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

NCT ID: NCT04146298

Last Updated: 2025-12-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-10-21
• Study Completion Date: 2028-12-31

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.

Conditions

Pancreatic Cancer; Pancreatic Neoplasms; Pancreatic Ductal Adenocarcinoma; Advanced Cancer

Keywords

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

TCR Transduced T cell therapy

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.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide will be administered prior to cell infusion.

Fludarabine

Intervention Type: DRUG

Fludarabine will be administered prior to cell infusion.

Mutant KRAS G12V-specific TCR transduced autologous T cells

Intervention Type: BIOLOGICAL

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

Anti-PD-1 monoclonal antibody

Intervention Type: DRUG

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

Interventions

Cyclophosphamide

Cyclophosphamide will be administered prior to cell infusion.

Intervention Type: DRUG

Fludarabine

Fludarabine will be administered prior to cell infusion.

Intervention Type: DRUG

Mutant KRAS G12V-specific TCR transduced autologous T cells

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: BIOLOGICAL

Anti-PD-1 monoclonal antibody

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

Intervention Type: DRUG

Other Intervention Names

Anti-PD-1

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Changhai Hospital

OTHER

Sponsor Role: lead

Responsible Party

Guo ShiWei

Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Changhai Hospital

Shanghai, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Shiwei Guo, Doctor

Role: CONTACT

Phone: +8618621500666

Email: gestwa@163.com

Facility Contacts

Shiwei Guo, Doctor

Role: primary

References

Xu X, Guo S, Gu H, Cha Z, Shi X, Yin X, Wang H, Gao S, Li B, Zhu L, Jing W, Zheng K, Shao Z, Cheng P, Zheng C, Shih YP, Li Y, Qian B, Gao D, Tran E, Jin G. Identification and validation of a T cell receptor targeting KRAS G12V in HLA-A*11:01 pancreatic cancer patients. JCI Insight. 2025 Jan 23;10(2):e181873. doi: 10.1172/jci.insight.181873.

Reference Type: RESULT

PMID: 39846249 (View on PubMed)

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.

Reference Type: RESULT

PMID: 30683863 (View on PubMed)

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.

Reference Type: RESULT

PMID: 27959684 (View on PubMed)

Other Identifiers

ChanghaiH-PP06

Identifier Type: -

Identifier Source: org_study_id