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

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ClinicalTrials.gov Identifier: NCT05194735
Recruitment Status : Recruiting
First Posted : January 18, 2022
Last Update Posted : April 11, 2022
Sponsor:
Information provided by (Responsible Party):
Alaunos Therapeutics

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

Condition or disease Intervention/treatment Phase
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) Phase 1 Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : April 2022
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : March 2029


Arm Intervention/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


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 Measures :
  1. 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 [ Time Frame: Approximately one month ]
    Arm A: To define the incidence of DLT and the MTD of TCR-T cell drug product delivered as a single administration.

  2. 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 [ Time Frame: Approximately one month ]
    Arm B: To determine the MTD/MAD/RP2D of TCR-T cell drug product delivered as a single administration followed by IL-2 administration.

  3. Phase II: Objective response rate (ORR) evaluated by Investigator assessments using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). [ Time Frame: Up to 2 years ]
    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.

  4. Phase II: Incidence of Adverse Events as characterized by type, frequency, severity (NCI CTCAE Version 5.0), timing, seriousness, and relationship to study therapy. [ Time Frame: Up to 2 years ]
    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 :
  1. Phase I: To evaluate the feasibility of neoantigen-specific T-Cell Receptor T cells (herein referred to as TCR-T cells) manufacturing. [ Time Frame: approximately one month ]
    The number of subjects who have undergone apheresis for TCR-T cell manufacturing and for whom the product was successfully released for infusion

  2. Phase I: To investigate translational hypotheses related to TCR-T cell persistence without IL-2 (Arm A) or with IL-2 (Arm B). [ Time Frame: approximately one month ]
    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

  3. 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). [ Time Frame: approximately one month ]
    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


Other Outcome Measures:
  1. 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. [ Time Frame: Up to 2 years ]
    Determine the Objective response rate (ORR) per RECIST v1.1 and iRECIST

  2. 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). [ Time Frame: Up to 2 years ]
    TCR-T cellular persistence in peripheral blood (e.g., Cmax, Tmax, AUCD0-D28, etc.) over time determined by VCN.

  3. 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). [ Time Frame: Up to 2 years ]
    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.

  4. 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). [ Time Frame: Up to 2 years ]
    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.

  5. 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). [ Time Frame: Up to 2 years ]
    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.

  6. 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) [ Time Frame: Up to 2 years ]
    Objective Response Rate (ORR) is defined as the proportion of FAS subjects achieving a confirmed PR or CR according to iRECIST during study.

  7. 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). [ Time Frame: Up to 2 years ]
    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.

  8. 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). [ Time Frame: Up to 2 years ]
    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.

  9. 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. [ Time Frame: Up to 2 years ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05194735


Contacts
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Contact: Nathan Demars 617-315-1790 TCR001-201@alaunos.com

Locations
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United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Kim Ross    713-794-1623    kdross@mdanderson.org   
Principal Investigator: Scott Kopetz, MD, PhD         
Sub-Investigator: Marcelo Negrao, MD         
Sponsors and Collaborators
Alaunos Therapeutics
Investigators
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Principal Investigator: Scott Kopetz, MD, PhD MD Anderson
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Responsible Party: Alaunos Therapeutics
ClinicalTrials.gov Identifier: NCT05194735    
Other Study ID Numbers: TCR001-201
First Posted: January 18, 2022    Key Record Dates
Last Update Posted: April 11, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alaunos Therapeutics:
adoptive cell therapy
neoantigen
T cell receptor
T lymphocyte
TCR-engineered T cells
cell therapy
immunotherapy
IL-2
Gene therapy
Additional relevant MeSH terms:
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Lung Neoplasms
Ovarian Neoplasms
Endometrial Neoplasms
Cholangiocarcinoma
Adenocarcinoma of Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Endocrine Gland Neoplasms
Endocrine System Diseases
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Gonadal Disorders
Uterine Neoplasms
Uterine Diseases
Aldesleukin
Antineoplastic Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents