Treatment of Malignant Melanoma With GPA-TriMAR-T Cell Therapy

Adoptive Immunotherapy for HLA_A2 Genotype gp100 Positive Malignant Melanoma With GPA-TriMAR-T Cell

Malignant melanoma have been reported to be characterized with high gp100 expression. Patients' autologous T cells will be isolated and transduced by GPA-TriMAR lentivirus to generate the GPA-TriMAR-T cells. When infused back to the patient, the GPA-TriMAR-T cells will recognize and kill target cells that express gp100(209-217) peptides in the form MHC-I complex, thus eliminating malignant melanoma from the body.

Study Overview

• Status: Unknown
• Conditions: Malignant Melanoma
• Intervention / Treatment: Biological: GPA-TriMAR-T

Detailed Description

GPA-TriMAR is a modified chimeric antigen receptor (CAR) that consist of three subunit in it's outer membrane domain. The outer membrane domain linked to the inner membrane 4-1BB/CD3ζ domain through the transmembrane domain, thus compose the complete chimeric antigen receptor. Patients' autologous T cells will be isolated and transduced by GPA-TriMAR lentivirus to generate the GPA-TriMAR-T cells. When infused back to the patient, the modified GPA-TriMAR-T cells will recognize and kill malignant melanoma cells in the body, and in the meanwhile the other two subunits function to stimulate the innate immune system and enhance GPA-TriMAR-T cells tumor Infiltration.

• Study Type: Interventional
• Enrollment (Anticipated): 6
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Hainan
    • Haikou, Hainan, China, 570100
      • Recruiting
      • Hainan Cancer Hospital
      • Contact: Yuyang Tian; Phone Number: +86 18686853849; Email: tianyuyang@163.com
    • Haikou, Hainan, China, 570100
      • Recruiting
      • The Second Affiliated Hospital of Hainan Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. All subjects must personally sign and date the consent form before initiating any study specific procedures or activities;
2. All subjects must be able to comply with all the scheduled procedures in the study;
3. HLA_A2 genotype and gp100 positive malignant melanoma： Ⅳ stage or relapsed after surgery or chemotherapy or no available standard therapy;
4. At least one measurable lesion per RECIST V1.1;
5. Aged 18 to 69 years;
6. Expected survival ≥12 weeks; Eastern cooperative oncology group (ECOG) performance status of≤2;
7. Systematic usage of immunosuppressive drug or corticosteroid must have been stopped for more than 4 weeks;
8. All other treatment induced adverse events must have been resolved to ≤grade 1;
9. Laboratory tests must fulfill the following criteria: ANC ≥ 1000/uL, HGB>70g/L, Platelet count ≥ 50,000/uL, Creatinine clearance ≤1.5 ULN, Serum ALT/AST ≤2.5 ULN, Total bilirubin ≤1.5 ULN (except in subjects with Gilbert's syndrome);

Exclusion Criteria:

1. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring iv antimicrobials for management. (Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment);
2. Patients with symptomatic central nervous system metastasis, intracranial metastasis, and cancer cells found in cerebrospinal fluid are not recommended to participate in this study. Symptom free or post-treatment stable disease or disappearance of lesions should not be excluded. The specific selection is ultimately determined by the investigator;
3. Lactating women or women of childbearing age who plan to conceive during the time period;
4. Active infection with hepatitis B (HBsAG positive) or hepatitis C virus (anti-HCV positive);
5. Known history of infection with HIV;
6. Subjects need systematic usage of corticosteroid;
7. Subjects need systematic usage of immunosuppressive drug;
8. Planed operation, history of other related disease, or any other related laboratory tests restrict patients for the study;
9. Other reasons the investigator consider the patient may not be suitable for the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GPA-TriMAR-T; Patients' autologous T cells will be isolated and transduced by GPA-TriMAR lentivirus to generate the GPA-TriMAR-T cells, and these cells will then be infused back into the patient for intervention.	Biological: GPA-TriMAR-T; Patients will undergo leukapheresis to isolate autologous T cells, these T cells will be activated and modified to express GPA-TriMAR in the manufacture facility, and eventually infused back into the body for treatment.; Other Names: TCR-mimic-CAR-T

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety （Incidence of treatment-related adverse events as assessed by CTCAE v4.03）	Incidence of treatment-related adverse events as assessed by CTCAE v4.03	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Partial response rate [PR] （Partial response rate per the revised International Working Group (IWG) Response Criteria）	Partial response rate per the revised International Working Group (IWG) Response Criteria	24 months
Duration of Response （The time from response to relapse or progression）	The time from response to relapse or progression	24 months
Overall Survival （The number of patient alive, with or without signs of cancer）	The number of patient alive, with or without signs of cancer	24 months
Complete response rate[CR] （Complete response rate per the revised International Working Group (IWG) Response Criteria）	Complete response rate per the revised International Working Group (IWG) Response Criteria	24 months
Progression Free Survival （The time from the first day of treatment to the date on which disease progresses.）	The time from the first day of treatment to the date on which disease progresses.	24 months

Collaborators and Investigators

• Sponsor: Timmune Biotech Inc.
• Collaborators: The Second Affiliated Hospital of Hainan Medical University; Hainan Cancer Hospital

Publications and helpful links

General Publications

• Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018 Jan;15(1):47-62. doi: 10.1038/nrclinonc.2017.148. Epub 2017 Sep 19.
• Zhang G, Liu R, Zhu X, Wang L, Ma J, Han H, Wang X, Zhang G, He W, Wang W, Liu C, Li S, Sun M, Gao B. Retargeting NK-92 for anti-melanoma activity by a TCR-like single-domain antibody. Immunol Cell Biol. 2013 Nov-Dec;91(10):615-24. doi: 10.1038/icb.2013.45. Epub 2013 Oct 8.
• Zhang G, Wang L, Cui H, Wang X, Zhang G, Ma J, Han H, He W, Wang W, Zhao Y, Liu C, Sun M, Gao B. Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor. Sci Rep. 2014 Jan 6;4:3571. doi: 10.1038/srep03571.

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2018
• Primary Completion (Anticipated): September 15, 2021
• Study Completion (Anticipated): January 1, 2022

Study Registration Dates

• First Submitted: August 23, 2018
• First Submitted That Met QC Criteria: August 26, 2018
• First Posted (Actual): August 28, 2018

Study Record Updates

• Last Update Posted (Actual): December 6, 2019
• Last Update Submitted That Met QC Criteria: December 5, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: gp100; HLA-A2
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: T2018-7

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No