Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients
- Conditions
- Rectal CancerColon CancerGastric CancerGastrointestinal CancerPancreatic Cancer
- Interventions
- Registration Number
- NCT03745326
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 70
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Phase I Fludarabine Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin 1/Phase I Cyclophosphamide Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin 1/Phase I Aldesleukin Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin 1/Phase I anti-KRAS G12D mTCR PBL Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12D mTCR PBL + highdose aldesleukin 2/Phase II anti-KRAS G12D mTCR PBL Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D mTCR PBL + high-dose aldesleukin 2/Phase II Aldesleukin Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D mTCR PBL + high-dose aldesleukin 2/Phase II Cyclophosphamide Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D mTCR PBL + high-dose aldesleukin 2/Phase II Fludarabine Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12D 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