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Phase I/II Study of Autologous T Cells to Express T-Cell Receptors (TCRs) in Subjects With Solid Tumors

2022-04-04

2024-11-30

2024-11-30

180

Study Overview

Phase I/II Study of Autologous T Cells to Express T-Cell Receptors (TCRs) in Subjects With Solid Tumors

A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors

A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors. An HLA Typing and Tumor Neoantigen Mutation Testing Protocol (Protocol # TCR001-002) has been used to identify patients for potential enrollment into this Study Protocol. Subjects who have completed the HLA Typing and Tumor Neoantigen Mutation Testing Protocol, i.e., subjects for whom a TCR matching the subject's somatic mutation(s) and HLA type restriction combination is available in Alaunos' TCR library will be eligible for enrollment on this study. The Phase I part of this study is a prospective, open-label, dose-escalation study of TCR-T cell drug product in patients with progressive or recurrent solid tumors who have failed standard therapy. The Phase II part is a prospective, open-label, single dose portion of the study. The Phase II part will begin once the MTD/RP2D in the Phase I part has been determined. Subjects with one of the following histologically confirmed solid tumors will be included: * Cohort 1: Gynecologic cancer (e.g., ovarian, endometrial) * Cohort 2: Colorectal cancer * Cohort 3: Pancreatic cancer * Cohort 4: Non-small cell lung cancer (NSCLC); NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous carcinoma or adenocarcinomas * Cohort 5: Cholangiocarcinoma Subject must have a tumor mutation and HLA typing combination that matches to at least one of the following TCRs in the Alaunos' library (mutation & HLA type): * KRAS G12D & HLA-A*11:01 * KRAS G12D & HLA-C*08:02 * KRAS G12V & HLA-A*11:01 * KRAS G12V & HLA-C*01:02 * TP53 R175H & HLA-A*02:01 * TP53 R175H & HLA-DRB1*13:01 * TP53 R248W & HLA-A*68:01 * TP53 Y220C & HLA-A*02:01 * TP53 Y220C & HLA-DRB3*02:02 * EGFR E746-A750del & HLA-DPA1*02:01, DPB1*01:01

  • Gynecologic Cancer
  • Colorectal Cancer
  • Pancreatic Cancer
  • Non-small Cell Lung Cancer
  • Cholangiocarcinoma
  • Ovarian Cancer
  • Endometrial Cancer
  • Ovarian Carcinoma
  • Ovary Neoplasm
  • Squamous Cell Lung Cancer
  • Adenocarcinoma of Lung
  • Adenosquamous Cell Lung Cancer
  • BIOLOGICAL: Neoantigen specific TCR-T cell drug product
  • BIOLOGICAL: Aldesleukin (IL-2)
  • TCR001-201

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates Results Reporting Dates Study Record Updates

2021-12-06  

N/A  

2024-05-25  

2022-01-03  

N/A  

2024-05-29  

2022-01-18  

N/A  

2024-05  

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

Arms and Interventions

Participant Group/ArmIntervention/Treatment
EXPERIMENTAL: TCR-T Cell Drug Product

Phase I: Dose-escalation of TCR-T Cell Drug Product Phase II: Single dose of TCR-T Cell Drug Product after MTD/RP2D determine in Phase I portion of the study

BIOLOGICAL: Neoantigen specific TCR-T cell drug product

  • Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D

BIOLOGICAL: Aldesleukin (IL-2)

  • To support growth and activation of TCR-T cell drug product
EXPERIMENTAL: TCR-T Cell Drug Product with Aldesleukin (IL-2)

Phase I: Dose-escalation of TCR-T Cell Drug Product with Aldesleukin (IL-2) Phase II: Single dose of TCR-T Cell Drug Product with Aldesleukin (IL-2) after MTD/RP2D determine in Phase I portion of the study

BIOLOGICAL: Neoantigen specific TCR-T cell drug product

  • Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D

BIOLOGICAL: Aldesleukin (IL-2)

