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出境医 / 临床实验 / Interventional Therapy Sequential With the Fourth-generation CAR-T Targeting Nectin4/FAP for Malignant Solid Tumors

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

Study Description
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

Study Design
Layout table for study information
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
Arms and Interventions
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.
Outcome Measures
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


Eligibility Criteria
Layout table for eligibility information
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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Bingmu Fang, M.D 0578-2780108 fbm636@163.com

Locations
Layout table for location information
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
Layout table for investigator information
Principal Investigator: Bingmu Fang, M.D Lishui Country People's Hospital
Tracking Information
First Submitted Date  ICMJE April 27, 2019
First Posted Date  ICMJE April 30, 2019
Last Update Posted Date November 18, 2020
Actual Study Start Date  ICMJE February 13, 2019
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 27, 2019) 		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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2019)
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Interventional Therapy Sequential With the Fourth-generation CAR-T Targeting Nectin4/FAP for Malignant Solid Tumors
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Nectin4-positive Advanced Malignant Solid Tumor
Intervention  ICMJE 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.
Study Arms  ICMJE 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 .
Intervention: Biological: CAR-T therapy for nectin4-positive malignant solid tumor
Publications *
  • Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, Solomides CC, June CH, Puré E, Albelda SM. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014 Feb;2(2):154-66. doi: 10.1158/2326-6066.CIR-13-0027. Epub 2013 Nov 12.
  • Lo A, Wang LS, Scholler J, Monslow J, Avery D, Newick K, O'Brien S, Evans RA, Bajor DJ, Clendenin C, Durham AC, Buza EL, Vonderheide RH, June CH, Albelda SM, Puré E. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells. Cancer Res. 2015 Jul 15;75(14):2800-2810. doi: 10.1158/0008-5472.CAN-14-3041. Epub 2015 May 15.
  • Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015 Apr 3;348(6230):74-80. doi: 10.1126/science.aaa6204. Review.
  • Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, Raitano A, Nadell R, Liu W, Lortie DR, Capo L, Verlinsky A, Leavitt M, Malik F, Aviña H, Guevara CI, Dinh N, Karki S, Anand BS, Pereira DS, Joseph IB, Doñate F, Morrison K, Stover DR. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016 May 15;76(10):3003-13. doi: 10.1158/0008-5472.CAN-15-1313. Epub 2016 Mar 24.
  • Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010 Nov 5;330(6005):827-30. doi: 10.1126/science.1195300.
  • Lopez M, Ghidouche A, Rochas C, Godelaine D, Carrasco J, Colau D, Hames G, Montero-Julian FA, Coulie PG, Olive D. Identification of a naturally processed HLA-A*02:01-restricted CTL epitope from the human tumor-associated antigen Nectin-4. Cancer Immunol Immunother. 2016 Oct;65(10):1177-88. doi: 10.1007/s00262-016-1877-7. Epub 2016 Aug 11.
  • Targeting Nectin-4 in Bladder Cancer. Cancer Discov. 2017 Aug;7(8):OF3. doi: 10.1158/2159-8290.CD-NB2017-095. Epub 2017 Jun 20.
  • Tsiatas M, Grivas P. Immunobiology and immunotherapy in genitourinary malignancies. Ann Transl Med. 2016 Jul;4(14):270. doi: 10.21037/atm.2016.06.29. Review.
  • Srivastava S, Riddell SR. Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy. J Immunol. 2018 Jan 15;200(2):459-468. doi: 10.4049/jimmunol.1701155. Review.
  • Mirzaei HR, Rodriguez A, Shepphird J, Brown CE, Badie B. Chimeric Antigen Receptors T Cell Therapy in Solid Tumor: Challenges and Clinical Applications. Front Immunol. 2017 Dec 22;8:1850. doi: 10.3389/fimmu.2017.01850. eCollection 2017. Review. Erratum in: Front Immunol. 2019 Apr 17;10:780.
  • Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018 Apr;36(4):346-351. doi: 10.1038/nbt.4086. Epub 2018 Mar 5.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 27, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date June 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bingmu Fang, M.D 0578-2780108 fbm636@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03932565
Other Study ID Numbers  ICMJE Lishui People's Hospital
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party The Sixth Affiliated Hospital of Wenzhou Medical University
Study Sponsor  ICMJE The Sixth Affiliated Hospital of Wenzhou Medical University
Collaborators  ICMJE Zhejiang Qixin Biotech
Investigators  ICMJE
Principal Investigator: Bingmu Fang, M.D Lishui Country People's Hospital
PRS Account The Sixth Affiliated Hospital of Wenzhou Medical University
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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