HRYZ-T101 TCR-T Cell for HPV-18 Positive Advanced Solid Tumor

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

Official Title
-----------------
A Phase I Study to Evaluate the Safety, Tolerance and Efficacy of HRYZ-T101 TCR-T Cell for HPV18 Positive Advanced Solid Tumor

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

Intervention / Treatment
-----------------
* Drug: Fludarabine + Cyclophosphamide
* Biological: HRYZ-T101 TCR-T Cell


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The patient must be willing to sign the informed consent form. Age ≥18 years and ≤70 years. Histologically-confirmed advanced metastatic or recurrent solid tumors with confirmed HPV18 infection and HLA-DRB1*09:01 allele. Subjects who have failed at least first-line treatment in the past and lack effective treatment options. ECOG performance status of 0-1. Estimated life expectancy ≥ 3 months. Patients must have at least one measurable lesion defined by RECIST 1.1. Subjects with potential fertility must agree to use effective contraceptive methods during the whole trials period and at least 6 months after receiving HRYZ-T101 cell transfusion treatment. Patients with any organ dysfunction as defined below: 1) Leukocytes≥3.0 x 10^9/L; 2) absolute neutrophil count ≤1.5 x 10^9/L; 3) blood platelets ≥75 x 10^9/L; 4) hemoglobin≥90g/L; 5) Serum albumin ≥ 3.0g/dL; 6) total bilirubin≤1.5×ULN; ALT/AST≤2.5×ULN; 7) Creatinine clearance ≥50mL/min; 8) INR≤1.5×ULN; APTT≤1.5×ULN; 9) LVEF≥50%; 10) SpO2≥92%. Exclusion Criteria: Organ transplanters and allogeneic cell transplanters. 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. Those who have undergone major surgery within 4 weeks before enrollment, and those who have received conventional chemotherapy, large-area radiotherapy, targeted therapy, endocrine therapy, immunotherapy or biological therapy, and Chinese herbal medicine and other anti-tumor treatment. Have received live attenuated vaccine within 4 weeks before enrollment. Subjects with clinical cardiac symptoms or diseases that cannot be well controlled. The subject has active infection or fever more than 38.5 degrees of unknown cause during screening and before cell transfusion. Subjects have any active autoimmune disease or history of autoimmune disease. Subjects with other malignant tumors. Patients with central nervous system metastasis. Active, uncontrolled bacterial or fungal infection requiring systemic treatment. Known HIV or syphilis infection, and/or active hepatitis B virus or hepatitis C virus infection. It is planned to use immunosuppressive agents, or systemic corticosteroids, immunomodulators. Have received any investigational drug within 4 weeks before enrollment, or have participated in another clinical study at the same time. Pregnant or lactating subjects, or those who are unwilling to contraception during the test. Known uncontrolled diabetes, pulmonary fibrosis, interstitial lung disease, acute lung disease or liver failure. Other serious organic diseases and mental disorders. Have received any gene therapy products before. According to the judgment of the researcher, those who are not suitable for the group, such as poor compliance.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Dose-limiting toxicity | 28 days | 
| Incidence of treatment related AEs, AEs of special interest and serious adverse events (SAEs). | Assessed by CTCAE V5.0 | 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 | 
| Overall Survival (OS) | From enrollment to death of patients. | 2 years | 
| Duration of Response（DOR） | The length of time from the first appearance of a treatment response to the first occurrence of progressive disease or recurrence. | 2 years | 
| Progression-Free Survival（PFS） | The length of time from enrollment until the time of progression of disease. | 2 years | 
| Duration of TCR T cells in-vivo persistence | Blood samples were collected to measure persistence of infused HRYZ-T101. | Up to 2 years |