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

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ClinicalTrials.gov Identifier: NCT03932565
Recruitment Status : Recruiting
First Posted : April 30, 2019
Last Update Posted : November 18, 2020
Sponsor:
Collaborator:
Zhejiang Qixin Biotech
Information provided by (Responsible Party):
The Sixth Affiliated Hospital of Wenzhou Medical University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Nectin4-positive Advanced Malignant Solid Tumor Biological: CAR-T therapy for nectin4-positive malignant solid tumor Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 13, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : December 31, 2021

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.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03932565


Contacts
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Contact: Bingmu Fang, M.D 0578-2780108 fbm636@163.com

Locations
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China, Zhejiang
The Sixth Affiliated Hospital of Wenzhou Medical University Recruiting
Lishui, Zhejiang, China, 323000
Contact: Bingmu Fang, M.D    0578-2780108    fbm636@163.com   
Contact: M.D         
Principal Investigator: Bingmu Fang, M.D         
Zhejiang QiXin Biotech Recruiting
Wenzhou, Zhejiang, China, 325035
Contact: Jimin Gao, M.D., Ph.D.    86-577-86699341    jimingao@yahoo.com   
Contact: Ai Zhao, M.D., Ph.D.    86-577-86699341    zhaoai618@126.com   
Principal Investigator: Jimin Gao, M.D., Ph.D.         
Sub-Investigator: Ai Zhao, M.D., Ph.D.         
Sponsors and Collaborators
The Sixth Affiliated Hospital of Wenzhou Medical University
Zhejiang Qixin Biotech
Investigators
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Principal Investigator: Bingmu Fang, M.D Lishui Country People's Hospital
Publications:

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Responsible Party: The Sixth Affiliated Hospital of Wenzhou Medical University
ClinicalTrials.gov Identifier: NCT03932565    
Other Study ID Numbers: Lishui People's Hospital
First Posted: April 30, 2019    Key Record Dates
Last Update Posted: November 18, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms