Clinical Trials /

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

NCT04146298

Description:

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.

Related Conditions:
  • Pancreatic Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: ChanghaiH-PP06
  • NCT ID: NCT04146298

Conditions

  • Pancreatic Cancer
  • Pancreatic Neoplasms
  • Pancreatic Ductal Adenocarcinoma
  • Advanced Cancer

Interventions

DrugSynonymsArms
CyclophosphamideTCR Transduced T cell therapy
FludarabineTCR Transduced T cell therapy
Mutant KRAS G12V-specific TCR transduced autologous T cellsTCR Transduced T cell therapy
Anti-PD-1 monoclonal antibodyAnti-PD-1TCR Transduced T cell therapy

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
TCR Transduced T cell therapyExperimentalPre-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) Anti-PD-1 therapy: anti-PD-1 will be administered if needed.
  • Cyclophosphamide
  • Fludarabine
  • Mutant KRAS G12V-specific TCR transduced autologous T cells
  • Anti-PD-1 monoclonal antibody

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 70 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 75,000/mm^3.

               -  Hemoglobin > 8.0 g/dL.

          -  Baseline chemistry criteria:

               -  Serum ALT/AST less than or equal to 5.0 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.

               -  eGFR> 60 mL/m or a formal 6-24h CrCl> 60 mL/m.

          -  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.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency and severity of treatment-related adverse events
Time Frame:2 years following cell infusion
Safety Issue:
Description:Aggregate of all adverse events, as well as their frequency and severity

Secondary Outcome Measures

Measure:The percentage of TCR transduced T cells in peripheral blood
Time Frame:2, 6 and 12 weeks after cell infusion, then every 3 months, and up to 24 months after cell infusion.
Safety Issue:
Description:The percentage of TCR transduced T cells in peripheral blood will be detected with an established flow cytometric assay.
Measure:Overall survival
Time Frame:From date of cell infusion until the date of death from any cause, whichever came first, assessed up to 24 months after cell infusion.
Safety Issue:
Description:The time between cell infusion and the death of patients

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Guo ShiWei

Trial Keywords

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

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