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HPV16 E6 TCR T Cells for Cervical Carcinoma

Primary Purpose

Cervical Carcinoma

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

TC-E202 cells

IL-2

Fludarabine

Cyclophosphamide Capsules

About this trial

This is an interventional treatment trial for Cervical Carcinoma focused on measuring HPV16 E6, TCR T Cells, Cervical Carcinoma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Be able to understand and sign the Informed of Consent Document. Be willing to follow the procedure and protocol of the clinical trial.
Age ≥ 18 years and ≤ 70 years.
Expected survival time > 3 months.
ECOG score 0-1.
Recurrent or metastatic cervical carcinoma based on TNM & FIGO staged histopathological investigation.
Received at least second-line standard treatment and diagnosed as PD through image assessment. (previously received radio-therapy, chemo-therapy, targeted-therapy or immune-therapy, wash-out period > 14 or 5 half life)
Be able provide fresh or preserved tissue specimen. (fresh specimen first, paraffine specimen or at least 12 tumor section, tumor tissue >20%)
At least 1 measurable lesion (according to RECIST1.1 standard）.
HPV16 positive.
HLA-A2 positive.
Hematology should at least meet the following criteria:
Absolute neutrophil count (ANC) ≥ 1.5× 109/L (±20%)； Platelet (PLT） ≥ 75× 109/L (±20%）； Hemoglobin (HGB) ≥ 90 g/L (±20%).
Blood biochemistry should at least meet the following criteria:
Serum creatinine (Cr) ≤ 1.5 times of upper limit of normal (ULN) or creatine clearance ≥ 60 ml/min; Serum Alanine aminotransferase (ALT) or/and Aspartate aminotransferase (AST) ≤ 2.5 times of upper limit of normal; Total bilirubin (TBIL) ≤ 15 times of upper limit of normal.
Blood coagulation function is normal: Prothrombin time (PT) ≤ 1.5 ULN, International Normalized Ratio (INR) ≤ 1.5 ULN, or Activated Partial Thromboplastin Time (APTT) ≤ 1.5 ULN.
Women of childbearing potential should be ascetic or take contraception since the signing of ICF to 24 weeks or later after the last administration of drug.
Recovered from toxic effect of previous treatment (CTCAE ≤ 1), or related AE(s) is not defined as safety issue.
Catheter insertion is feasible and No White Blood Cells collection contraindications.

Exclusion Criteria:

Under pregnancy or lactation, or positive based on blood pregnancy test.
Severe allergic to related ingredients in the clinical trial.
Received any other investigational treatment within 4 weeks before the first administration or enrolled in another clinical trial the same time (exception: the other treatment is observational and non-investigational or the patient is under follow-up period)
Primary central nerve system (CNS) cancer, or subjects with CNS metastasis after localized treatment (except patients without CNS metastasis, clinically stable and neither steroid treatment nor treatment for CNS metastasis).
Patients with active autoimmune disease or require systemic steroid treatment. (except patients with cutaneous condition but without systemic treatment, or subjects with asthma in childhood but without intervention after grown-up, or subjects with hypothyroidism mediated by autoimmune dysfunction and receiving thyroxine as replaced treatment)
Immunodeficiency including HIV positive, harvested or natural immunodeficiency.
Patients with ≥ grade 3 thromboembolic events within 2 years or under thrombolysis treatment.
Patients with hereditary or acquired hemorrhagic disease
Patients with cardiovascular disease or symptoms:
congestive heart failure (NYHA > 2); history of unstable angina pectoris; miocardial infarction within 48 weeks; clinically significant malignant arrhythmia (except atrial fibrillation and paroxysmal supraventricular tachycardia); Clinically significant prolonged QTcF (Male QTcF > 450 msec, Female QTcF > 470 msec); Uncontrolled hypertension.
Patients under active infection (except subjects with fever caused by tumor)
Patients with active tuberculosis, or history of active tuberculosis within 1 year before enrollment, or history of active tuberculosis over a year before enrollment but without standard treatment.
Patient with Active Hepatitis B or Active Hepatitis C.
Treponema pallidum antibody positive.
Received major surgery or under severe injury within 4 weeks before enrollment.
History of drug abuse, alcohol or drug addiction.
Received cell therapy before enrollment，such as TCR-T，CAR-T and TIL .
Allergic to IL-2.
Received treatment related chemo-therapy within 14 days of TC-E202 infusion (except lymphodepletion) .
Patient not suitable for the clinical trial according to investigators.

