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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04146298
Recruitment Status : Recruiting
First Posted : October 31, 2019
Last Update Posted : June 15, 2022
Sponsor:
Information provided by (Responsible Party):
Guo ShiWei, Changhai Hospital

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.

Condition or disease Intervention/treatment Phase
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 Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Trial Evaluating the Safety and Activity of Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer
Actual Study Start Date : October 21, 2021
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : March 2025

Resource links provided by the National Library of Medicine


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 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.

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.
Other Name: Anti-PD-1




Primary Outcome Measures :
  1. Frequency and severity of treatment-related adverse events [ Time Frame: 18 months following cell infusion ]
    Aggregate of all adverse events, as well as their frequency and severity

  2. Objective response rate [ Time Frame: From the date of cell infusion to disease progression (up to 18 months after cell infusion). ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)


Secondary Outcome Measures :
  1. The percentage of TCR transduced T cells in peripheral blood [ 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. ]
    The percentage of TCR transduced T cells in peripheral blood will be detected with an established flow cytometric assay.

  2. Overall survival [ 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. ]
    The time between cell infusion and the death of patients



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04146298


Contacts
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Contact: Shiwei Guo, Doctor +8618621500666 gestwa@163.com

Locations
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China
Changhai Hospital Recruiting
Shanghai, China, 200433
Contact: Shiwei Guo, Doctor    +8618621500666    gestwa@163.com   
Principal Investigator: Gang Jin, Doctor         
Sponsors and Collaborators
Changhai Hospital
Publications of Results:
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Responsible Party: Guo ShiWei, Doctor, Changhai Hospital
ClinicalTrials.gov Identifier: NCT04146298    
Other Study ID Numbers: ChanghaiH-PP06
First Posted: October 31, 2019    Key Record Dates
Last Update Posted: June 15, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Guo ShiWei, Changhai Hospital:
pancreatic cancer
TCR transduced T cells
adoptive cell therapy
KRAS
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Cyclophosphamide
Fludarabine
Antibodies
Antibodies, Monoclonal
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists