Treatment of Advanced Solid Tumors With TSA-CTL(Tumor Specific Antigen-Induced Cytotoxic T Lymphocytes)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety of TSA-CTL in the treatment of advanced solid tumors. The secondary objective of this study is to evaluate preliminarily the effect of TSA-CTL in the treatment of advanced solid tumors.

Detailed Description
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This is a single arm, open label and non-randomized clinical study with two parts. In Part 1, 9 subjects with advanced solid tumors will be enrolled into Groups A (no non-myeloablative lymphodepletion), B and C (non-myeloablative lymphodepletion with different chemotherapy intensities) to assess the safety and dose intensity of non-myeloablative lymphodepletion chemotherapy before cell infusion. Depending on results in Part 1, the study may proceed to Part 2, where 15 subjects with advanced solid tumors will be enrolled to receive TSA-CTL cell infusions with or without non-myeloablative lymphodepletion.

Official Title
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Phase I Clinical Trial of TSA-CTL (Tumor Specific Antigen-Induced Cytotoxic T Lymphocytes) In the Treatment of Advanced Solid Tumors

Conditions
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Solid Cancer

Intervention / Treatment
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* Biological: TSA-CTL
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Greater than or equal to 18 years of age and less than or equal to 70 years of age; all genders. Advanced solid tumors including but not limited to some high frequency somatic mutations, such as melanoma, colorectal cancer, gastric cancer, esophageal cancer, squamous cell carcinoma of the lung, triple-negative breast cancer, etc. Advanced solid tumors patients who are HLA - A0201 /A1101/A2402 subtypes. Measurable solid tumors with at least one lesion that is resectable or tumor biopsies for DNA extraction. Patients who failed or were intolerant to standard treatment. Patients (or their legal representatives) who are able to understand and sign the Informed Consent Form and willing to sign a durable power of attorney. Clinical performance status of ECOG is 0 or 1 and expected lifetime is greater than six month and patients who are able to cooperate to observe adverse reactions and the effect of the treatment. Patients of both genders must be willing to practice birth control from the time of enrollment to five months after treatment on this study. Serology: HIV antibody(-), hepatitis B antigen(-), and hepatitis C antibody(-). A fertile woman must have a negative pregnancy test. Hematology: Absolute neutrophil count is greater than 1500/mm3 without the support of filgrastim; WBC is greater than or equal to 3000/mm3; lymphocyte count is greater than or equal to 800/mm3; Platelet count is greater than or equal to 100,000/mm3; Hemoglobin is greater than or equal to 9.0 g/dL ; Chemistry: Serum ALT/AST is less than or equal to 2.5 times the upper limit of normal; Serum Creatinine is less than or equal to 1.5 times the upper limit of normal ; Total bilirubin is less than or equal to 1.5 the upper limit of normal, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3 times the upper limit of normal. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the lymphodepletion regimen, and toxicities must have recovered to grade 1 or less (except for toxicities such as alopecia or vitiligo). Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less. Exclusion Criteria: Pregnant or lactating women. Any primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). Opportunistic infection. History of autoimmune disease. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system. Systemic steroid therapy in the past 4 weeks. History of severe immediate hypersensitivity reaction to any of the agents used in this study. Patients with unstable brain metastases. Choroidal melanoma and clear cell sarcoma patients. Negative for expression of MHC molecules.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: medium-dose lymphodepletion regimen<br>Patients will receive medium-dose lymphodepletion regimen consisting of cyclophosphamide and fludarabine followed by TSA-CTL. | Biological: TSA-CTL<br>* Patients will receive TSA-CTL iv over 20-30 minutes on day 0.<br>* Other names: Tumor Specific Antigen Induced Cytotoxic Lymphocyte;Drug: Fludarabine<br>* Fludarabine 25 mg/m2/day iv over 30 minutes on day -5 and -4 for two days.<br>* Other names: Fludarabine Phosphate;Drug: Cyclophosphamide<br>* Cyclophosphamide 500 mg/m2/day iv on day -5 and -4 for two days.<br>* Other names: Cytoxan;|
| Experimental: low-dose lymphodepletion regimen<br>Patients will receive low-dose lymphodepletion regimen consisting of cyclophosphamide and fludarabine followed by TSA-CTL. | Biological: TSA-CTL<br>* Patients will receive TSA-CTL iv over 20-30 minutes on day 0.<br>* Other names: Tumor Specific Antigen Induced Cytotoxic Lymphocyte;Drug: Cyclophosphamide<br>* Cyclophosphamide 500 mg/m2/day iv on day -5 for one day.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* Fludarabine 25 mg/m2/day iv over 30 minutes on day -5 and -4 for two days.<br>* Other names: Fludarabine Phosphate;|
| Experimental: No lymphodepletion regimen<br>Patients will only receive TSA-CTL. | Biological: TSA-CTL<br>* Patients will receive TSA-CTL iv over 20-30 minutes on day 0.<br>* Other names: Tumor Specific Antigen Induced Cytotoxic Lymphocyte;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events as assessed by CTCAE v5.0. | Keep records the adverse events experienced by subjects in 30 days after the first infusion. | one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate(DCR) | DCR is defined as the proportion of participants with tumor size reduction(CR,PR) and stable disease(SD) assessed by RECIST 1.1 and iRECIST. | one year | 
| overall survival(OS) | The time from the first infusion of Investigational Product until death. | one year | 
| progression-free survival(PFS) | PFS is defined as the time from the first infusion of Investigational Product until objective tumor progression, as assessed by RECIST 1.1 and iRECIST, or death, whichever occurs first. | one year | 
| Duration of Response(DOR) | DOR refers to the period from the first evaluation of tumor as CR or PR to the first evaluation as PD(Progressive Disease) per RECIST1.1 and iRECIST. | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Melanoma, Colorectal Cancer, neoantigen