Gene-Modified T Cells, Vaccine Therapy, and Ipilimumab in Treating Patients With Locally Advanced or Metastatic Malignancies

NCT02070406 | Terminated Phase 1 DMC

• 3 other identifiers: 13-001624NCI-2014-00221P30CA016042
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

This pilot phase I trial studies the side effects of taking ipilimumab after gene-modified T cells and vaccine therapy when treating patients with advanced cancer that has spread to other areas of the body and has not responded to standard therapies. This trial also will determine the best dose of Ipilimumab to use in this combination treatment. T cells are a special type of white blood cell (immune cell) that have the ability to kill cancer cells. T cells are taken from the blood and modified in the laboratory to recognize a specific protein expressed on cancer cells, called NY-ESO-1. This may allow the T cells to target and kill cancer cells that express that protein. Dendritic cells are another type of blood cell that can teach other cells in the body to look for cancer cells and attack them. Giving a dendritic cell vaccine with the NY-ESO-1 protein may help dendritic cells teach the immune system to target cancer cells expressing that protein, and further help the T cells attack cancer. Ipilimumab is a monoclonal antibody, a type of drug manufactured in the laboratory that is similar to antibodies made in the human body that fight off infection. Ipilimumab blocks a protein that turns down the immune system, so blocking this protein may make the immune system more active. This may increase the ability of immune cells to kill cancer cells and improve the effectiveness of the T cell transplant. Giving gene-modified T-cells, a dendritic cell vaccine, and ipilimumab together may teach the immune system to recognize and kill cancer cells that have the NY-ESO-1 protein.

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Outcome Measures

Primary Outcomes (2)

• Incidence of toxicity as defined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0

  Simple descriptive statistics will be used to summarize toxicities observed after each TCR transgenic cell infusion in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by toxicity table) and nadir or maximum values for the laboratory measures, time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented, as well.

  Up to 5 years

• Maximum tolerable dose (MTD) based on the number of subjects experiencing dose limiting toxicities (DLTs)

  Adverse events are defined following the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3.0.

  60 days

Secondary Outcomes (4)

• Feasibility of NY-ESO-1 TCR cells, determined by incidence of preparation not meeting the lot release criteria

  1 month

• Transgenic cell persistence, analyzed using immune monitoring and molecular techniques

  Up to 5 years

• NY-ESO-1 TCR transgenic cell tumor trafficking (imaging), assessed using 18F-FDG PET

  Up to 60 days after ACT

• Antitumor activity, assessed using RECIST

  Up to day 90

Study Arms (1)

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

EXPERIMENTAL

CONDITIONING CHEMOTHERAPY REGIMEN: Patients receive cyclophosphamide IV on days -5 and -4 and fludarabine phosphate IV over 30 minutes daily on days -4 to -1. NY-ESO-1 TCR PBMC INFUSION: Patients receive NY-ESO-1 reactive TCR retroviral vector transduced autologous T cells IV on day 0. IPILIMUMAB ADMINISTRATION: Patients receive ipilimumab IV over 90 minutes before the NY-ESO-1 TCR PBMC infusion on day 0 or after the infusion on day 1. Treatment repeats every 3 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity. NY-ESO-1(157-165) PEPTIDE PULSED DC ADMINISTRATION: Patients receive NY-ESO-1(157-165) peptide pulsed DC vaccine ID on days 1, 14, and 30. LOW DOSE IL-2 ADMINISTRATION: Patients receive aldesleukin (IL-2) SC BID on days 1-14.

Drug: cyclophosphamide; Drug: fludarabine phosphate; Biological: NY-ESO-1 reactive TCR retroviral vector transduced autologous PBL; Biological: dendritic cell vaccine therapy; Biological: aldesleukin; Radiation: fludeoxyglucose F 18; Procedure: positron emission tomography; Other: laboratory biomarker analysis

Interventions

cyclophosphamide DRUG

Given IV

Also known as: CPM, CTX, Cytoxan, Endoxan, Endoxana

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

fludarabine phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, Beneflur, Fludara

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

NY-ESO-1 reactive TCR retroviral vector transduced autologous PBL BIOLOGICAL

Given NY-ESO-1 reactive TCR retroviral vector transduced autologous T cells IV

Also known as: anti-NY-ESO-1 TCR gene-engineered lymphocytes, anti-NY-ESO-1 TCR retroviral vector-transduced lymphocytes

