This is an open-label, multi-centre, single-arm Phase 1/2 clinical trial of the safety, expansion, persistence and clinical activity of a set of engineered autologous T cells products each capable of recognizing a specific combination mutated KRAS and HLA, activating the T cells and exerting anti- tumour activity in patients with metastatic or locally advanced PDAC.
Adult patient (18 years or older) with newly diagnosed metastatic PDAC or locally advance PDAC disease.
HLA genotyping confirmed with a high-resolution method.
Confirmed KRAS G12V or KRAS G12D mutation in tumour using biopsy sample.
Fertile male and female patients must use a highly effective contraceptive method before, during, and for at least 6 months after the last mutKRAS TCR infusion. Acceptable contraception for women includes implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence, or a partner who has been vasectomized for at least 6 months. Acceptable contraception for male includes having had a vasectomy for at least 6 months, sexual abstinence, to condoms plus spermicide. Fertile female and male patients must adhere to any treatment-specific pregnancy prevention guidelines for cyclophosphamide (refer to SmPC).
Another malignancy other than PDAC.
Current or history of brain metastasis.
Patient with known genetic status for whom other treatments are available e.g. BRCA, MSI-H.
Parallel
ANOC-001 (TCR-T cells targeting KRAS G12V mutation presented by specific HLA alleles)
Biological/VaccineThe cells will be gene edited and administered by a single IV infusion on Day 1. Drugs: Cyclophosphamide and Fludarabine will be used as a lymphodepleting chemotherapy.
ANOC-002 (TCR-T cells targeting KRAS G12V mutation presented by specific HLA alleles)
Biological/VaccineThe cells will be gene edited and administered by a single IV infusion on Day 1. Drugs: Cyclophosphamide and Fludarabine will be used as a lymphodepleting chemotherapy.
ANOC-003 (TCR-T cells targeting KRAS G12D mutation presented by specific HLA alleles)
Biological/VaccineThe cells will be gene edited and administered by a single IV infusion on Day 1. Drugs: Cyclophosphamide and Fludarabine will be used as a lymphodepleting chemotherapy
Phase 1-Proportion of participants with dose limiting toxicity of ANOC-001, ANOC-002 and ANOC-003, graded according to American Society of Transplantation and Cellular Therapy (ASTCT) consensus criteria.
Phase 1-Number of participants with adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v5.0.
Phase 1- Identification of the Maximum tolerated dose/Maximum administered dose and Recommended Phase 2 Dose of ANOC-001/ANOC-002/ANOC-003 cells that can be administered safely in patients with metastatic and locally advanced PDAC.
Phase 2-Number of participants with adverse events of special interest (AESI) according to NCI CTCAE v5.0.
Phase 1 and Phase 2: Percentage of patients who receive protocol-defined target dose of ANOC-001, ANOC-002 and ANOC-003.
Phase 1 and Phase 2: Proportion of investigational product- ANOC-001, ANOC-002 and ANOC-003 that comply with the specifications as compared to the total number of the IMP manufactured
Phase 1 and Phase 2-Maximum expansion and persistence of TCR T cells following infusion by quantitative PCR
Phase 1 and Phase 2- Proportion of participants achieving Progression Free Survival (PFS) defined as the time from study treatment to the first occurrence of disease progression or death, whichever occurs first.
Exploratory-Phase 1 and 2-To evaluate correlation of T cell persistence with safety and clinical response and with phenotype of infused T cells
Exploratory-Phase 1 and 2-To evaluate types and levels of cytokines in peripheral blood
Exploratory-Phase 1 and 2-To evaluate change in ctDNA and CTC/exosome load
Exploratory-Phase 1 and 2-Conventional serum markers e.g., CA19-9, CEA and exploratory/emerging biomarkers, e.g. but not limited to PRO-C3, for PDAC will be tested locally
