Genetically Engineered PBMC and PBSC Expressing NY-ESO-1 TCR After a Myeloablative Conditioning Regimen to Treat Patients With Advanced Cancer

NCT03240861 | Terminated Phase 1 DMC FDA Drug

• 3 other identifiers: 15-000511NCI-2017-00896Ribas NYESO SCT Cancer
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I clinical trial evaluates the safety and feasibility of administering NY-ESO-1 TCR (T cell receptor)engineered peripheral blood mononuclear cells (PBMC) and peripheral blood stem cells (PBSC) after a myeloablative conditioning regimen to treat patients with cancer that has spread to other parts of the body. The conditioning chemotherapy makes room in the patient?s bone marrow for new blood cells (PBMC) and blood-forming cells (stem cells) to grow. Giving NY-ESO-1 TCR PBMC 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.

Conditions

HLA-A*0201 Positive Cells Present; Locally Advanced Malignant Neoplasm; NY-ESO-1 Positive; Unresectable Malignant Neoplasm; Sarcoma

Keywords

T cells; stem cells; gene therapy; NYESO; Sarcoma

Outcome Measures

Primary Outcomes (1)

• Incidence of dose limiting toxicity

  Safety will be assessed by monitoring and recording potential adverse effects of the treatment using the Common Toxicity Criteria at each study visit. Subjects will be monitored by medical histories, physical examinations and blood studies to detect potential toxicities from the treatment. If there are no dose limiting toxicities observed, the cohort will be expanded to 12 subjects. If 1/3 are observed, up to 6 subjects will be recruited. If less than 2/6 are observed, the cohort will be expanded to a total of 12 subjects. If a dose limiting toxicity is observed in 2 or more of 6 subjects, the

  Up to 90 days

Secondary Outcomes (11)

• Detection of replication competent retrovirus and replication competent lentivirus

  Up to 12 months post cell administration

• Duration of overall complete response

  From the time measurement criteria has been first met for complete response until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years

• Duration of overall response

  From the time measurement criteria is met for complete response/partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 15 years

• Persistence of transduced T cells

  Time Frame: Up to 2 years after transgenic cell adoptive transfer

• Engraftment and persistence of transduced progeny T cells

  Time Frame: Up to 2 years after transgenic cell adoptive transfer

Other Outcomes (1)

• Regional uptake of 18F-FHBG within metastatic tumor sites and secondary lymphoid organs

  Up to 15 years

Study Arms (1)

Treatment (Genetically engineered PBMC and PBSC)

EXPERIMENTAL

G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF SC on mobilization days 1-8 and plerixafor SC on mobilization days 4-7. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells. CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan IV on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2. Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin SC BID for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive 18F-FHBG IV, and after 1 hour, undergo PET/CT on days 25 and 120.

Other: 18F-FHBG; Biological: Aldesleukin; Drug: Busulfan; Biological: Cellular Therapy; Procedure: Computed Tomography; Biological: Filgrastim; Drug: Fludarabine; Procedure: Leukapheresis; Drug: Plerixafor; Procedure: Positron Emission Tomography

Interventions

18F-FHBG OTHER

Given IV

Also known as: Reporter Probe 18F-FHBG

Treatment (Genetically engineered PBMC and PBSC)

Aldesleukin BIOLOGICAL

Given SC

Also known as: 125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2

Treatment (Genetically engineered PBMC and PBSC)

Busulfan DRUG

Given IV

Also known as: 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508

Treatment (Genetically engineered PBMC and PBSC)

Cellular Therapy BIOLOGICAL

Given LV-NYESO TCR/sr39TK PBSC IV and RV-NYESO TCR PBMC IV

Also known as: Cell Therapy

Treatment (Genetically engineered PBMC and PBSC)

Computed Tomography PROCEDURE

Undergo PET/CT

Also known as: CAT, CAT Scan, Computerized Axial Tomography, Computerized Tomography, CT, CT SCAN, tomography

Treatment (Genetically engineered PBMC and PBSC)

Filgrastim BIOLOGICAL

Given SC

Also known as: Filgrastim XM02, Filgrastim-sndz, G-CSF, Granix, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tbo-filgrastim, Tevagrastim, Zarxio

Treatment (Genetically engineered PBMC and PBSC)

Fludarabine DRUG

Given IV

Also known as: Fluradosa

Treatment (Genetically engineered PBMC and PBSC)

Leukapheresis PROCEDURE

Undergo leukapheresis

Also known as: Leukocytopheresis, Therapeutic Leukopheresis

Treatment (Genetically engineered PBMC and PBSC)

Plerixafor DRUG

Given SC

Also known as: AMD 3100, JM-3100, Mozobil, SDZ SID 791

Treatment (Genetically engineered PBMC and PBSC)

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET SCAN, Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging

Treatment (Genetically engineered PBMC and PBSC)

