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

Primary Purpose

Gynecologic Cancer, Colorectal Cancer, Pancreatic Cancer

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Neoantigen specific TCR-T cell drug product
Aldesleukin (IL-2)
Sponsored by
Alaunos Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gynecologic Cancer focused on measuring adoptive cell therapy, neoantigen, T cell receptor, T lymphocyte, TCR-engineered T cells, cell therapy, immunotherapy, IL-2, Gene therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

TCR-T Cell Drug Product

TCR-T Cell Drug Product with Aldesleukin (IL-2)

Arm Description

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

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

Outcomes

Primary Outcome Measures

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 cells
Arm A: To define the incidence of DLT and the MTD of TCR-T cell drug product delivered as a single administration.
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 cells
Arm B: To determine the MTD/MAD/RP2D of TCR-T cell drug product delivered as a single administration followed by IL-2 administration.
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.
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).

Secondary Outcome Measures

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 infusion
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 samples
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 samples

Full Information

First Posted
December 6, 2021
Last Updated
August 24, 2023
Sponsor
Alaunos Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT05194735
Brief Title
Phase I/II Study of Autologous T Cells to Express T-Cell Receptors (TCRs) in Subjects With Solid Tumors
Official Title
Phase I/II Study of Autologous T Cells Engineered Using the Sleeping Beauty System to Express T-Cell Receptors (TCRs) Reactive Against Cancer-specific Mutations in Subjects With Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 4, 2022 (Actual)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
March 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alaunos Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
Detailed Description
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
adoptive cell therapy, neoantigen, T cell receptor, T lymphocyte, TCR-engineered T cells, cell therapy, immunotherapy, IL-2, Gene therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
180 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TCR-T Cell Drug Product
Arm Type
Experimental
Arm Description
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
Arm Title
TCR-T Cell Drug Product with Aldesleukin (IL-2)
Arm Type
Experimental
Arm Description
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
Intervention Type
Biological
Intervention Name(s)
Neoantigen specific TCR-T cell drug product
Intervention Description
Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D
Intervention Type
Biological
Intervention Name(s)
Aldesleukin (IL-2)
Intervention Description
To support growth and activation of TCR-T cell drug product
Primary Outcome Measure Information:
Title
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 cells
Description
Arm A: To define the incidence of DLT and the MTD of TCR-T cell drug product delivered as a single administration.
Time Frame
Approximately one month
Title
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 cells
Description
Arm B: To determine the MTD/MAD/RP2D of TCR-T cell drug product delivered as a single administration followed by IL-2 administration.
Time Frame
Approximately one month
Title
Phase II: Objective response rate (ORR) evaluated by Investigator assessments using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Description
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.
Time Frame
Up to 2 years
Title
Phase II: Incidence of Adverse Events as characterized by type, frequency, severity (NCI CTCAE Version 5.0), timing, seriousness, and relationship to study therapy.
Description
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).
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Phase I: To evaluate the feasibility of neoantigen-specific T-Cell Receptor T cells (herein referred to as TCR-T cells) manufacturing.
Description
The number of subjects who have undergone apheresis for TCR-T cell manufacturing and for whom the product was successfully released for infusion
Time Frame
approximately one month
Title
Phase I: To investigate translational hypotheses related to TCR-T cell persistence without IL-2 (Arm A) or with IL-2 (Arm B).
Description
Determine the TCR-T persistence, defined by the duration of TCR-T cell drug product measurable by vector copy number (VCN) in peripheral blood samples
Time Frame
approximately one month
Title
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).
Description
Determine the TCR-T persistence, defined by the duration of TCR-T cell drug product measurable by vector copy number (VCN) in peripheral blood samples
Time Frame
approximately one month
Other Pre-specified Outcome Measures:
Title
Phase I: To evaluate the objective response rate (ORR) (RECIST and iRECIST criteria) of subjects with solid cancers who receive TCR-T cell drug product.
Description
Determine the Objective response rate (ORR) per RECIST v1.1 and iRECIST
Time Frame
Up to 2 years
Title
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).
Description
TCR-T cellular persistence in peripheral blood (e.g., Cmax, Tmax, AUCD0-D28, etc.) over time determined by VCN.
Time Frame
Up to 2 years
Title
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).
Description
Insertion-site clonality of TCR-T cell drug product will be measured by tracking the transposon insertion-site(s) of gene-modified cells in peripheral blood samples.
Time Frame
Up to 2 years
Title
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).
Description
Serum cytokine concentrations including, but not limited to IFN-γ, IL-6, TNF-α, GM-CSF, IL-2, IL-7, and IL-15 will be determined by multiplex immunoassay.
Time Frame
Up to 2 years
Title
Phase I: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).
Description
Immunogenicity elicited against the transgenic components of the TCR therapy (i.e., anti-drug antibody and T-cell responses) will be assessed by immunoassay of peripheral blood and serum samples.
Time Frame
Up to 2 years
Title
Phase II: To explore anti-tumor and immunotherapy response of TCR-T cell drug product without IL-2 (Arm A) or with IL-2 (Arm B)
Description
Objective Response Rate (ORR) is defined as the proportion of FAS subjects achieving a confirmed PR or CR according to iRECIST during study.
Time Frame
Up to 2 years
Title
Phase II: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).
Description
The collection of tumor tissue samples is to enable the investigation of all T cells (T cell and TCR-T cell infiltration) in the tumor.
Time Frame
Up to 2 years
Title
Phase II: To explore translational hypotheses related to molecular signatures, mechanism of action, immunogenicity, and serum cytokine profiles associated with TCR-T cell drug product infusion without IL-2 (Arm A) or with IL-2 (Arm B).
Description
To evaluate the levels of blood-based tumor neoantigen biomarkers, peripheral blood samples collected from all subjects according to the schedule shown in may be analyzed.
Time Frame
Up to 2 years
Title
Phase II: To evaluate anti-tumor activity (ORR) (iRECIST) of TCR-T cell drug product without IL-2 (Arm A) or with IL-2 (Arm B) in each of the tumor types.
Description
An estimate of the ORR is determined by the proportion of confirmed objective responses and will be summarized separately for each of the tumor type subgroup.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 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): Ovarian cancer Endometrial cancer Subgroup 2. Colorectal cancer Subgroup 3. Pancreatic cancer Subgroup 4. Non-small cell lung cancer (NSCLC) Subgroup 5. Cholangiocarcinoma 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. Patients must be able to provide written informed consent. Patients must be age ≥ 18 years. Clinical Performance Status of ECOG 0 or 1. Approval from the Alaunos Medical Monitor is required for ECOG of 2. 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. Adequate bone marrow reserves as assessed by the following hematology laboratory criteria: Adequate major organ system function 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. Patients may have undergone minor surgical procedures or limited-field radiotherapy provided any major organ toxicities have recovered to ≤ Grade 1. Female patients must not be pregnant or breastfeeding. Exclusion Criteria: Patients with known active CNS metastases Concurrent systemic steroid therapy Any form of primary immunodeficiency Patients who have decreased immune competence History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, aldesleukin or bendamustine Severe chronic respiratory condition History of a bleeding disorder or unexplained major bleeding diathesis 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; Any major bronchial occlusion or bleeding not amenable to palliation. Patients with psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements. Participants with known active, uncontrolled bacterial, fungal, or viral infection Patients with a prior history or concurrent malignancy Active unstable or clinically significant medical condition History of any major cardiovascular conditions within the past 6 months
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Scott Kopetz, MD, PhD
Organizational Affiliation
MD Anderson
Official's Role
Principal Investigator
Facility Information:
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35537408
Citation
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.
Results Reference
derived

Learn more about this trial

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

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