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
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- STATUS
- Recruiting
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- End date
- Dec 1, 2028
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- participants needed
- 70
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- sponsor
- National Cancer Institute (NCI)
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 18-70 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.
Description
- Background
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- 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-y 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 70 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 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.
Details
| Condition | Gastrointestinal Cancer, Pancreatic Cancer, Gastric Cancer, Colon Cancer, Rectal Cancer |
|---|---|
| Treatment | aldesleukin, cyclophosphamide, Fludarabine, anti-KRAS G12D mTCR PBL |
| Clinical Study Identifier | NCT03745326 |
| Sponsor | National Cancer Institute (NCI) |
| Last Modified on | 22 October 2022 |
Eligibility
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