  • To support growth and activation of TCR-T cell drug product
Primary Outcome MeasuresMeasure DescriptionTime Frame
Phase I: To define the incidence of dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of T-Cell Receptor T cellsArm A: To define the incidence of DLT and the MTD of TCR-T cell drug product delivered as a single administration.Approximately one month
Phase I: To define the incidence of dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of T-Cell Receptor T cellsArm B: To determine the MTD/MAD/RP2D of TCR-T cell drug product delivered as a single administration followed by IL-2 administration.Approximately one month
Phase II: Objective response rate (ORR) evaluated by Investigator assessments using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).Objective Response Rate (ORR) is defined as the proportion of FAS subjects achieving a confirmed PR or CR according to RECIST v1.1 during study.Up to 2 years
Phase II: Incidence of Adverse Events as characterized by type, frequency, severity (NCI CTCAE Version 5.0), timing, seriousness, and relationship to study therapy.Treatment-emergent AEs through 28 days after last protocol therapy will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) Version 13.1 (or higher) System Organ Class and preferred term. The incidences and percentages of participants experiencing each AE preferred term will be summarized with descriptive statistics. AEs will also be summarized by NCI CTCAE, Version 5.0, by grade and by causality (attribution to study treatment).Up to 2 years
Secondary Outcome MeasuresMeasure DescriptionTime Frame
Phase I: To evaluate the feasibility of neoantigen-specific T-Cell Receptor T cells (herein referred to as TCR-T cells) manufacturing.The number of subjects who have undergone apheresis for TCR-T cell manufacturing and for whom the product was successfully released for infusionapproximately one month
Phase I: To investigate translational hypotheses related to TCR-T cell persistence without IL-2 (Arm A) or with IL-2 (Arm B).Determine the TCR-T persistence, defined by the duration of TCR-T cell drug product measurable by vector copy number (VCN) in peripheral blood samplesapproximately one month
Phase II: To confirm Phase I results of translational hypotheses related to TCR-T cell persistence without IL-2 (Arm A) or with IL-2 (Arm B).Determine the TCR-T persistence, defined by the duration of TCR-T cell drug product measurable by vector copy number (VCN) in peripheral blood samplesapproximately one month

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

    Inclusion Criteria:
    1. Patients who have completed the HLA Typing and Tumor Neoantigen Identification Protocol (TCR001-002) and for whom a TCR(s) matching the subject's somatic mutation(s) and HLA type restriction combination is available in Alaunos' Clinical TCR library 2. Patients who have previously received at least one line of standard systemic therapy for their advanced/metastatic cancer and have either progressed, recurred, or were intolerant to the previous treatment. Specifically:

  • Subgroup 1. Gynecologic cancers (i.e., ovarian or endometrial):

    • 1. Ovarian cancer 2. Endometrial cancer
  • Subgroup 2. Colorectal cancer
  • Subgroup 3. Pancreatic cancer
  • Subgroup 4. Non-small cell lung cancer (NSCLC)
  • Subgroup 5. Cholangiocarcinoma 3. Patients must have evaluable or measurable disease per RECIST 1.1 with at least one lesion that can be measured that is not the biopsied lesion. 4. Patients must be able to provide written informed consent. 5. Patients must be age ≥ 18 years. 6. Clinical Performance Status of ECOG 0 or 1. Approval from the Alaunos Medical Monitor is required for ECOG of 2. 7. Patient must be willing and able to provide written informed consent for the long-term follow-up protocol (TCR001-202) for up to 15 years post TCR-T Cell drug product infusion per FDA requirements. 8. Adequate bone marrow reserves as assessed by the following hematology laboratory criteria: 9. Adequate major organ system function 10. A washout period must have elapsed since completion of any prior systemic therapy, and apheresis with guidelines as follows (windows other than what is listed below should be allowed only after consultation with the Medical Monitor); subjects' non-hematologic toxicities from any prior systemic therapy must have recovered to ≤ Grade 1 (with the exception of neuropathy and alopecia) or baseline prior to starting the protocol's therapy. 11. Patients may have undergone minor surgical procedures or limited-field radiotherapy provided any major organ toxicities have recovered to ≤ Grade 1. 12. Female patients must not be pregnant or breastfeeding.

    • Exclusion Criteria:
    1. Patients with known active CNS metastases 2. Concurrent systemic steroid therapy 3. Any form of primary immunodeficiency 4. Patients who have decreased immune competence 5. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, aldesleukin or bendamustine 6. Severe chronic respiratory condition 7. History of a bleeding disorder or unexplained major bleeding diathesis 8. Arm B Criteria only: Clinically significant patient history which in the judgment of the principal investigator (PI) would compromise the subject's ability to tolerate high-dose aldesleukin; 9. Any major bronchial occlusion or bleeding not amenable to palliation. 10. Patients with psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements. 11. Participants with known active, uncontrolled bacterial, fungal, or viral infection 12. Patients with a prior history or concurrent malignancy 13. Active unstable or clinically significant medical condition 14. History of any major cardiovascular conditions within the past 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

    • PRINCIPAL_INVESTIGATOR: Scott Kopetz, MD, PhD, MD Anderson

    Publications

    The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

    General Publications

    • 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.
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