MAGE-A4ᶜ¹º³²T for Multi-Tumor

Study Overview
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Brief Summary
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This study will investigate the safety and tolerability of MAGE-A4ᶜ¹º³²T cell therapy in subjects who have the appropriate HLA-A2 tissue marker and whose urinary bladder, melanoma, head and neck, ovarian, non-small cell lung, esophageal, gastric, synovial sarcoma, or myxoid/round call liposarcoma (MRCLS) tumor has the MAGE-A4 protein expressed. This study will take a subject's T cells and give them a T cell receptor protein that recognizes and attacks the tumors. This study has a substudy component that will investigate the safety and tolerability of MAGE-A4c1032T cell therapy in combination with low dose radiation in up to 10 subjects.

Official Title
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Phase 1 Dose Escalation, Multi-tumor Study to Assess the Safety, Tolerability and Antitumor Activity of Genetically Engineered MAGE-A4ᶜ¹º³²T in HLA-A2+ Subjects With MAGE-A4 Positive Tumors

Conditions
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Urinary Bladder Cancer, Melanoma, Head and Neck Cancer, Ovarian Cancer, Non-Small Cell Lung Cancer, Esophageal Cancer, Gastric Cancer, Synovial Sarcoma, Myxoid Round Cell Liposarcoma, Gastroesophageal Junction

Intervention / Treatment
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* Genetic: Autologous genetically modified MAGE-A4ᶜ¹º³²T cells
* Radiation: Autologous genetically modified MAGE-A4c1032T cells combined with low dose radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥18 to 75 years of age at the time of signing the study informed consent. Subject has histologically confirmed diagnosis of any one of the indicated tumor types Subject is HLA-A*02 positive. (This determination will be made under screening protocol ADP-0000-001). Subject's tumor shows expression of the MAGE-A4 RNA or protein. (This determination will be made under screening protocol ADP-0000-001). Adequate organ function as indicated in the study protocol Subject has measurable disease according to RECIST v1.1 criteria prior to lymphodepletion Subject meets disease-specific requirements per protocol 7. Subject has anticipated life expectancy > 6 months prior to leukapheresis and >3 months prior to lymphodepletion. Exclusion Criteria: Subject does not express appropriate HLA-A genotype Subject is receiving excluded therapy/treatment per protocol Subject has symptomatic CNS metastases. Subject has any other active malignancy besides the tumor under study within 3 years prior to Screening. Subject has uncontrolled intercurrent illness. Subject has active infection with HIV, HBV, HCV or HTLV Subject is pregnant or breastfeeding. Additional Exclusion Criteria for the Radiation Substudy: Subject does not meet eligibility criteria for the main study (ADP-0044-001). Subject does not have at least one target lesion amenable to radiation. Certain radiation therapy within 6 months of clinical trial are an exclusion. Metastatic disease impinging on the spinal cord or threatening spinal cord compression.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous genetically modified MAGE-A4ᶜ¹º³²T cells<br> | Genetic: Autologous genetically modified MAGE-A4ᶜ¹º³²T cells<br>* Infusion of autologous genetically modified MAGE-A4ᶜ¹º³²T on Day 1<br>|
| Experimental: Radiation Sub-Study: Autologous genetically modified MAGE-A4c1<br> | Radiation: Autologous genetically modified MAGE-A4c1032T cells combined with low dose radiation<br>* Up to 10 subjects will be considered for Radiation sub-study. Radiation with an intensity of 1.4Gy for 5 days before infusion of MAGE-A4c1032T cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events (AE), including serious adverse events (SAEs). | Determine if treatment with autologous genetically modified T cells (MAGE-A4ᶜ¹º³²T) is safe and tolerable through laboratory assessments including chemistry, hematology and coagulation. | 3.5 years | 
| Determining dose limiting toxicities (DLT) and optimally tolerated dose range | Evaluate DLTs and toxicity assessment using NCI CTCAE. | 3.5 years | 
| Evaluation of persistence of genetically modified T cells. | Evaluation of persistence of genetically modified T cells in the periphery. | 3.5 years | 
| Measurement of RCL in genetically modified T cells. | Evaluation of RCL in subject PBMCs using PCR-based assay. | 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with a confirmed Complete Response (CR) and/or Partial Response (PR). | Evaluation of the efficacy of the treatment by assessment of the Overall Response Rate according to RECIST v1.1 | 3.5 years | 
| Interval between the date of first T cell infusion dose and first documented evidence of CR or PR. | Evaluation of the efficacy of the treatment by assessment of time to first response. | 3.5 years | 
| Interval between the date of first documented evidence of CR or PR until first documented disease progression or death due to any cause. | Evaluation of the efficacy of the treatment by assessment of duration of response. | 3.5 years | 
| Interval between the date of first documented evidence of stable disease (SD) until first documented disease progression or death due to any cause. | Evaluation of the efficacy of the treatment by assessment of duration of stable disease. | 3.5 years | 
| Interval between the date of first T cell infusion and the earliest date of disease, progression or death due to any cause | Evaluation of the efficacy of the treatment by assessment of progression-free survival. | 3.5 years | 
| Interval between the date of first T cell infusion and date of death due to any cause. | Evaluation of the efficacy of the treatment by assessment of overall survival. | 3.5 years | 
| Number and % of subjects having any Long Term Follow Up Adverse Events (AEs) | New occurrence of any malignancy New occurrence or exacerbation of a pre-existing neurologic disorder New occurrence or exacerbation of a prior rheumatologic or other autoimmune disorder New occurrence of a hematologic disorder New occurrence of any opportunistic and/or serious infections New occurrence of any unanticipated illness and/or hospitalization deemed related to gene modified cell therapy | 15 years post last treatment (infusion) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cell Therapy, T Cell Therapy, SPEAR T Cell, MAGE-A4, Immuno-oncology, Metastatic, Urothelial Cancer, Previously Treated, T Cell Receptor, Squamous, adenosquamous, adenocarcinoma or large cell NSCLC, Squamous or adenocarcinoma esophageal cancer, Sarcoma, Melanoma, Bladder, Ovarian, Radiation therapy