Clinical trial NCT05194735: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Alaunos Therapeutics
Sponsor class: INDUSTRY
First posted: 2022-01-18
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: Approximately one month
measure: 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
timeFrame: Approximately one month
measure: Phase II: Objective response rate (ORR) evaluated by Investigator assessments using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
timeFrame: Up to 2 years
measure: Phase II: Incidence of Adverse Events as characterized by type, frequency, severity (NCI CTCAE Version 5.0), timing, seriousness, and relationship to study therapy.
timeFrame: Up to 2 years
Secondary outcomes:
measure: Phase I: To evaluate the feasibility of neoantigen-specific T-Cell Receptor T cells (herein referred to as TCR-T cells) manufacturing.
timeFrame: approximately one month
measure: Phase I: To investigate translational hypotheses related to TCR-T cell persistence without IL-2 (Arm A) or with IL-2 (Arm B).
timeFrame: approximately one month
measure: 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).
timeFrame: approximately one month
Other outcomes:
measure: 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.
timeFrame: Up to 2 years
measure: 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).
timeFrame: Up to 2 years
measure: 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).
timeFrame: Up to 2 years
measure: 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).
timeFrame: Up to 2 years
measure: 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).
timeFrame: Up to 2 years
measure: 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)
timeFrame: Up to 2 years
measure: 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).
timeFrame: Up to 2 years
measure: 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).
timeFrame: Up to 2 years
measure: 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.
timeFrame: Up to 2 years
Locations:
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: MD Anderson
name: Scott Kopetz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.