A Basket Study of Customized Autologous TCR-T Cell Therapies in Patients With Locally Advanced (Unresectable) or Metastatic Solid Tumors

Study Overview
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Brief Summary
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TScan Therapeutics is developing cellular therapies across multiple solid tumors in which autologous participant-derived T cells are engineered to express a T cell receptor that recognizes cancer-associated antigens presented on specific Human Leukocyte Antigen (HLA) molecules. This is a multi-center, non-randomized, multi-arm, open-label, basket study evaluating the safety and preliminary efficacy of single and repeat dose regimens of TCR'Ts as monotherapies and as T-Plex combinations after lymphodepleting chemotherapy in participants with locally advanced, metastatic solid tumors disease.

Detailed Description
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Participants will be screened in a separate screening study, TSCAN-003 (NCT05812027), to assess their HLA type, tumor-associated antigen (TAA) expression and loss of heterozygosity (LOH) status. The results of these tests will be used to determine initial eligibility in this study. Depending on the genetic type, participants will be assigned to one of the following study groups: Monotherapy: Cohort A: TSC-204-A0201 targeting MAGE-A1 on HLA-A*02:01 Cohort B: TSC-204-C0702 targeting MAGE-A1 on HLA-C*07:02 Cohort C: TSC-200-A0201 targeting HPV16 E7 on HLA-A*02:01 Cohort D: TSC-203-A0201 targeting PRAME on HLA-A*02:01 T-Plex Combination: COHORT AB: TSC-204-A0201 + TSC-204-C0702 COHORT AC: TSC-204-A0201 + TSC-200-A0201 COHORT BC: TSC-204-C0702 + TSC-200-A0201 COHORT AD: TSC-204-A0201 + TSC-203-A0201 COHORT BD: TSC-204-C0702 + TSC-203-A0201 COHORT CD: TSC-200-A0201 + TSC-203-A0201 Participants will undergo leukapheresis to collect cells to manufacture the TCR-T products. They will then undergo lymphodepletion and receive one or two doses of the TCR-T cell therapy product as a monotherapy or part of a combination of TCR-Ts (referred to as T-Plex combinations in this study).

Official Title
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A Phase 1 Basket Study Evaluating the Safety and Feasibility of T-Plex, Autologous Customized T Cell Receptor-Engineered T Cells Targeting Multiple Peptide/HLA Antigens in Participants With Antigen-positive Locally Advanced (Unresectable) or Metastatic Solid Tumors

Conditions
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Head and Neck Cancer, Cervical Cancer, Non-small Cell Carcinoma, Melanoma, Ovarian Cancer, Anogenital Cancers, HPV - Anogenital Human Papilloma Virus Infection, HPV-Related Cervical Carcinoma, HPV-Related Carcinoma, HPV-Related Squamous Cell Carcinoma, HPV-Related Malignancy, HPV-Related Adenocarcinoma, HPV Positive Oropharyngeal Squamous Cell Carcinoma, HPV-Related Adenosquamous Carcinoma, HPV-Associated Vaginal Adenocarcinoma, HPV-Related Endocervical Adenocarcinoma, HPV-Related Anal Squamous Cell Carcinoma, HPV-Related Verrucous Carcinoma, HPV-Related Penile Squamous Cell Carcinoma, HPV-Related Vulvar Squamous Cell Carcinoma, HPV Positive Rectal Squamous Cell Carcinoma

