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

• ClinicalTrials.gov Identifier: NCT05194735
• Recruitment Status: Recruiting
• First Posted: January 18, 2022
• Last Update Posted: March 6, 2023
• Sponsor: Alaunos Therapeutics
• Information provided by (Responsible Party): Alaunos Therapeutics

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

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

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

Study Design

• 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
• Actual Study Start Date: April 4, 2022
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: March 2029

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Contacts

Contact: Sandra Sinclair, BSBA, MHA/Ed, RN; 832-622-1699; TCR001-201@alaunos.com

Locations

United States, Texas

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Kim Ross GIClinicalTrials@mdanderson.org

Principal Investigator: Scott Kopetz, MD, PhD

Sub-Investigator: Marcelo Negrao, MD

Sponsors and Collaborators

Alaunos Therapeutics

Investigators

• Principal Investigator: Scott Kopetz, MD, PhD; MD Anderson

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Alaunos Therapeutics
• ClinicalTrials.gov Identifier: NCT05194735
• Other Study ID Numbers: TCR001-201
• First Posted: January 18, 2022
• Last Update Posted: March 6, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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