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

dendritic cell vaccine therapy BIOLOGICAL

NY-ESO-1157-165 peptide pulsed DC vaccine given ID

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

aldesleukin BIOLOGICAL

Given SC

Also known as: IL-2, Proleukin, recombinant human interleukin-2, recombinant interleukin-2

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

fludeoxyglucose F 18 RADIATION

Correlative studies

Also known as: 18FDG, FDG

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

positron emission tomography PROCEDURE

Correlative studies

Also known as: FDG-PET, PET, PET scan, tomography, emission computed

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (gene-modified T-cells, vaccine therapy, ipilimumab)

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 cancers for which no alternative therapies with proven survival advantage are available
• At least 1 lesion amenable for outpatient biopsies; this should be a cutaneous or palpable metastatic site or a deeper site accessible by image-guided biopsy that is deemed safe to access by the treating physicians and interventional radiologists; patients without accessible lesions for biopsy but with prior tissue available from metastatic disease would be eligible at the investigator's discretion
• NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commonly available NY-ESO-1 antibodies
• Human leukocyte antigen (HLA)-A\*0201 (HLA-A2.1) positivity by molecular subtyping
• Life expectancy greater than 3 months assessed by a study physician
• 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)
• No restriction based on prior treatments
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Absolute neutrophil count \>= 1.5 x 10\^9 cells/L
• Platelets \>= 100 x 10\^9/L
• Hemoglobin \>= 10 g/dL
• Aspartate and alanine aminotransferases (AST, ALT) =\< 2.5 x upper limit of normal (ULN) (=\< 5 x ULN, if documented liver metastases are present)
• Total bilirubin =\< 2 x ULN (except patients with documented Gilbert's syndrome)

You may not qualify if:

• Previously known hypersensitivity to any of the agents used in this study
• Received systemic treatment for cancer, including immunotherapy, within one month prior to initiation of dosing within this protocol
• History of inflammatory bowel disease, celiac disease, or other chronic gastrointestinal conditions associated with diarrhea or bleeding, or current acute colitis of any origin
• Potential requirement for systemic corticosteroids or concurrent immunosuppressive drugs based on prior history or received systemic steroids within the last 4 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 6 months after; 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 or arrhythmias and have a left ventricular ejection fraction (LVEF) \< 45% on a cardiac stress test (stress thallium, stress multi gated acquisition (MUGA) scan, dobutamine echocardiogram, or other stress test)
• Similarly, patients who are 50 years old with a baseline LVEF \< 45% will be excluded
• Patients with ECG results of any conduction delays (PR interval \> 200 ms, corrected QT interval \[QTC\] \> 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 PVCs per minute), ventricular tachycardia, 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 of the lung in 1 second (FEV1)/forced vital capacity (FVC) \< 70% of predicted for normality will be excluded
• Evidence of diverticulitis at baseline, including evidence limited to computed tomography (CT) scan only

Sponsors & Collaborators

• Jonsson Comprehensive Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095, United States

Location

Related Publications (1)

• Nowicki TS, Berent-Maoz B, Cheung-Lau G, Huang RR, Wang X, Tsoi J, Kaplan-Lefko P, Cabrera P, Tran J, Pang J, Macabali M, Garcilazo IP, Carretero IB, Kalbasi A, Cochran AJ, Grasso CS, Hu-Lieskovan S, Chmielowski B, Comin-Anduix B, Singh A, Ribas A. A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab. Clin Cancer Res. 2019 Apr 1;25(7):2096-2108. doi: 10.1158/1078-0432.CCR-18-3496. Epub 2018 Dec 20.

  PMID: 30573690 DERIVED

MeSH Terms

Interventions

Cyclophosphamide; fludarabine phosphate; aldesleukin; Interleukin-2; Fluorodeoxyglucose F18; Magnetic Resonance Spectroscopy; 2-phenyl-6-(2'-(4'-(ethoxycarbonyl)thiazolyl))thiazolo(3,2-b)(1,2,4)triazole

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Deoxyglucose; Deoxy Sugars; Carbohydrates; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Antoni Ribas

  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: February 21, 2014
• First Posted: February 25, 2014
• Study Start: July 17, 2014
• Primary Completion: December 18, 2018
• Study Completion: December 18, 2018
• Last Updated: February 28, 2019

Record last verified: 2019-02

Locations

US (1)