041. Epub 2023 Oct 3.

  PMID: 37794590 DERIVED

• Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.

  PMID: 31215818 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Melanoma; Sarcoma, Synovial; Liposarcoma, Myxoid

Interventions

Cyclophosphamide; fludarabine

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Liposarcoma; Neoplasms, Adipose Tissue

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Edward Stadtmauer, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2017
• First Posted: January 16, 2018
• Study Start: September 5, 2018
• Primary Completion: February 29, 2020
• Study Completion: October 9, 2020
• Last Updated: June 22, 2023

Record last verified: 2020-10

Locations

US (1)