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Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer

Primary Purpose

Pancreatic Cancer, Pancreatic Neoplasms, Pancreatic Ductal Adenocarcinoma

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

Cyclophosphamide

Fludarabine

Mutant KRAS G12V-specific TCR transduced autologous T cells

Anti-PD-1 monoclonal antibody

About this trial

This is an interventional treatment trial for Pancreatic Cancer focused on measuring pancreatic cancer, TCR transduced T cells, adoptive cell therapy, KRAS

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with measurable and pathologically confirmed advanced pancreatic cancer, including metastatic pancreatic cancer (who have received standard chemotherapy) and recurrent pancreatic cancer (who have received surgery and adjuvant chemotherapy previously).
Patient's tumor must express the KRAS G12V mutation, or a G12V mutation in HRAS or NRAS, as determined by DNA or RNA sequencing methods.
Patients must be HLA-A*11:01.
Patients with brain metastasis may be eligible if they are asymptomatic and there are fewer than 3 brain lesions that are each less than 1 cm in diameter.
Patients between 18 to 75 years old are eligible.
Patients should have good clinical performance status (ECOG 0 or 1).
Patients must practice birth control once enrolled into the study and for up to four months after therapy.
Patients must be seronegative for HIV antibody.
Patients must be seronegative for hepatitis B surface antigen and core antibody (or HBV non-detectable by QPCR).
Patients must be seronegative for hepatitis C antibody (or HCV non-detectable by QPCR).
Baseline hematology criteria:
- Absolute neutrophil count of at least 1000/mm^3.
- White blood cell count of at least 3000/mm^3.
- Platelet count of at least 100,000/mm^3.
- Hemoglobin > 8.0 g/dL.
Baseline chemistry criteria:
- Serum ALT/AST less than or equal to 3.0 x ULN.
- Total bilirubin less than or equal to 1.5 mg/dL, unless the patient has Gilbert's Syndrome in which case total bilirubin must be less than or equal to 3.0 mg/dL.
- Serum creatinine less than or equal to 1.6 mg/dL.
Anticipated lifespan greater than 12 weeks.
Patients must be willing and able to comply with all study-related procedures and follow-up requirements.
Patients must be able to understand and sign a written Informed Consent Document as well as a durable power of attorney.

Exclusion Criteria:

Women who are pregnant or breastfeeding.
Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease or HIV).
Patients with active systemic infections, coagulation disorders, or any other major medical illnesses.
Patients with concurrent opportunistic infections.
Patients on concurrent systemic steroid therapy.
Patients with a history of severe immediate hypersensitivity reaction to any of the medicines used in this study (e.g., cyclophosphamide, fludarabine).
Patients with active coronary ischemic symptoms.
Patients who are receiving any other investigational agents.

Sites / Locations

Changhai HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

TCR Transduced T cell therapy

Arm Description

Pre-conditioning: Non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine TCR transduced T cell infusion: mutant KRAS G12V-specific TCR transduced autologous T cells (1e9~1e11). If the participant responds to the first infusion, the second or more infusions will be considered when the disease is progressing. Anti-PD-1 therapy: anti-PD-1 will be administered if needed.

Outcomes

Primary Outcome Measures

Frequency and severity of treatment-related adverse events

Aggregate of all adverse events, as well as their frequency and severity

Objective response rate

Percentage of patients who have a clinical response to treatment (objective tumor regression)

Secondary Outcome Measures

The percentage of TCR transduced T cells in peripheral blood

The percentage of TCR transduced T cells in peripheral blood will be detected with an established flow cytometric assay.

Overall survival

The time between cell infusion and the death of patients

Full Information

NCT ID

NCT04146298

First Posted

October 26, 2019

Last Updated

August 31, 2023

Sponsor

Changhai Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04146298

Brief Title

Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer

Official Title

Clinical Trial Evaluating the Safety and Activity of Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 21, 2021 (Actual)

Primary Completion Date

December 2024 (Anticipated)

Study Completion Date

March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Changhai Hospital

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 clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients who express the KRAS G12V mutation and HLA-A*11:01 allele. The theoretical basis of this study is that mutant KRAS antigen-specific TCR transduced autologous Tcells will target and kill HLA-matched mutant KRAS cancer cells but not normal cells.

Detailed Description

Hotspot KRAS mutations exist in various cancers, especially pancreatic, lung and colorectal cancer. Mutations in KRAS are implicated in the development of pancreatic cancer and are associated with poor prognosis of the patients. KRAS is an attractive target for cancer treatment because it is a driver mutation and is likely expressed by all cells in a tumor. Recently,T cells targeting mutant KRAS have been identified in patients with epithelial cancers, and these T-cell receptors (TCR) have been characterized. For example, TCRs that target mutant KRAS G12D peptides presented by HLA-C*08:02, and a TCR that targets a KRAS G12V peptide presented by HLA-A*11:01 have been identified. Mutant KRAS-reactive T cells appear capable of inducing tumor regression as highlighted in a patient with metastatic colorectal cancer who experienced regression of metastatic tumors after infusion of HLA-C*08:02-restricted KRAS-G12D reactive tumor-infiltrating lymphocytes (TIL). The investigators will test the safety and activity of adoptive transfer of autologous T cells genetically engineered to express a TCR that targets mutant KRAS G12V in the context of HLA-A*11:01 in HLA-matched patients with advanced pancreatic cancer that express mutant KRAS G12V. The investigators will also measure the in vivo survival of engineered T cells.

