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EpCAM CAR-T for Treatment of Advanced Solid Tumors

Primary Purpose

Malignant Neoplasm of Nasopharynx TNM Staging Distant Metastasis (M), Breast Cancer Recurrent, Gastric Cancer With Metastasis

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

EpCAM CAR-T cells

About this trial

This is an interventional treatment trial for Malignant Neoplasm of Nasopharynx TNM Staging Distant Metastasis (M) focused on measuring EpCAM CAR-T, solid tumors, cancer immunotherapy

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Inclusion criteria at the time of procurement:

Recurrent or refractory nasopharyngeal carcinoma and breast cancer and other solid tumors.
Karnofsky score of greater than or equal to 60.
Informed consent explained to, understood by and signed by subject/guardian. -
Subject/guardian given copy of informed consent

Treatment Inclusion criteria:

Recurrent or refractory EpCAM-positive nasopharyngeal carcinoma, breast cancer, gastric cancer and other epithelial tumors determined by Immunohistochemistry (IHC) or RT-PCR. EpCAM expression in tumors on IHC should be greater than or equal to grade 2 and greater than or equal to 2+ intensity score. Wherein grades are defines as: Grade 0: no staining; Grade 1: 1-25%; Grade 2: 26-50% and Grade 3: 51-100% of cell staining for EpCAM and intensity scores are: negative; 1+; 2+ and 3+ using breast cancer standard arrays as a guide for intensity.
Age ≥ 18 years
Life expectancy ≥ 6 weeks
Karnofsky score ≥ 60
Bilirubin less than or equal to 3x normal, AST less than or equal to 5x normal,
ALT less than or equal to 5x, serum creatinine less than or equal to 2x upper limit of normal for age, and Hgb greater than or equal to 8.0
Pulse oximetry of greater than or equal to 90% on room air.
Sexually active subjects must be willing to utilize one of the more effective birth control methods for 6 months after the T cell infusion. The male partner should use a condom.
Available autologous transduced T lymphocytes with greater than or equal to 20% expression of EpCAM CAR determined by flow-cytometry and killing of EpCAM-positive targets greater than or equal to 20% in cytotoxicity assay.
Subjects should have been off other investigational antineoplastic therapy for two weeks prior to entry in this study.
Cyclophosphamide will be allowed 72 hours preinfusion.
Dexamethasone up to a total dose of 2 mg per day will be allowed if medically indicated.
Informed consent explained to, understood by and signed by research subjects/guardian.
Subject/guardian given copy of informed consent.

Exclusion Criteria:

Exclusion Criteria at the time of procurement:

Known HIV positivity.

Treatment Exclusion Criteria:

Severe intercurrent infection.
Known HIV positivity.
Pregnant or lactating.
History of hypersensitivity reactions to murine protein-containing products.

Sites / Locations

West China Hospital, Sichuan UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

EpCAM CAR-T cells

Arm Description

Autologous T cells from patient are engineered to expressing a special chimeric antigen receptor to recognizing EpCAM by lentiviral vector. The engineered T cells were then endowed cytotoxicity to the tumor cells and hold the potential to inhibit the advance of tumors.

Outcomes

Primary Outcome Measures

Number of participants with treatment-related adverse events/dose limiting toxicity as assessed by CTCAE v4.0

Determine the largest dose of EpCAM CAR-T cells for patients with nasopharyngeal carcinoma, breast cancer and other tumors expressing EpCAM.

Secondary Outcome Measures

Response rate of participants treated with EpCAM CAR-T cells assessed by RECIST v1.1

Determine whether there is therapeutic efficacies of the safe dose infusion of EpCAM CAR-T cells for patients with solid tumors.

Persistence of EpCAM CAR-T cells and correlation with the Response rate

Full Information

NCT ID

NCT02915445

First Posted

September 21, 2016

Last Updated

October 8, 2022

Sponsor

Sichuan University

1. Study Identification

Unique Protocol Identification Number

NCT02915445

Brief Title

EpCAM CAR-T for Treatment of Advanced Solid Tumors

Official Title

T Cells Armed With Chimeric Antigen Receptor Recognizing EpCAM for Patients With Advanced Solid Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Recruiting

Study Start Date

July 2016 (undefined)

Primary Completion Date

July 2023 (Anticipated)

Study Completion Date

July 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Sichuan University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study is for patients that have nasopharyngeal carcinoma, breast cancer, gastric cancer and other solid tumors. As epithelial cell adhesion molecule (EpCAM) is a well characterized molecule that is closely with poor prognosis and tumor metastasis and invasion. Many therapies targeting EpCAM have shown benefits for cancer patients. This study is to determine the safety of the engineered T cells armed with chimeric antigen receptor (CAR-T) recognizing EpCAM. At the same time, efficacy is to be evaluated by the criteria of RECIST. The EpCAM CAR-T were produced by lentiviral transduction of the novel 2nd generation of CAR genes. Different cohorts of patients receive EpCAM CAR-T with a dose-escalating manner. This study is to find the largest dose of EpCAM CAR-T, to learn what the adverse effects are and to find out whether this experimental intervention might help patients with nasopharyngeal carcinoma, breast cancer and other EpCAM positive solid tumors.

Detailed Description

In this study, the original tumor tissue specimen should be stained to determine the expression levels of EpCAM. Only the patients having tumor with high expression levels will be included. 50-100ml blood with be drawn to get enough CD3 T cells at least 2x10^7. After separation, PBMC will be activated via antibodies of CD3 and CD28 and then transduced by lentivirus bearing the EpCAM CAR gene. Then the EpCAM CAR-T cells will proliferate up to 10-100 folds for infusion. The produced cells will be frozen or infused if available. Included patients will be preconditioned by cyclophosphamide for lymphodepletion if the levels of white blood cells and lymphocytes are normal. Infusion of T cells, at least 1 day after lymphodepletion, is dose escalating and beginning at the lowest level. If the first level is proven to be safe, the next level will be proceeded. Once severe side effects were observed, the dose will be lowered or the dose will be stopped. During infusion, patients will be taken care of by cardiogram monitor. Blood drawing will be taken before infusion, at 4h after infusion and on day 4, 7, 14, 30, 60, 90, 120, 150, 180 to determine the presence of CAR-T cells. At the same time, cytokines including IL-6, TNF-alpha and IFN-gamma and C-reactive protein levels will be determined. Routine imaging studies will be proceeded. To see whether there are long-term side effects of this therapy, patients received CAR-T cells will be followed up to at least 15 years.

6. Conditions and Keywords

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

Malignant Neoplasm of Nasopharynx TNM Staging Distant Metastasis (M), Breast Cancer Recurrent, Gastric Cancer With Metastasis

Keywords

EpCAM CAR-T, solid tumors, cancer immunotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

EpCAM CAR-T cells

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

EpCAM CAR-T cells

Intervention Description

Patients included will be infused the autologous T cells armed with CAR recognizing EpCAM. After infusion, cytokines and other medical test will be performed.

Primary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events/dose limiting toxicity as assessed by CTCAE v4.0

Description

Determine the largest dose of EpCAM CAR-T cells for patients with nasopharyngeal carcinoma, breast cancer and other tumors expressing EpCAM.

Time Frame

6 weeks after infusion

Secondary Outcome Measure Information:

Title

Response rate of participants treated with EpCAM CAR-T cells assessed by RECIST v1.1

Description

Determine whether there is therapeutic efficacies of the safe dose infusion of EpCAM CAR-T cells for patients with solid tumors.

Time Frame

24 months after infusion of the CAR-T cells

Title

Persistence of EpCAM CAR-T cells and correlation with the Response rate

Time Frame

24 months post CAR-T infusion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Inclusion criteria at the time of procurement: Recurrent or refractory nasopharyngeal carcinoma and breast cancer and other solid tumors. Karnofsky score of greater than or equal to 60. Informed consent explained to, understood by and signed by subject/guardian. - Subject/guardian given copy of informed consent Treatment Inclusion criteria: Recurrent or refractory EpCAM-positive nasopharyngeal carcinoma, breast cancer, gastric cancer and other epithelial tumors determined by Immunohistochemistry (IHC) or RT-PCR. EpCAM expression in tumors on IHC should be greater than or equal to grade 2 and greater than or equal to 2+ intensity score. Wherein grades are defines as: Grade 0: no staining; Grade 1: 1-25%; Grade 2: 26-50% and Grade 3: 51-100% of cell staining for EpCAM and intensity scores are: negative; 1+; 2+ and 3+ using breast cancer standard arrays as a guide for intensity. Age ≥ 18 years Life expectancy ≥ 6 weeks Karnofsky score ≥ 60 Bilirubin less than or equal to 3x normal, AST less than or equal to 5x normal, ALT less than or equal to 5x, serum creatinine less than or equal to 2x upper limit of normal for age, and Hgb greater than or equal to 8.0 Pulse oximetry of greater than or equal to 90% on room air. Sexually active subjects must be willing to utilize one of the more effective birth control methods for 6 months after the T cell infusion. The male partner should use a condom. Available autologous transduced T lymphocytes with greater than or equal to 20% expression of EpCAM CAR determined by flow-cytometry and killing of EpCAM-positive targets greater than or equal to 20% in cytotoxicity assay. Subjects should have been off other investigational antineoplastic therapy for two weeks prior to entry in this study. Cyclophosphamide will be allowed 72 hours preinfusion. Dexamethasone up to a total dose of 2 mg per day will be allowed if medically indicated. Informed consent explained to, understood by and signed by research subjects/guardian. Subject/guardian given copy of informed consent. Exclusion Criteria: Exclusion Criteria at the time of procurement: Known HIV positivity. Treatment Exclusion Criteria: Severe intercurrent infection. Known HIV positivity. Pregnant or lactating. History of hypersensitivity reactions to murine protein-containing products.

Central Contact Person:

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

Wei Wang, Ph.D

Phone

+86 028 85164063

weiwang@scu.edu.cn

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Wei Wang, Ph.D

Organizational Affiliation

State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University

Official's Role

Principal Investigator

Facility Information:

Facility Name

West China Hospital, Sichuan University

City

Chengdu

State/Province

Sichuan

ZIP/Postal Code

610041

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nianyong Chen, MD

Phone

+86 028 85422952

nchenyy@yahoo.com

First Name & Middle Initial & Last Name & Degree

Nianyong Cheng, MD

First Name & Middle Initial & Last Name & Degree

Kun Yang, MD

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

15313925

Citation

Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004 Aug 15;64(16):5818-24. doi: 10.1158/0008-5472.CAN-04-0754.

Results Reference

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PubMed Identifier

17606723

Citation

Burges A, Wimberger P, Kumper C, Gorbounova V, Sommer H, Schmalfeldt B, Pfisterer J, Lichinitser M, Makhson A, Moiseyenko V, Lahr A, Schulze E, Jager M, Strohlein MA, Heiss MM, Gottwald T, Lindhofer H, Kimmig R. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study. Clin Cancer Res. 2007 Jul 1;13(13):3899-905. doi: 10.1158/1078-0432.CCR-06-2769.

Results Reference

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PubMed Identifier

16796747

Citation

Stoecklein NH, Siegmund A, Scheunemann P, Luebke AM, Erbersdobler A, Verde PE, Eisenberger CF, Peiper M, Rehders A, Esch JS, Knoefel WT, Hosch SB. Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker. BMC Cancer. 2006 Jun 23;6:165. doi: 10.1186/1471-2407-6-165.

Results Reference

background

PubMed Identifier

16678891

Citation

Spizzo G, Went P, Dirnhofer S, Obrist P, Moch H, Baeuerle PA, Mueller-Holzner E, Marth C, Gastl G, Zeimet AG. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006 Nov;103(2):483-8. doi: 10.1016/j.ygyno.2006.03.035. Epub 2006 May 6.

Results Reference

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PubMed Identifier

25043563

Citation

Murakami N, Mori T, Yoshimoto S, Ito Y, Kobayashi K, Ken H, Kitaguchi M, Sekii S, Takahashi K, Yoshio K, Inaba K, Morota M, Sumi M, Itami J. Expression of EpCAM and prognosis in early-stage glottic cancer treated by radiotherapy. Laryngoscope. 2014 Nov;124(11):E431-6. doi: 10.1002/lary.24839. Epub 2014 Jul 14.

Results Reference

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PubMed Identifier

25636521

Citation

Deng Z, Wu Y, Ma W, Zhang S, Zhang YQ. Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol. 2015 Jan 31;16(1):1. doi: 10.1186/s12865-014-0064-x.

Results Reference

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EpCAM CAR-T for Treatment of Advanced Solid Tumors

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