Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
- Conditions
- Pancreatic CancerGastric CancerColon CancerRectal CancerGastrointestinal Cancer
- Interventions
- Registration Number
- NCT03190941
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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.
- Detailed Description
Background:
* 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 alpha and beta chains that confer 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: 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 72 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:
* 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, lymphodepleting 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 up to 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 110
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Phase I Cyclophosphamide Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 1/Phase I Fludarabine Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 1/Phase I Anti-KRAS G12V mTCR PBL Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 1/Phase I Aldesleukin Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 2/Phase II Cyclophosphamide Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 2/Phase II Fludarabine Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 2/Phase II Anti-KRAS G12V mTCR PBL Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin 2/Phase II Aldesleukin Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
- Primary Outcome Measures
Name Time Method Response rate 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per PI discretion Percentage of patients who have a clinical response (PR+CR) to treatment (objective tumor regression)
Frequency and severity of treatment-related adverse events From time of cell infusion to two weeks after cell infusion Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States