HRYZ-T101 Injection for HPV18 Positive Solid Tumor

Study Overview
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Brief Summary
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A multicenter, open label, single arm dose escalation phase I study to evaluate the safety, tolerability, and efficacy of HRYZ-T101 injection for HPV18 positive solid tumor. The study will investigate RP2D of HRYZ-T101 TCR-T cell injection.

Official Title
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A Multicenter, Single Arm, Open Label, Phase I Clinical Study to Evaluate the Safety, Tolerability and Efficacy of HRYZ-T101 Injection for HPV18 Positive Solid Tumor

Conditions
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Cervical Cancer, Head and Neck Squamous Cell Carcinoma, Carcinoma of Vagina, Carcinoma of Penis, Anal Cancer, Carcinoma of Vulva

Intervention / Treatment
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* Biological: HRYZ-T101 Injection
* Drug: Fludarabine + Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. The patient must be willing to sign the informed consent form. 2. Age ≥18 years and ≤75 years. 3. Metastatic or recurrent solid tumors with confirmed HPV18 infection based on TNM & FIGO staged histopathological investigation. . 4. Subjects who have failed anti-tumor treatment in the past and lack effective treatment options. 5. HPV18 positive and HLA-DRB1*0901 allele. 6. ECOG performance status ≤1. 7. Estimated life expectancy ≥ 3 months. 8. Patients must have at least one measurable lesion defined by RECIST 1.1. 9. Patients with any organ dysfunction as defined below: Leukocytes≥3.0 x 10^9/L; blood platelets ≥75 x 10^9/L; hemoglobin≥85g/L; Absolute lymphocyte count≥0.8 x 10^9/L Serum albumin ≥ 30g/L; total bilirubin≤1.5×ULN; ALT/AST≤3×ULN or ≤5×ULN for liver metastases; Creatinine clearance ≥50mL/min; or serum creatinine ≤1.5×ULN; INR≤1.5×ULN; APTT≤1.5×ULN; LVEF≥50%; SpO2≥92%. 10. Subjects with potential fertility must agree to use effective contraceptive methods during the whole trials period and at least 1 year after receiving HRYZ-T101 cell transfusion treatment. HCG test for female with potential fertility must be negative within 7 days before apheresis. Exclusion Criteria: 1. Have a history of hypersensitivity to cyclophosphamide or fludarabine, and it is known that any ingredient used in the treatment of this study will produce allergic reactions. 2. Those who have undergone systemic anti-tumor treatment within 4 weeks before apheresis, including who have received conventional chemotherapy, large-area radiotherapy, targeted therapy, immunotherapy or biological therapy, and other anti-tumor treatment. Have received small molecule targeted drugs and oral fluorouracils or Chinese herbal medicine within 2 weeks before apheresis. 3. Have received any investigational drug within 4 weeks before apheresis, or have participated in another clinical study at the same time. 4. Have received any cell therapy products before. 5. Those who have undergone major surgery within 4 weeks before apheresis, or minor surgery within 2 weeks before apheresis. 6. Toxicity of previous treatment has not been mitigated or ≤ Grade 1 before apheresis. 7. Have received live attenuated vaccine or adenovirus vector vaccine within 4 weeks before apheresis. 8. Have central nervous system metastasis with symptoms. 9. Subjects with clinical cardiac symptoms or diseases that cannot be well controlled. 10. Subjects with serious or uncontrolled systemic disease or any unstable systemic disease. 11. Subjects with active infection requiring systemic treatment with anti-infective drugs within 2 weeks before apheresis. 12. Subjects have any active autoimmune disease or history of autoimmune disease. 13. Have received immunosuppressive agents, or systemic corticosteroids, immunomodulators within 2 weeks before apheresis. 14. Subjects with other malignant tumors. Except for: (1) Carcinoma in situ with curative treatment and no evidence of recurrence for at least 2 years; (2) the primary malignant tumor has been completely resected and achieved CR for ≥ 2 years. 15. Subjects with history of thromboembolism ≥ Grade 3 within 6 months before apheresis, or is receiving thrombolytic or anticoagulant for high-risk of thromboembolism. 16. Known HIV or syphilis infection, and/or active hepatitis B virus or hepatitis C virus infection. 17. Organ transplanters and allogeneic cell transplanters. 18. Subjects with active pulmonary tuberculosis infection within 1 year or have not received treatment at least 1 year before apheresis. 19. Pregnant or lactating female, or those whose HCG test is positive before enrollment. 20. According to the judgment of the researcher, those who are not suitable for the group, such as poor compliance.

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: HRYZ-T101 Injection<br>Patients will undergo lymphocytapheresis, then treatment with HRYZ-T101 TCR-T cells. | Biological: HRYZ-T101 Injection<br>* On day 1, the TCR-T cells will be administered intravenously.<br>Drug: Fludarabine + Cyclophosphamide<br>* Fludarabine: 25mg/m²/day×3days; Cyclophosphamide: 250mg/m²/day×3 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Dose-limiting toxicity | 28 days | 
| Adverse events and serious adverse events | Incidence of adverse events and serious adverse events | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate（ORR） | The percentage of subjects with PR or CR assessed by RECIST 1.1. | 2 years | 
| Disease Control Rate (DCR) | The percentage of subjects with a confirmed CR, PR, or stable disease (SD) assessed by RECIST 1.1. | 2 years | 
| Duration of response (DoR) | Subjects who show a confirmed CR or PR as assessed by RECIST 1.1. | 2 years | 
| Time to response (TTR) | Time from date of T-cell administration to first documented evidence of confirmed (CR or PR) as assessed by RECIST 1.1. | 2 years | 
| Progression-Free Survival（PFS） | The length of time from enrollment until the time of progression of disease. | 2 years | 
| Overall Survival (OS) | The interval of time between the date of T-cell infusion and the date of death. | 2 years | 
| Duration of TCR T cells in-vivo persistence | Blood samples were collected to measure persistence of infused HRYZ-T101. | 2 years | 
| Concentration of Cytokines (IL-2、IL-6、IL-10、TNFα、IFNγ) | Collect blood samples and analyze for presence of cytokines (IL-2、IL-6、IL-10、TNFα、IFNγ) at specified intervals before and after treatment with HRYZ-T101. | 2 years |