Sites / Locations

Xiaochun ChengRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TC-E202 dose

Arm Description

This study uses the "3+3" dose escalation method. The initial dose is Dose1, the maximum dose that patients can tolerate is determined as the phase II recommended dose (RPIID), and at least 6 patients are receiving RPIID treatment . If patients develop intolerance in Dose 1 (≥3 subjects with DLT), then the subsequent enrolled patients will receive Dose-1 infusion.

Outcomes

Primary Outcome Measures

Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)

Dose Limiting Toxicity (DLT) is defined as patients with the adverse event (AE) or laboratory abnormality recognized by SRC, and should be possibly related to TC-E202 cell therapy, and should be unrelated to the disease itself, disease progression, concomitant diseases or concomitant medication. The MTD is the highest dose at which ≤1 of 6 patients experienced a dose limiting toxicity (DLT) or the highest dose level studied if DLTs are not observed at any of the dose levels.

Overall response rate

The efficacy of TC-E202 will be assessed by the objective response rate (ORR) is evaluated according to RECIST 1.1 and iRECIST. ORR is described as patients assessed with partial response (PR) and complete response (CR).

Treatment-related adverse events as assessed by CTCAE v5.0

The type, incidence and severity of adverse events include abnormal laboratory examination results with clinical significance after treatment, abnormal physical examination and blood examination results, bone marrow examination results, etc. Clinical and laboratory adverse events will be classified according to the National Cancer Institute general terminology standard for adverse events (NCI CTCAE) version 5.0.

Secondary Outcome Measures

Duration of response

The efficacy of TC-E202 will be assessed by duration of response (DOR). The DOR refers to the length of time from the first appearance of a treatment response to the first occurrence of progressive disease or recurrence.

Progression free survival

The efficacy of TC-E202 will be assessed by progression free survival (PFS). The PFS refers to the time from treatment to progressive disease or death for any reason.

Overall survival

The efficacy of TC-E202 will be assessed by overall survival (OS). The OS refers to the time from treatment to death.

Maximum Persistence (Cmax) of TC-E202

Blood samples were collected to measure persistence of infused TC-E202 using polymerase chain reaction of a vector specific sequence in deoxyribonucleic acid (DNA) extracted from peripheral blood mononuclear cell (PBMC).

Time to Maximum Persistence

Blood samples were collected to measure persistence of infused TC-E202 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC.

Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC[0-28])

Blood samples were collected to measure persistence of infused TC-E202 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC.

Anti-PD-1 single chain antibody concentration

The pharmacodynamics of TC-E202 will be assessed by Anti-PD-1 single chain antibody content.

Full Information

NCT ID

NCT05357027

First Posted

January 3, 2022

Last Updated

October 20, 2022

Sponsor

TCRCure Biopharma Ltd.

Collaborators

Fudan University

1. Study Identification

Unique Protocol Identification Number

NCT05357027

Brief Title

HPV16 E6 TCR T Cells for Cervical Carcinoma

Official Title

A Phase I/II Clinical Trail of TC-E202 Targeting HPV16 E6 for Relapsed/Refractory to Standard Treatment or Metastatic Cervical Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

August 10, 2022 (Actual)

Primary Completion Date

March 31, 2023 (Anticipated)

Study Completion Date

August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

TCRCure Biopharma Ltd.