6. Conditions and Keywords

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

Pancreatic Cancer, Pancreatic Neoplasms, Pancreatic Ductal Adenocarcinoma, Advanced Cancer

Keywords

pancreatic cancer, TCR transduced T cells, adoptive cell therapy, KRAS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

TCR Transduced T cell therapy

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Intervention Description

Cyclophosphamide will be administered prior to cell infusion.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

Fludarabine will be administered prior to cell infusion.

Intervention Type

Biological

Intervention Name(s)

Mutant KRAS G12V-specific TCR transduced autologous T cells

Intervention Description

After preconditioning regimen, T cells will be infused to the patient intravenously in the Patient Care Unit over approximately 30 to 50 minutes.

Intervention Type

Drug

Intervention Name(s)

Anti-PD-1 monoclonal antibody

Other Intervention Name(s)

Anti-PD-1

Intervention Description

During the treatment, anti-PD-1 monoclonal antibody will be administered if needed.

Primary Outcome Measure Information:

Title

Frequency and severity of treatment-related adverse events

Description

Aggregate of all adverse events, as well as their frequency and severity

Time Frame

18 months following cell infusion

Title

Objective response rate

Description

Percentage of patients who have a clinical response to treatment (objective tumor regression)

Time Frame

From the date of cell infusion to disease progression (up to 18 months after cell infusion).

Secondary Outcome Measure Information:

Title

The percentage of TCR transduced T cells in peripheral blood

Description

The percentage of TCR transduced T cells in peripheral blood will be detected with an established flow cytometric assay.

Time Frame

1, 3, 5, 7, 10, 14, 28, 42 and 84 days after cell infusion, then every 3 months, and up to 18 months after cell infusion.

Title

Overall survival

Description

The time between cell infusion and the death of patients

Time Frame

From date of cell infusion until the date of death from any cause, whichever came first, assessed up to 18 months after cell infusion.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with measurable and pathologically confirmed advanced pancreatic cancer, including metastatic pancreatic cancer (who have received standard chemotherapy) and recurrent pancreatic cancer (who have received surgery and adjuvant chemotherapy previously). Patient's tumor must express the KRAS G12V mutation, or a G12V mutation in HRAS or NRAS, as determined by DNA or RNA sequencing methods. Patients must be HLA-A*11:01. Patients with brain metastasis may be eligible if they are asymptomatic and there are fewer than 3 brain lesions that are each less than 1 cm in diameter. Patients between 18 to 75 years old are eligible. Patients should have good clinical performance status (ECOG 0 or 1). Patients must practice birth control once enrolled into the study and for up to four months after therapy. Patients must be seronegative for HIV antibody. Patients must be seronegative for hepatitis B surface antigen and core antibody (or HBV non-detectable by QPCR). Patients must be seronegative for hepatitis C antibody (or HCV non-detectable by QPCR). Baseline hematology criteria: Absolute neutrophil count of at least 1000/mm^3. White blood cell count of at least 3000/mm^3. Platelet count of at least 100,000/mm^3. Hemoglobin > 8.0 g/dL. Baseline chemistry criteria: Serum ALT/AST less than or equal to 3.0 x ULN. Total bilirubin less than or equal to 1.5 mg/dL, unless the patient has Gilbert's Syndrome in which case total bilirubin must be less than or equal to 3.0 mg/dL. Serum creatinine less than or equal to 1.6 mg/dL. Anticipated lifespan greater than 12 weeks. Patients must be willing and able to comply with all study-related procedures and follow-up requirements. Patients must be able to understand and sign a written Informed Consent Document as well as a durable power of attorney. Exclusion Criteria: Women who are pregnant or breastfeeding. Patients with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease or HIV). Patients with active systemic infections, coagulation disorders, or any other major medical illnesses. Patients with concurrent opportunistic infections. Patients on concurrent systemic steroid therapy. Patients with a history of severe immediate hypersensitivity reaction to any of the medicines used in this study (e.g., cyclophosphamide, fludarabine). Patients with active coronary ischemic symptoms. Patients who are receiving any other investigational agents.

Central Contact Person:

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

Shiwei Guo, Doctor

Phone

+8618621500666

gestwa@163.com

Facility Information:

Facility Name

Changhai Hospital

City

Shanghai

ZIP/Postal Code

200433

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Shiwei Guo, Doctor

Phone

+8618621500666

gestwa@163.com

First Name & Middle Initial & Last Name & Degree

Gang Jin, Doctor

12. IPD Sharing Statement

Citations:

PubMed Identifier

30683863

Citation

Cafri G, Yossef R, Pasetto A, Deniger DC, Lu YC, Parkhurst M, Gartner JJ, Jia L, Ray S, Ngo LT, Jafferji M, Sachs A, Prickett T, Robbins PF, Rosenberg SA. Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients. Nat Commun. 2019 Jan 25;10(1):449. doi: 10.1038/s41467-019-08304-z.

Results Reference

result

PubMed Identifier

27959684

Citation

Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, Pasetto A, Zheng Z, Ray S, Groh EM, Kriley IR, Rosenberg SA. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016 Dec 8;375(23):2255-2262. doi: 10.1056/NEJMoa1609279.

Results Reference

result

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Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer

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