Non-Viral TCR Gene Therapy

NCT04102436 | Withdrawn Phase 2 FDA Drug

• 2 other identifiers: 19014319-C-0143
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: A person s white blood cells can be modified in a lab to recognize certain changes in their tumor. Many of these cells are collected from the person, modified, then given back to the person. This may help treat some cancers. Objective: To learn if a person s white blood cells modified with T-cell receptors can cause solid tumors to shrink. Eligibility: People ages 18-70 who have cancer of the gastrointestinal tract, genitourinary tract, ovary, breast, or lung that has spread, or who have glioblastoma. Design: Participants will be screened and have their cells prepared for treatment in another protocol. Participants will be hospitalized one week before treatment. They will stay approximately 3 - 4 weeks after treatment. Participants will get the modified white blood cells and chemotherapy through an IV catheter, which is a small plastic tube inserted in a vein. Participants will take drugs by mouth to prevent infection. They will receive filgrastim as a shot or injection under the skin. Participants will have tests before, during, and after treatment: Heart, blood, and urine tests Chest X-ray Physical exam Scans: They will lie in a machine that takes pictures of the body. Possible apheresis: The participant s blood is removed through a needle in an arm. The blood goes through a machine that removes the white blood cells. The rest of the blood is returned through a needle in the other arm. Participants will have visits about 6 and 12 weeks after treatment. If they are responding to treatment, they will then have visits every 3-6 months for 3 years. Then they will join another study and be followed about 12 more years.

Conditions

Endocrine/Neuroendocrine; Non-Small Cell Lung Cancer; Breast Cancer; Gastrointestinal/Genitourinary Cancers; Ovarian Cancer

Keywords

Adoptive Cell Therapy; Cell Therapy; Immunotherapy; Gene Therapy

Outcome Measures

Primary Outcomes (1)

• Response rate

  Percentage of patients who have a clinical response to treatment (objective tumor regression)

  6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion

Secondary Outcomes (3)

• Phenotypic and functional characteristics of PBL

  2-4 years post cell infusion

• Safety and tolerance

  6 weeks (+/- 2 weeks) following administration of the cell product

• Immune monitoring

  6 weeks (+/-2 weeks) following administration of the cell product

Study Arms (1)

1/Sleeping Beauty

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Sleeping Beauty Transposed PBL + high- or low-dose aldesleukin.

Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Aldesleukin; Biological: Sleeping Beauty Transposed PBL

Interventions

Fludarabine DRUG

Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.

1/Sleeping Beauty

Cyclophosphamide DRUG

Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.

1/Sleeping Beauty

Aldesleukin DRUG

Aldesleukin 720,000 IU/kg or 72,000 IU/kg (based on total body weight) IV over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 10 doses).

1/Sleeping Beauty

Sleeping Beauty Transposed PBL BIOLOGICAL

Day 0: Cells are to be infused at a dose not to exceed 1.5e11 in 400 mL intravenously on the Patient Care Unit over 20-30 minutes or as clinically determined by an investigator for patient safety (between 2-4 days after the last dose of fludarabine).

1/Sleeping Beauty

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically confirmed solid cancer that falls into one of four cohorts:
• Gastrointestinal and genitourinary (Cohort 1),
• Breast and ovarian (Cohort 2),
• Non-small cell lung cancer (NSCLC), NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas (Cohort 3),
• Glioblastoma (Cohort 4)
• Patients must have evaluable or measurable disease per RECIST 1.1 with at least one lesion that is resectable for TIL generation with minimal morbidity plus at least one other lesion that can be measured. Metastatic disease is required for Cohorts 1-3 but is not required for Cohort 4.
• Patients must have:
• previously received standard systemic therapy for their advanced cancer and have been either non-responders or have recurred, specifically:
• Patients with metastatic colorectal cancer must have received oxaliplatin or irinotecan (or similar agents)
• Patients with breast and ovarian cancer must be refractory to first-line treatments
• Patients with lung cancer must have received at least one platinum-based chemotherapy regimen and at least one FDA-approved targeted treatment (when appropriate)
• Patients with glioblastoma must have progression of disease after radiotherapy (including patients that undergo surgery for recurrent disease and are rendered NED). This includes recurrent GBM after receiving all standard first-line treatment, including surgery (if feasible due to neurosurgical and neuro- anatomical considerations) and adjuvant radiotherapy +/- chemotherapy. OR
• declined standard treatment
• For Cohorts 1-3: Patients with 3 or fewer brain metastases that are \< 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
• For Cohort 3: Patients must have documented FEV1 \> 60% predicted.

You may not qualify if:

• Pregnant women are excluded from this study because study treatment s potential for teratogenic or abortifacient effects is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study therapy, breastfeeding should be discontinued if the mother is treated on this trial.
• Concurrent systemic steroid therapy, except for patients with glioblastoma (Cohort 4).
• Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active or uncompensated major medical illnesses.
• For Cohort 3: Any major bronchial occlusion or bleeding not amenable to palliation.
• For Cohort 4: Clinically significant hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding six months that were not related to glioma surgery.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune- competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
• History of coronary revascularization or ischemic symptoms.
• Documented LVEF less than or equal to 45% tested in patients:
• Age greater than or equal to 65 years
• With clinically significant atrial and/or ventricular arrhythmias, including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block, or have a history of ischemic heart disease and/or chest pain.
• Documented FEVl less than or equal to 50% predicted tested in patients with:
• A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history within the past two years).
• Symptoms of respiratory dysfunction.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Deniger DC, Switzer K, Mi T, Maiti S, Hurton L, Singh H, Huls H, Olivares S, Lee DA, Champlin RE, Cooper LJ. Bispecific T-cells expressing polyclonal repertoire of endogenous gammadelta T-cell receptors and introduced CD19-specific chimeric antigen receptor. Mol Ther. 2013 Mar;21(3):638-47. doi: 10.1038/mt.2012.267. Epub 2013 Jan 8.

  PMID: 23295945 BACKGROUND

• Ivics Z, Hackett PB, Plasterk RH, Izsvak Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997 Nov 14;91(4):501-10. doi: 10.1016/s0092-8674(00)80436-5.

  PMID: 9390559 BACKGROUND

• Maiti SN, Huls H, Singh H, Dawson M, Figliola M, Olivares S, Rao P, Zhao YJ, Multani A, Yang G, Zhang L, Crossland D, Ang S, Torikai H, Rabinovich B, Lee DA, Kebriaei P, Hackett P, Champlin RE, Cooper LJ. Sleeping beauty system to redirect T-cell specificity for human applications. J Immunother. 2013 Feb;36(2):112-23. doi: 10.1097/CJI.0b013e3182811ce9.

  PMID: 23377665 BACKGROUND

• Levy PL, Gros A. Fast track to personalized TCR T cell therapies. Cancer Cell. 2022 May 9;40(5):447-449. doi: 10.1016/j.ccell.2022.04.013. Epub 2022 May 9.

  PMID: 35537408 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Breast Neoplasms; Urogenital Neoplasms; Ovarian Neoplasms

Interventions

fludarabine; Cyclophosphamide; aldesleukin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

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

Study Officials

• Steven A Rosenberg, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2019
• First Posted: September 25, 2019
• Study Start: March 8, 2024
• Primary Completion: March 8, 2024
• Study Completion: March 8, 2024
• Last Updated: March 12, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)