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Stage IV or locally advanced unresectable cancers for which no alternative therapies with proven survival advantage are available
• NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commercially available NY-ESO-1 antibodies
• HLA-A\*0201 (HLA-A2.1) positivity by molecular subtyping
• Age greater than or equal to 16 years old; if patients 16-17 years old are enrolled in the trial, they will only be enrolled after 3 patients \>= 18 years old have been treated, and the treatment has been shown to be safe
• A minimum of one measurable lesion defined as:
• Meeting the criteria for measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
• Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be accurately measured and recorded by color photography with a ruler to document the size of the target lesion(s)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Adequate bone marrow and major organ function to undergo a PBSC transplant determined within 30-60 days prior to enrollment using standard phase 1 criteria for organ function defined as:
• Absolute neutrophil count (ANC) \>= 1.5 x 10\^9 cells/L
• Platelets \>= 100 x 10\^9/L
• Hemoglobin \>= 9 g/dL
• Aspartate and alanine aminotransferases (AST, ALT) =\< 2.5 x ULN (upper limit of normal) (=\< 5 x ULN, if documented liver metastases are present)
• Total bilirubin =\< 2 x ULN (except patients with documented Gilbert?s syndrome)
• Creatinine \< 2 mg/dl (or a glomerular filtration rate \> 60)

You may not qualify if:

• Inability to purify \>= 2.5 x 10\^6 CD34-enriched cells/kg of patient weight from the pooled G-CSF mobilized leukapheresis products
• Previously known hypersensitivity to any of the agents used in this study; known sensitivity to busulfan or fludarabine
• Received systemic treatment for cancer, including immunotherapy, within 28 days prior to initiation of conditioning chemotherapy administration within this protocol
• Potential requirement for systemic corticosteroids or concurrent immunosuppressive drugs based on prior history or received systemic steroids within the last 2 weeks prior to enrollment (inhaled or topical steroids at standard doses are allowed)
• Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired immune deficiency state, which would increase the risk of opportunistic infections and other complications during chemotherapy-induced lymphodepletion; if there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist
• Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would increase the likelihood of hepatic toxicities from the chemotherapy conditioning regimen and supportive treatments; if there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist
• Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol
• Pregnancy or breast-feeding; female patients must be surgically sterile or be postmenopausal for two years, or must agree to use effective contraception during the period of treatment and for 6 months afterwards; all female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 14 days from starting the conditioning chemotherapy; the definition of effective contraception will be based on the judgment of the study investigators
• Since IL-2 is administered following cell infusion:
• Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence of ischemia on a cardiac stress test (stress thallium, stress multigated acquisition \[MUGA\], dobutamine echocardiogram or other stress test)
• Similarly, patients with a baseline left ventricular ejection fraction (LVEF) \< 45% will be excluded.
• Patients with ECG results of any conduction delays (PR interval \> 200 ms, corrected QT \[QTC\] \> 480 ms), sinus bradycardia (resting heart rate \< 50 beats per minute), sinus tachycardia (heart rate \>120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as \> 20 premature ventricular contractions \[PVCs\] per minute), ventricular tachycardia or 3rd degree heart block will be excluded from the study unless cleared by a cardiologist
• Patients with pulmonary function test abnormalities as evidenced by a (forced expiratory volume 1 \[FEV1\]/forced vital capacity \[FVC \] \< 70% of predicted for normality will be excluded
• Bone marrow involvement based on PET/CT scan at screening
• Active or recent herpes simplex virus (HSV) infection or cytomegalovirus (CMV) based on symptoms with positive swab culture and/or positive IgM (immunoglobulin M) screening

Sponsors & Collaborators

• Jonsson Comprehensive Cancer Center: lead
• California Institute for Regenerative Medicine (CIRM): collaborator

Study Sites (1)

UCLA / Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Related Publications (1)

• Nowicki TS, Deen NNA, Peters CW, Comin-Anduix B, Medina E, Puig-Saus C, Carretero IB, Kaplan-Lefko P, Macabali MH, Garcilazo IP, Chen D, Pang J, Berent-Maoz B, Haile S, Rodriguez J, Kawakami M, Kidd CK, Champhekar A, Carlucci G, Vega-Crespo A, Chmielowski B, Singh A, Federman N, Schiller GM, Larson SJ, Allen-Auerbach M, Klomhaus AM, Zack J, Baltimore D, Yang L, Kohn DB, Witte ON, Ribas A. Human cancer-targeted immunity via transgenic hematopoietic stem cell progeny. Nat Commun. 2025 Jul 1;16(1):5599. doi: 10.1038/s41467-025-60816-z.

  PMID: 40593578 DERIVED

MeSH Terms

Conditions

Sarcoma

Interventions

9-(4-fluoro-3-hydroxymethylbutyl)guanine; aldesleukin; Busulfan; Cell- and Tissue-Based Therapy; Filgrastim; Granulocyte Colony-Stimulating Factor; fludarabine; Leukapheresis; plerixafor; ferric pyrophosphate; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Biological Therapy; Therapeutics; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Cytapheresis; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Theodore Scott Nowicki, M.D.

  UCLA / Jonsson Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2017
• First Posted: August 7, 2017
• Study Start: July 26, 2017
• Primary Completion: October 19, 2023
• Study Completion: October 19, 2023
• Last Updated: November 1, 2023

Record last verified: 2023-10

Locations

US (1)