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-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12(G12D) murine T-cell receptor (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 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.
Background: * We generated an human leukocyte antigen (HLA)-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the Glycine(G) to Aspartic Acid(D) substitution at codon 12 (G12D)-mutated variant of Kirsten rat sarcoma virus (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 peripheral blood lymphocytes (PBL). * In co-cultures with HLA-A11:01+ target cells expressing this mutated oncogene, mTCR transduced T-cells lyse target cells and secrete interferon (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 rat sarcoma (RAS) G12D 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 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-cluster of differentiation 3 (CD3) Ortho-Kung T-cell 3 (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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
5
Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days intravenous (IV) in 250 mL 5% Dextrose in water (D5W) infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.
Days -7 to -3: Fludarabine 25 mg/m\^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Aldesleukin 720,000 IU/kg intravenous (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).
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).
Baseline within 14 days prior to preparative regimen
Within 6 weeks and post treatment follow-up
Within 6 weeks and post treatment follow-up
Within 6 weeks and post treatment follow-up
Baseline within 14 days prior to preparative regimen
Within 6 weeks and post treatment follow-up
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Phase I: Number of Grades 1, 2, 3, 4, and/or 5 and Type of Serious and/or Non-serious Toxicities Experienced by Participants at Each Dose Level
All participants will be evaluable for toxicity from the time of their first treatment with cyclophosphamide. Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Time frame: from the start of cyclophosphamide, through the first follow-up evaluation (6 weeks [± 2 weeks]) following administration of the cell product) until off study, whichever comes first, an average of 2.3 months
Phase I: Percentage of Participants Who Experienced a Grade 3, 4 and/or 5 Serious Dose-Limiting Toxicity (DLT) Reported With Type at Each Dose Level
Toxicity was assessed by the Common Terminology Criteria for Adverse Events. A DLT is all grade 3 and greater toxicities related to the cell infusion with exceptions, such as myelosuppression, defined as lymphopenia, neutropenia, decreased hemoglobin and thrombocytopenia due to the non-myeloablative lymphodepleting preparative regimen, expected chemotherapy toxicities, Aldesleukin expected toxicities, immediate hypersensitivity reactions occurring within 2 hours of cell infusion that are reversible to a grade 2 or less within 24 hours of cell administration with standard therapy, Grade 3 fever, Grade 3 metabolic laboratory abnormalities without significant clinical sequela that resolve to grade 2 within 7 days, Grade 3 autoimmune toxicity that resolves to grade 2 or less within 10 days unless immunosuppression is required, and events that are clearly related to the participants disease. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Time frame: At the time of cell infusion and end two weeks after cell infusion, an average of one month
Phase II: Percentage of Participants With a Clinical Response (Complete Response (CR) + Partial Response (PR) Reported With 80% Confidence Interval
Percentage of participants who have a clinical response (PR+CR) to treatment (objective tumor regression). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). CR is a disappearance of all target lesions. PR is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: 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 principal investigator (PI) discretion
Phase II: Percentage of Participants With a Clinical Response (Complete Response (CR) + Partial Response (PR) Reported With 95% Confidence Interval
Percentage of participants who have a clinical response (PR+CR) to treatment (objective tumor regression). Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). CR is a disappearance of all target lesions. PR is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: 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 principal investigator (PI) discretion
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