Master protocol of TCR-modified T cell therapy targeting HLA-restricted KRAS antigen administered in adult patients with metastatic or locally advanced PDAC

Prior treatment

• Another malignancy other than PDAC. Participants with concomitant second malignancies (except adequately treated no melanomatous skin cancers, carcinoma in situ of the breast, treated superficial bladder cancer or prostate cancer, or in situ cervical cancers) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period. Long-term adjuvant therapy example: breast cancer is acceptable.
• Currently receiving other investigational medicinal products
• Participants with concurrent opportunistic infections.
• Participants on concurrent systemic steroid therapy.

Other illness

• Current or history of brain metastasis.
• Participants with any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease [SCID] or human immunodeficiency virus (HIV).
• Participants with active systemic infections, coagulation disorders, or any other major medical illnesses e.g. Hepatitis B or C.
• Participants with a history of severe immediate hypersensitivity reaction to any of the medicines used in this study (e.g., cyclophosphamide, fludarabine).
• Resectable PDAC disease

Other

• Participants with known genetic status for whom other treatments are available e.g. BRCA, MSI-H.
• Women who are pregnant or breastfeeding.
• Current or past employees, or any of their immediate family members (spouse, parent, child, sibling) or members of their household, of the Sponsor, Contract Research Organization (CRO) or Clinical Trial Site who were/are directly involved in the study design, conduct, or analysis.
• Participants with active coronary ischaemic symptoms.
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• Current treatment on another therapeutic clinical trial. Supportive care trials or non-treatment trials e.g., participant reported outcomes (PRO) methods studies, are allowed.
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• Pre-screening: Adult participants (18 years or older) with newly diagnosed metastatic PDAC or locally advanced PDAC disease.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): ECOG performance status of <=1 or Karnofsky performance status >=70%.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Renal: Creatinine clearance >=50 mL/min by chronic kidney disease epidemiology collaboration (CKD-EPI) or 24-hour urine clearance.
• Leukapheresis: Redacted
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Hepatic: Total bilirubin <2.0 mg/dL
• Leukapheresis: Redacted
• Leukapheresis: Redacted
• Leukapheresis: Adequate venous access suitable for leukapheresis.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Redacted
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Measurable disease by RECIST 1.1 criteria at the time of first line treatment. Baseline imaging (for example, diagnostic computed tomography (CT) chest/abdomen/pelvis and imaging of the affected extremity or brain, as appropriate), magnetic resonance imaging (MRI) or CT scan) must be obtained before the first planned T cell infusion. CT can be substituted for MRI in participants who are unable to have CT contrast.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Participants must be at 2-3 weeks from last systemic treatment; 2-3 weeks must have passed since any: immunotherapy (for example, T-cell infusions, immunomodulatory agents, interleukins, vaccines), small molecule or chemotherapy cancer treatment, other investigational agents. If a resolution of any residual toxicity of Grade <=1 occurs before 2-3 weeks, participants can start the treatment at the PI discretion.
• Leukapheresis: Fertile male and female participants must use a highly effective contraceptive method before, during, and after the last mutKRAS TCR infusion, per timelines defined in Protocol. 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, condom plus spermicide. Fertile female and male participants must adhere to any treatment-specific pregnancy prevention guidelines.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): There is no washout period for radiation, so long as radiated lesion is not the lesion being evaluated for RECIST measurements on the protocol. Bisphosphonates are permitted.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <5x upper limit of normal (ULN).
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Participants with suspected hyperbilirubinemia may be included if total bilirubin >3 mg/dl but no other evidence of hepatic dysfunction.
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Hematologic: Absolute neutrophil count (ANC) >=1000 cells/ mm3
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Nutrition: Albumin >=3 g/dL
• Inclusion Criteria for Start of Treatment with IMP (intention-to- treat group [ITT]): Avoid using granulocyte-macrophage colony-stimulating factor (GM-CSF) supportive therapy within 72 hours of sample collection.
• Leukapheresis: 18 years or older at the time of enrolment.
• Leukapheresis: Capable of understanding and providing a written informed consent.
• Leukapheresis: Eastern Cooperative Oncology Group (ECOG) performance status of <=1 or Karnofsky performance status >=70% (no uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated uncontrolled pleural drainage more than once every 28 days).
• Pre-screening: Capable of understanding and willing to sign a written informed consent
• Pre-screening: Participants must be willing and able to comply with all study-related procedures and follow-up requirements.
• Leukapheresis: Diagnosis of metastatic PDAC or locally advanced PDAC.
• Leukapheresis: Confirmation of PDAC diagnosis.