NCT03745326

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 5 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 72 Years
• Healthy volunteers: Not accepted

Summary

Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-72 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: * Get 2 chemotherapy medicines by IV over 5 days. * Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. * Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.

Detailed description

Background: * We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of KRAS (and other RAS family genes), expressed by many human cancers and constructed a single retroviral vector that contains alpha and beta chains that confer recognition of this antigen when transduced into PBL. * In co-cultures with HLA-A11:01+ target cells expressing this mutated oncogene, mTCR transduced T-cells lyse target cells and secrete IFN-gamma with high specificity. Objectives: -Primary objectives: * Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2; aldesleukin). * Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. Eligibility: * Patients must be/have: * Age greater than or equal to 18 years and less than or eqaul to 72 years * HLA-A\*11:01 positive * Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available). * Patients may not have: * Allergies or hypersensitivities to high-dose aldesleukin, cyclophosphamide, or fludarabine. Design: * This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A\*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. * PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. * Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR. * All patients will receive a non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine. * On Day 0, patients will receive their PBL transduced with the anti-KRAS G12D mTCR and will then begin high-dose aldesleukin. * A complete evaluation of lesions will be conducted approximately 6 weeks (plus-minus 2 weeks) after treatment. * The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. * A total of up to 70 patients may be required; approximately 24 patients in the Phase I portion of the study and 46 (21, plus an allowance of up to 2 non-evaluable per Phase II cohort) patients in the Phase II portion of the study.

Conditions

• Gastrointestinal Cancer
• Pancreatic Cancer
• Gastric Cancer
• Colon Cancer
• Rectal Cancer

Interventions

Type	Name	Description
DRUG	Cyclophosphamide	Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.
DRUG	Fludarabine	Days -7 to -3: Fludarabine 25 mg/m\^2/day IVPB daily over 30 minutes for 5 days.
DRUG	Aldesleukin	Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).
BIOLOGICAL	anti-KRAS G12D mTCR PBL	Day 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes (2-4 days after the last dose of fludarabine).

Timeline

• Start date: 2019-05-16
• Primary completion: 2022-08-22
• Completion: 2022-08-22
• First posted: 2018-11-19
• Last updated: 2026-03-19

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study