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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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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

Intervention / Treatment
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* Biological: Neoantigen specific TCR-T cell drug product
* Biological: Aldesleukin (IL-2)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TCR-T Cell Drug Product<br>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<br>* Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D<br>|
| Experimental: TCR-T Cell Drug Product with Aldesleukin (IL-2)<br>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<br>* Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D<br>Biological: Aldesleukin (IL-2)<br>* To support growth and activation of TCR-T cell drug product<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time 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 cells | Arm 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 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. | 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 Measures

| Outcome Measure | Measure Description | Time 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 infusion | approximately 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 samples | approximately 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 samples | approximately one month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adoptive cell therapy, neoantigen, T cell receptor, T lymphocyte, TCR-engineered T cells, cell therapy, immunotherapy, IL-2, Gene therapy