Interventional Therapy Sequential With the Fourth-generation CAR-T Targeting Nectin4/FAP for Malignant Solid Tumors

November 16, 2020 updated by: The Sixth Affiliated Hospital of Wenzhou Medical University

Clinical Trial Study of Interventional Therapy Sequential With the Fourth-generation CAR-T Cells (IL7 and CCL19 or / and IL12) Targeting Nectin4/FAP in the Treatment of Advanced Malignant Solid Tumors With Nectin4-positive

According to the high expression of tumor cell-associated antigen Nectin4 in patients with solid tumors such as non-small cell lung cancer, breast cancer, ovarian cancer, bladder cancer, and pancreatic cancer, and in order to target FAP-positive CAFs in the tumor-associated stroma, the Intravenous minimally invasive surgery combined with intratumoral injection of Nectin4/FAP-targeted fourth-generation CAR-T cells (expressing IL7 and CCL19, or IL12) are used to treat Nectin4-positive advanced malignant solid tumors, maximally eliminating residual cancer cells and preventing recurrence.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Currently, malignant tumors are the leading cause of death. Surgery, chemotherapy, radiation therapy, and targeted therapy have become the four foundations of cancer treatment for many years. With the development of science and technology, immunotherapy has become the "fifth pillar" of cancer treatment. The most hot topic in immunotherapy is CAR-T therapy. The basic principle of CAR-T therapy (chimeric antigen receptor-T cells) is mainly to use the patient's own immune cells to clear cancer cells. CAR is a core component of CAR-T, conferring T cell a HLA-independent way to recognize tumor antigens, allowing CAR-modified T cells to recognize a broader target than the natural T cell surface receptor TCR. The basic design of CAR includes a tumor associated antigen (TAA) binding region, an extracellular hinge region, a transmembrane region and an intracellular signaling region. The selection of target antigens is a key determinant of the specificity and effectiveness of CAR and the safety of genetically modified T cells themselves.

Nectin-4 is a type I transmembrane protein whose extracellular domain is composed of three Ig-like domains (V-C-C type), which together with cadherin participate in the formation and maintenance of adhesion junctions. Nectin-4 is ubiquitously expressed in human embryonic cells but is hardly expressed in normal adult tissues. Nectin-4 is highly expressed on the surface of breast cancer, bladder cancer, non-small cell lung cancer, and pancreatic cancer cells, and plays a key role in the occurrence, invasion and metastasis of these epithelial malignancies. In conclusion, Nectin-4 is one of the important targets for the diagnosis and treatment of many solid tumors. The antibody-conjugated drug Enfortumab Vedotin targeting Nectin-4 was highly effective in Phase I clinical trials in 81 advanced bladder cancers, and was awarded FDA breakthrough therapy in March 2018. Fibroblast activation protein (FAP) belongs to the serine protease family and is highly expressed on the surface of cancer-associat

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Zhejiang
      • Lishui, Zhejiang, China, 323000
        • Recruiting
        • The Sixth Affiliated Hospital of Wenzhou Medical University
        • Contact:
        • Principal Investigator:
          • Bingmu Fang, M.D
      • Wenzhou, Zhejiang, China, 325035
        • Recruiting
        • Zhejiang QiXin Biotech
        • Contact:
        • Contact:
        • Principal Investigator:
          • Jimin Gao, M.D., Ph.D.
        • Sub-Investigator:
          • Ai Zhao, M.D., Ph.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Patients who meet the requirements voluntarily participate in the study and sign the Informed Consent Form.
  2. Age is 18 to 75 years old, gender is not limited; the Eastern Cancer Cooperative Group (ECOG) scores 0 to 3
  3. Pathological diagnosis of malignant solid tumors.
  4. Advanced malignant solid tumors meet the CSCO malignant tumor diagnosis and treatment guidelines (2018 version). (Flow or pathology shows that tumor cells express Nectin4 antigen and tumor-associated fibroblasts express FAP antigen)
  5. Head magnetic resonance or CT examination showed no central invasion of malignant tumors.
  6. Collection of peripheral blood mononuclear cells must be more than 2 weeks from radiotherapy and chemotherapy.
  7. Peripheral blood neutrophils number ≥ 1000 / μl, platelets ≥ 50,000 / μl.
  8. Heart, liver and kidney function: creatinine <2.5mg/dl; ALT (alanine aminotransferase) / AST (aspartate aminotransferase) <3 times lower than the upper limit of normal; total bilirubin <2.0mg/dl.
  9. Cardiac ejection fraction (EF) ≥ 50%, echocardiography without pericardial effusion.
  10. Have fertility must be willing to use contraceptive methods.
  11. The expected survival period is more than 12 weeks.
  12. No other malignant tumors, severe autoimmune diseases or congenital immunodeficiency, serious progressive infection, cranial nerve disorder or mental illness.

Exclusion Criteria:

  1. Pregnant or lactating women.
  2. Patients with uncontrollable active infections.
  3. Patients with systemic steroids; recent or current use of inhaled steroids is not excluded.
  4. Previously involved CAR-T cell therapies produced any uncontrolled disease.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: The fourth-generation CAR-T therapy
Clinical trial study of Interventional therapy sequential with the fourth-generation CAR-T cells (IL7 and CCL19 or / and IL12) targeting Nectin4/FAP in the treatment of advanced malignant solid tumors with Nectin4-positive .
Biological: CAR-T therapy for nectin4-positive malignant solid tumor
The Intravenous minimally invasive surgery combined with intratumoral injection of Nectin4/FAP-targeted the fourth-generation CAR-T cells (expressing IL7 and CCL19, or IL12) are used to treat Nectin4-positive advanced malignant solid tumors, maximally eliminating residual cancer cells and preventing recurrence.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse events that are related to treatment
Time Frame: 2 years
Safety and tolerability measured by occurrence of study related adverse effects defined by NCI-CTCAE v4.03
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
2 year overall survival(OS)
Time Frame: 2 years
To estimate 2 year overall survival(OS) after the fourth-generation CAR-T cells (IL7 and CCL19 or / and IL12) targeting Nectin4/FAP in the treatment of advanced malignant solid tumors with Nectin4-positive
2 years
3 year progression free survival (PFS)
Time Frame: 3 years
To estimate 3 year progression free survival after the fourth-generation CAR-T cells (IL7 and CCL19 or / and IL12) targeting Nectin4/FAP in the treatment of advanced malignant solid tumors with Nectin4-positive
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Sixth Affiliated Hospital of Wenzhou Medical University

Collaborators

Zhejiang Qixin Biotech

Investigators

  • Principal Investigator: Bingmu Fang, M.D, Lishui Country People's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 13, 2019

Primary Completion (Anticipated)

June 30, 2021

Study Completion (Anticipated)

December 31, 2021

Study Registration Dates

First Submitted

April 27, 2019

First Submitted That Met QC Criteria

April 27, 2019

First Posted (Actual)

April 30, 2019

Study Record Updates

Last Update Posted (Actual)

November 18, 2020

Last Update Submitted That Met QC Criteria

November 16, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Lishui People's Hospital

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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