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

Study Overview

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

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.

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.

Pancreatic Cancer
Pancreatic Neoplasms
Pancreatic Ductal Adenocarcinoma
Advanced Cancer

DRUG: Cyclophosphamide
DRUG: Fludarabine
BIOLOGICAL: Mutant KRAS G12V-specific TCR transduced autologous T cells
DRUG: Anti-PD-1 monoclonal antibody

ChanghaiH-PP06

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2019-10-26	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2023-08-31
First Submitted that Met QC Criteria 2019-10-29	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2023-09-01
First Posted (ACTUAL) 2019-10-31	Results First Posted N/A	Last Verified 2023-08

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 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	DRUG: Cyclophosphamide Cyclophosphamide will be administered prior to cell infusion. DRUG: Fludarabine Fludarabine will be administered prior to cell infusion. BIOLOGICAL: 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. DRUG: Anti-PD-1 monoclonal antibody During the treatment, anti-PD-1 monoclonal antibody will be administered if needed.

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: 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

DRUG: Cyclophosphamide

Cyclophosphamide will be administered prior to cell infusion.

DRUG: Fludarabine

Fludarabine will be administered prior to cell infusion.

BIOLOGICAL: 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.

DRUG: Anti-PD-1 monoclonal antibody

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

Primary Outcome Measures	Measure Description	Time Frame
Frequency and severity of treatment-related adverse events	Aggregate of all adverse events, as well as their frequency and severity	18 months following cell infusion
Objective response rate	Percentage of patients who have a clinical response to treatment (objective tumor regression)	From the date of cell infusion to disease progression (up to 18 months after cell infusion).

Secondary Outcome Measures	Measure Description	Time Frame
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.	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.
Overall survival	The time between cell infusion and the death of patients	From date of cell infusion until the date of death from any cause, whichever came first, assessed up to 18 months after cell infusion.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Shiwei Guo, Doctor

Phone Number: +8618621500666

Email: gestwa@163.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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.

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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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.
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.

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Clinical Trial Record