A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
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- STATUS
- Recruiting
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- End date
- Jun 29, 2028
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- participants needed
- 110
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- sponsor
- National Cancer Institute (NCI)
Summary
- Background
A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells.
- Objective
To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors.
- Eligibility
Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors.
- Design
In another protocol, participants will:
Be screened
Have cells harvested and grown
Have leukapheresis
In this protocol, participants will have the procedures below.
Participants will be admitted to the hospital.
Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest.
A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter.
For up to 3 days, participants will get a drug to make the cells active.
A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin.
Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests.
Participants will take an antibiotic for at least 6 months.
Participants will have visits every few months for 2 years, and then as determined by their doctor.
Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn.
Participants will have blood collected over several years.
Description
- Background
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- We generated an HLA-A*11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12V-mutated variant of KRAS (and other RAS family genes), expressed by many human cancers and constructed a single retroviral vector that contains its alpha and beta chains that confers recognition of this antigen when transduced into PBL.
- In co-cultures with HLA-A*11:01+ 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 G12V mTCR in concert with preparative lymphodepletion and high dose interleukin-2 (IL-2; aldesleukin).
- Phase II:To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression
of tumors harboring the RAS G12V mutation.
- Eligibility
Patients must be/have:
- Age greater than or equal to 18 years and less than or equal to 70 years
- HLA-A*11:01 positive
- Metastatic or unresectable RAS G12V-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
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- This is a Phase I/II, single center study of PBL transduced with anti-KRAS G12V mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12V 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 G12V mTCR.
- All patients will receive a non-myeloablative, lympho-depleting preparative regimen of cyclophosphamide and fludarabine.
- On day 0 patients will receive their PBL transduced with the anti-KRAS G12V mTCR and will then begin high-dose aldesleukin.
- A complete evaluation of lesions will be conducted approximately 6 weeks (+/- 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 G12V pancreatic
cancer, and Cohort 2b, patients with RAS G12V non-pancreatic cancer.
-A total of 110 patients may be required; approximately 24 patients in the phase I portion of the study and 86 (41, plus an allowance of up to 2 non-evaluable per phase II cohort) patients in the phase II portion of the study.
Details
| Condition | Pancreatic Cancer, Gastric Cancer, Gastrointestinal Cancer, Colon Cancer, Rectal Cancer |
|---|---|
| Treatment | aldesleukin, cyclophosphamide, Fludarabine, anti-KRAS G12V mTCR, Anti-KRAS G12V mTCR PBL, High-dose Aldesleukin |
| Clinical Study Identifier | NCT03190941 |
| Sponsor | National Cancer Institute (NCI) |
| Last Modified on | 20 October 2022 |
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