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.
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
| Drug | Synonyms | Arms |
|---|
| Cyclophosphamide | | TCR Transduced T cell therapy |
| Fludarabine | | TCR Transduced T cell therapy |
| Mutant KRAS G12V-specific TCR transduced autologous T cells | | TCR Transduced T cell therapy |
| Anti-PD-1 monoclonal antibody | Anti-PD-1 | TCR 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
| Name | Type | Description | Interventions |
|---|
| TCR Transduced T cell therapy | Experimental | 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)
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: | Recruiting |
| Lead Sponsor: | Changhai Hospital |
Trial Keywords
- pancreatic cancer
- TCR transduced T cells
- adoptive cell therapy
- KRAS
Last Updated
May 12, 2021