Collaborators

Fudan University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

Detailed Description

Background: Cervical cancer is the most common gynecologic malignant tumor. The occurrence and progression of cervical carcinoma is firmly relevant to HPV (Human papilloma virus) infection. Cancer cells infected by HPV expressing an HPV protein called E6. E6 is the main factors of HPV 16 carcinogenesis. T cells genetically engineered with a TCR targeting HPV-16 E6 (E6 TCR) display specific reactivity against HLA-A2+, HPV-16+ target cells. T cell receptor (TCR) gene engineered T cells infusion can induce objective tumor responses in certain malignancies including HPV-16+ cancer. Objective: Phase I: Determine the safety and tolerability of TC-E202 inHPV16 positive patients with relapsed/refractory to standard treatment or metastatic cervical carcinoma and determine the Recommended Phase II Dose (RPIID). Primary endpoints: safety and tolerability. The evaluation of safety and tolerability will be based on the following endpoints: 1) Whether DLT occurs or MTD is achieved; 2) The incidence of various adverse events and serious adverse events and their relationship with TCR-T, IL-2, lymphodepletion chemotherapy and leukapheresis. Secondary endpoints: efficacy. Objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were assessed based on RECIST 1.1 and iRECIST. Eligibility: Adults aging 18-70 with relapsed/refractory to standard treatment or metastatic cervical carcinoma. Eligible patients were HLA-A*02 and had metastatic HPV16-positive cervical cancer. Patients had received or declined previous systemic therapy, with more than 4 weeks elapsed since previous systemic treatment. Patients had an Eastern Cooperative Oncology Group performance score of 0 or 1 and adequate hematologic, hepatic, and renal function. Design: This is a Phase I/II clinical trial to evaluate the efficacy and safety of TC-E202. Dose escalation will proceed according to 3+3 procedure. All patients will receive a lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine followed by an infusion of E6 TCR (TC-E202) cells. Cell infusion will be followed by IL-2 administration. All patents will be evaluated based on ORR according to RECIST v1.1&iRECIST. Phase I clinical trials establish a Drug Safety Review Committee (SRC), and the SRC will hold regular and irregular meetings to evaluate the safety data of the subjects, the clinical pharmacology, along with associated clinical efficacy, to decide escalating dose and RPIID. In addition, the SRC will decide whether to explore higher or lower doses than planned doses based on specific data.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cervical Carcinoma

Keywords

HPV16 E6, TCR T Cells, Cervical Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

TC-E202 dose

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

TC-E202 cells

Other Intervention Name(s)

TCR T Cells

Intervention Description

T cells genetically engineered with a TCR targeting HPV16 E6 (E6 TCR) that display specific reactivity against HLA-A2+, HPV-16+ target cells

Intervention Type

Drug

Intervention Name(s)

IL-2

Intervention Description

Following cell infusion, the patient receives high-dose bolus IL-2, which is dosed to individual patient tolerance. IL-2 improves the survival of TC-E202 cells after infusion.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

Part of the non-myeloablative lymphocyte-depleting preparative regimen.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide Capsules

Intervention Description

Part of the non-myeloablative lymphocyte-depleting preparative regimen.

Primary Outcome Measure Information:

Title

Dose Limiting Toxicity or Maximum Tolerated Dose (MTD)

Description

Time Frame

Day 28 after the first TC-E202 infusion

Title

Overall response rate

Description

Time Frame

Day0-Day730

Title

Treatment-related adverse events as assessed by CTCAE v5.0

Description

Time Frame

Day0-Day730

Secondary Outcome Measure Information:

Title

Duration of response

Description

Time Frame

Day0-Day730

Title

Progression free survival

Description

The efficacy of TC-E202 will be assessed by progression free survival (PFS). The PFS refers to the time from treatment to progressive disease or death for any reason.

Time Frame

Day0-Day730

Title

Overall survival

Description

The efficacy of TC-E202 will be assessed by overall survival (OS). The OS refers to the time from treatment to death.

Time Frame

Day0-Day730

Title

Maximum Persistence (Cmax) of TC-E202

Description

Time Frame

Day0-Day730

Title

Time to Maximum Persistence

Description

Blood samples were collected to measure persistence of infused TC-E202 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC.

Time Frame

Day0-Day730

Title

Area Under the Plasma Concentration-time Curve From Zero to Day 28 (AUC[0-28])

Description

Blood samples were collected to measure persistence of infused TC-E202 using polymerase chain reaction of a vector specific sequence in DNA extracted from PBMC.

Time Frame

Day 28 after the first TC-E202 infusion

Title

Anti-PD-1 single chain antibody concentration

Description

The pharmacodynamics of TC-E202 will be assessed by Anti-PD-1 single chain antibody content.

Time Frame

Day0-Day730

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Be able to understand and sign the Informed of Consent Document. Be willing to follow the procedure and protocol of the clinical trial. Age ≥ 18 years and ≤ 70 years. Expected survival time > 3 months. ECOG score 0-1. Recurrent or metastatic cervical carcinoma based on TNM & FIGO staged histopathological investigation. Received at least second-line standard treatment and diagnosed as PD through image assessment. (previously received radio-therapy, chemo-therapy, targeted-therapy or immune-therapy, wash-out period > 14 or 5 half life) Be able provide fresh or preserved tissue specimen. (fresh specimen first, paraffine specimen or at least 12 tumor section, tumor tissue >20%) At least 1 measurable lesion (according to RECIST1.1 standard）. HPV16 positive. HLA-A2 positive. Hematology should at least meet the following criteria: Absolute neutrophil count (ANC) ≥ 1.5× 109/L (±20%)； Platelet (PLT） ≥ 75× 109/L (±20%）； Hemoglobin (HGB) ≥ 90 g/L (±20%). Blood biochemistry should at least meet the following criteria: Serum creatinine (Cr) ≤ 1.5 times of upper limit of normal (ULN) or creatine clearance ≥ 60 ml/min; Serum Alanine aminotransferase (ALT) or/and Aspartate aminotransferase (AST) ≤ 2.5 times of upper limit of normal; Total bilirubin (TBIL) ≤ 15 times of upper limit of normal. Blood coagulation function is normal: Prothrombin time (PT) ≤ 1.5 ULN, International Normalized Ratio (INR) ≤ 1.5 ULN, or Activated Partial Thromboplastin Time (APTT) ≤ 1.5 ULN. Women of childbearing potential should be ascetic or take contraception since the signing of ICF to 24 weeks or later after the last administration of drug. Recovered from toxic effect of previous treatment (CTCAE ≤ 1), or related AE(s) is not defined as safety issue. Catheter insertion is feasible and No White Blood Cells collection contraindications. Exclusion Criteria: Under pregnancy or lactation, or positive based on blood pregnancy test. Severe allergic to related ingredients in the clinical trial. Received any other investigational treatment within 4 weeks before the first administration or enrolled in another clinical trial the same time (exception: the other treatment is observational and non-investigational or the patient is under follow-up period) Primary central nerve system (CNS) cancer, or subjects with CNS metastasis after localized treatment (except patients without CNS metastasis, clinically stable and neither steroid treatment nor treatment for CNS metastasis). Patients with active autoimmune disease or require systemic steroid treatment. (except patients with cutaneous condition but without systemic treatment, or subjects with asthma in childhood but without intervention after grown-up, or subjects with hypothyroidism mediated by autoimmune dysfunction and receiving thyroxine as replaced treatment) Immunodeficiency including HIV positive, harvested or natural immunodeficiency. Patients with ≥ grade 3 thromboembolic events within 2 years or under thrombolysis treatment. Patients with hereditary or acquired hemorrhagic disease Patients with cardiovascular disease or symptoms: congestive heart failure (NYHA > 2); history of unstable angina pectoris; miocardial infarction within 48 weeks; clinically significant malignant arrhythmia (except atrial fibrillation and paroxysmal supraventricular tachycardia); Clinically significant prolonged QTcF (Male QTcF > 450 msec, Female QTcF > 470 msec); Uncontrolled hypertension. Patients under active infection (except subjects with fever caused by tumor) Patients with active tuberculosis, or history of active tuberculosis within 1 year before enrollment, or history of active tuberculosis over a year before enrollment but without standard treatment. Patient with Active Hepatitis B or Active Hepatitis C. Treponema pallidum antibody positive. Received major surgery or under severe injury within 4 weeks before enrollment. History of drug abuse, alcohol or drug addiction. Received cell therapy before enrollment，such as TCR-T，CAR-T and TIL . Allergic to IL-2. Received treatment related chemo-therapy within 14 days of TC-E202 infusion (except lymphodepletion) . Patient not suitable for the clinical trial according to investigators.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

XiaoHua Wu, doctor

Phone

+86-2164175590

Wu.XH@Fudan.edu.cm

First Name & Middle Initial & Last Name or Official Title & Degree

Jian Zhang, doctor

Phone

+86-2164175590

Syner2000@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

XiaoHua Wu, doctor

Organizational Affiliation

Fudan University

Official's Role

Study Director

Facility Information:

Facility Name

Xiaochun Cheng

City

Chongqing

State/Province

Chongqing

ZIP/Postal Code

400000

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Wang Miaomiao

Phone

+86 18716368572

miaomiao.wang@tcrcure.com

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

HPV16 E6 TCR T Cells for Cervical Carcinoma

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