Intervention / Treatment
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* Biological: TSC-204-A0201
* Biological: TSC-204-C0702
* Biological: TSC-200-A0201
* Biological: TSC-204-A0201 + TSC-204-C0702
* Biological: TSC-204-A0201 + TSC-200-A0201
* Biological: TSC-204-C0702 + TSC-200-A0201
* Biological: TSC-204-A0201 + TSC-203-A0201
* Biological: TSC-204-C0702 + TSC-203-A0201
* Biological: TSC-200-A0201 + TSC-203-A0201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be at least 18 years. Locally advanced (unresectable) or metastatic solid tumor for which there are no available curative treatment options, after failure of the standard of care systemic therapies for that particular indication. Any solid tumor, including but not limited to non-nasopharyngeal head and neck cancer, non-small cell lung cancer, cutaneous melanoma, cervical cancer, ovarian cancer, anal cancer and genital cancers. Participants must express one of the following HLA types, as assessed by a qualified genomics assay in screening study TSCAN-003: HLA-C*07:02, HLA-A*02:01 and HLA-C*07:02 plus HLA-A*02:01 Tumor must express MAGE-A1 and/or PRAME and/or HPV16-E7 as assessed by a qualified IHC or RNA-ISH performed in the last 6 months in screening study TSCAN-003 (NCT05812027). Eastern Cooperative Oncology Group (ECOG) Performance status 0-1 at screening. Participants must be able to understand and be willing to give informed consent; decision-impaired adults may consent with their legally authorized representative. At least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Adequate bone marrow and organ function. Exclusion Criteria: Medical or psychological conditions that would make the participant unsuitable candidate for cell therapy at the discretion of the PI. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, cardiac arrhythmia requiring antiarrhythmic or procedure, or other clinically significant cardiac disease within 12 months of enrollment History of stroke or transient ischemic attack (TIA) within 12 months of enrollment Systemic corticosteroid therapy >10 mg of prednisone daily or equivalent within 7 days of enrollment History of severe hypersensitivity to fludarabine or cyclophosphamide or study product excipients including human serum albumin, Cryostor (DMSO or Dextran 40), or Plasma-Lyte. Untreated or symptomatic central nervous system (CNS) metastases or cytology proven carcinomatous meningitis. Concurrent receipt of another anti-cancer therapy. Presence of fungal, bacterial, viral, or other infection requiring anti-microbials for management. Tumors that have HLA LOH using a central lab clinical trial assay of HLAs addressed by the monotherapy and/or T-Plex combination TCR-Ts in the protocol and have no available TCR-T options for intact HLAs in the participant's tumor. Participants who regularly require supplemental oxygen.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy Cohort A<br>TSC-204-A0201 | Biological: TSC-204-A0201<br>* Escalating doses of TSC-204-A0201 as a monotherapy<br>|
| Experimental: Monotherapy Cohort B<br>TSC-204-C0702 | Biological: TSC-204-C0702<br>* Escalating doses of TSC-204-C0702 as a monotherapy<br>|
| Experimental: Monotherapy Cohort C<br>TSC-200-A0201 | Biological: TSC-200-A0201<br>* Escalating doses of TSC-200-A0201 as a monotherapy<br>|
| Experimental: T-Plex Combination Cohort A + B<br>TSC-204-A0201 and TSC-204-C0702 | Biological: TSC-204-A0201 + TSC-204-C0702<br>* Escalating doses of TSC-204-A0201 in combination with TSC-204-C0702<br>|
| Experimental: T-Plex Combination Cohort B + C<br>TSC-204-C0702 and TSC-200-A0201 | Biological: TSC-204-A0201 + TSC-200-A0201<br>* Escalating doses of TSC-204-A0201 in combination with TSC-200-A0201<br>|
| Experimental: T-Plex Combination Cohort A + C<br>TSC-204-A0201 and TSC-200-A0201 | Biological: TSC-204-C0702 + TSC-200-A0201<br>* Escalating doses of TSC-204-C0702 in combination with TSC-200-A0201<br>|
| Experimental: Monotherapy Cohort D<br>TSC-203-A0201 | Biological: TSC-204-A0201<br>* Escalating doses of TSC-204-A0201 as a monotherapy<br>|
| Experimental: T-Plex Combination Cohort A + D<br>TSC-204-A0201 + TSC-203-A0201 | Biological: TSC-204-A0201 + TSC-203-A0201<br>* Escalating doses of TSC-204-A0201 in combination with TSC-203-A0201<br>|
| Experimental: T-Plex Combination Cohort B + D<br>TSC-204-C0702 + TSC-203-A0201 | Biological: TSC-204-C0702 + TSC-203-A0201<br>* Escalating doses of TSC-204-C0702 in combination with TSC-203-A0201<br>|
| Experimental: T-Plex Combination Cohort C + D<br>TSC-200-A0201 + TSC-203-A0201 | Biological: TSC-200-A0201 + TSC-203-A0201<br>* Escalating doses of TSC-200-A0201 in combination with TSC-203-A0201<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety of monotherapy and T- Plex combination TCR-Ts | Number of subjects with dose limiting toxicities (DLT) | 28 days | 
| Determine the recommended phase 2 dose of monotherapy and T- Plex combination TCR-Ts | Frequency and severity of DLTs, AEs and SAEs | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigate preliminary anti-tumor activity of monotherapy and T- Plex combination TCR-Ts | Response Evaluation Criteria In Solid Tumors RECIST 1.1 | Up to 12 months | 
| Investigate the feasibility of repeat dosing of monotherapy and T- Plex combination TCR-Ts | Frequency and severity of DLTs, AEs and SAEs | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV16 E7, MAGE-A1, TSC-204-A0201, TSC-204-C0702, TSC-200-A0201, TCR-T Therapy, Cell Therapy, Immunotherapy, TScan Therapeutics, TSCAN-002, TSCAN-003, PRAME