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
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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
8
Phase I: Ascending dose, single Infusion of TCR+ Cells Phase II: Single infusion at the RP2D
To support growth and activation of TCR-T cell drug product
MD Anderson Cancer Center
Houston, Texas, United States
Number of Participants With Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) were defined as any adverse event that began or worsened after initiation of lymphodepletion and up to 28 days following TCR-T cell infusion. TEAEs were coded using MedDRA and summarized by system organ class and preferred term, severity, and relationship to study treatment. Participants were followed for delayed or ongoing toxicities for up to 1 year.
Time frame: From initiation of lymphodepletion through Day 28 after TCR-T cell infusion, and through long-term follow-up for up to 1 year.
Frequency of Dose Limiting Toxicities
Number of participants experiencing DLTs, defined as specific adverse events attributable to the TCR-T cell drug product occurring within the first 28 days of infusion. DLTs include, but are not limited to, Grade 4 neutropenia lasting ≥ 14 days, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with significant bleeding, and ≥ Grade 3 febrile neutropenia with hemodynamic compromise. Non-hematologic DLTs include Grade 3 or 4 Cytokine Release Syndrome (CRS) that does not improve to Grade ≤ 2 within 72 hours, and Grade 3 Immune-effector cell-associated neurotoxicity syndrome (ICANS) that does not resolve to Grade ≤ 2 within 7 days, among others. The severity of adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time frame: From Day 0 to Day 28 post TCR-T cell drug product infusion.
Determination of Maximum Tolerated Dose (MTD) or Recommended Phase II Dose (RP2D)
The MTD and/or RP2D was to be determined based on dose-limiting toxicities observed during the dose-escalation phase. The planned definition required ≥2 patients at a given dose level to experience a DLT to declare that dose not tolerated.
Time frame: From Day 0 to Day 28 post TCR-T cell drug product infusion.
Feasibility of TCR-T Cell Drug Product Manufacturing
Feasibility will be assessed by the number of participants who met eligibility criteria at each step of the manufacturing process, including inability to undergo apheresis, failure of product manufacture, manufactured product not infused, and successful manufacture and infusion of TCR-T cell drug product.
Time frame: From apheresis collection to the release of the final TCR-T cell drug product for infusion, estimated to be approximately 5 weeks
TCR-T Cell Persistence
Persistence of TCR-T cells in peripheral blood was assessed by quantitative PCR for vector copy number per 1 × 10⁶ cells at baseline (1 week prior to infusion), predose (Day 0), and multiple post-infusion time points through Month 18. Only quantifiable values are summarized. Samples with "Not Detected (ND)" or "Below the Limit of Quantitation (BLOQ)" are reported as NA and excluded from summary statistics.
Time frame: Baseline through Month 18 post-infusion.
Percent Change in TCR-T Cell Count From Post Dose to Day 28
Assessed by comparing each participant's highest post-dose TCR-T cell count (copies per 1×10⁶ cells by qPCR) to the TCR-T cell count at Day 28. Percent change was calculated as: ((Day 28 - peak post-dose) / peak post-dose) × 100.
Time frame: Post-dose through Day 28
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