This study is NOT currently recruiting participants.
Number
001870-C
Sponsoring Institute
National Cancer Institute (NCI)
Recruitment Detail
Type: Recruitment has not started Gender: Male & Female Min Age: 18 Years Max Age: 72 Years
Referral Letter Required
No
Population Exclusion(s)
Pregnant Women;Neonates;Fetuses;Children
Keywords
KRAS Mutations; Cell Therapy; Gene Therapy; Tp53 Mutations; Immunotherapy; KRAS G12D; KRAS G12V; Tp53; R175H
Recruitment Keyword(s)
None
Condition(s)
gastrointestinal carcinoma; Pancreatic Cancer; Hepatocellular Cancer; Cholangiocarcinoma; duodenal cancer; Colorectal Cancer; small bowel cancer; Metastatic Cancers
Investigational Drug(s)
cyclophosphamide KRAS TCR-Transduced PBL
Investigational Device(s)
Intervention(s)
Biological/Vaccine: KRAS TCR-Transduced PBL Drug: Aldesleukin Drug: Fludarabine Drug: Cyclophosphamide
Supporting Site
National Cancer Institute
Gastrointestinal (GI) cancer affects the organs (such as the stomach, large and small intestine, pancreas, colon, liver, and biliary system) of the digestive tract. In some participants who have had surgery for GI cancer, blood tests show that the cancer has spread despite being unable to be identified by scans. Certain gene mutations (changes) in GI cancer (such as KRAS or TP53) can be targeted by T cells, a type of immune cell, in individuals with specific HLA types (genes that help proteins in the body know what is self and non-self). Researchers want to see if they can stop GI cancer from returning or spreading in people with these gene mutations and specific HLA types.
Objective:
To test therapy with modified T-cells to prevent or delay the return of GI cancer after standard treatment. T-cells play a role in the body s immune system.
Eligibility:
People aged 18 to 72 years with GI cancer that was treated with standard therapy and is not seen on imaging scans. They must have specific gene mutations and HLA types. They also must have certain clinical or blood tests showing the cancer is spreading (elevating CA19-9 or detectable ctDNA).
Design:
Participants will be divided into 2 groups. Participants nor the study team can choose what Group to participate in; this is done by randomization , like flipping a coin. Participants will have a 1-to-1 chance of being in Group 1 or Group 2.
Group 1 will receive T-cell therapy. Their own T-cells will be collected. In a lab, the cells will be combined with a virus that carries a protein to target cancer cells.
Group 1 participants will stay in the hospital for 3 weeks or more. They will have chemotherapy, and their modified T-cells will be infused through a tube attached to a needle inserted into a vein.
Group 1 participants will visit the clinic every 3 months for 1 year and then every 6 months for 5 years. Then they will have follow-up visits for another 10 years under a different protocol.
Group 2 participants will not receive treatment with T-cells. They will visit the clinic every 3 months for 1 year and then every 6 months for 5 years.
--Back to Top--
INCLUSION CRITERIA -Resected pancreas ductal adenocarcinoma (PDAC): --Resected pancreas ductal adenocarcinoma --If stage I-III has a history of detectable circulating tumor DNA (ctDNA) after resection/local treatment of all known disease. OR --If stage I-III, have a history of abnormally elevated cancer antigen (CA)19-9 at diagnosis (before surgery) AND a history of abnormally elevated post-operative CA19-9 measured at least 30 days after surgery AND a history of the relative increase of postoperative CA19-9 of 2.6-fold or more compared to the participant s post-operative baseline, as confirmed by two separate tests at least 3 weeks apart. OR --Had metastatic disease (stage IV) at diagnosis and were down staged with chemotherapy and underwent resection. -Colorectal liver, lung, and/or lymph node metastases (CRLM): --Participants with stage IV colorectal cancer with metastases to the liver, lung, and/or lymph nodes that were completely treated with local therapy (resection, ablation, and/or radiotherapy). --Must have a history of detectable ctDNA after resection/local treatment of all known disease. -Gastrointestinal carcinoma (GIC): --Participants with resected gastroesophageal cancer, hepatocellular cancer, cholangiocarcinoma, duodenal, small bowel, or primary colorectal cancer (i.e., pathologic stage I-III as distinguished from CRLM). --Must have a history of detectable ctDNA after resection/local treatment of all known disease. -Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology (LP). -Must have a history of: --KRAS G12D mutation plus HLA-A*11:01 OR --KRAS G12D mutation plus HLA-C*08:02 OR --KRAS G12V mutation plus HLA-C*01:02 OR --TP53 R175H mutation plus HLA-A*02:01. -Treated with standard systemic and/or radiotherapy if indicated unless participant refusal or non-tolerance of the standard regimen. For example: --Participants with PDAC should receive neoadjuvant or adjuvant chemotherapy (5-FU or gemcitabine-based). --Participants with CRLM should have received at least one line of 5FU-based chemotherapy (i.e., FOLFOX or FOLFIRI). --Participants with resected stage III colon cancer should have received 5FU-based adjuvant therapy (i.e., FOLFOX or FOLFIRI). -CRLM only: Participants with a history of brain metastases that have been treated with stereotactic radiosurgery or resection must be clinically stable for 3 months after treatment to be eligible. -Age >= 18 years and <= 72 years. -Clinical performance status of ECOG 0 or 1 -Individuals of child-bearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and up to and 12 months after the last dose of combined chemotherapy. Individuals that can father children must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 4 months after the last dose of study drugs. We also will recommend individuals that can father children with partners that can bear children ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals that can father children must not freeze or donate sperm within the same period. NOTE: IOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal. -Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 4 months after the last dose of the study drug(s). -Viral testing --Seronegative for human immunodeficiency virus (HIV) antibody. --Negative for hepatitis B (HBV) surface antigen (HbsAg), and seronegative for hepatitis C (HCV) antibody. If the HCV antibody test is positive, then the participant must be tested for the presence of antigen by RT-PCR and be HCV RNA negative to be eligible. -Hematology --Absolute neutrophil count (ANC) > 1000/mm^3 without the support of filgrastim --White blood cells (WBC) >= 2500/mm^3 --Platelet count >= 80,000/mm^3 --Hemoglobin > 8.0 g/dL. -Chemistry --Alanine aminotransferase (ALT) <= 5.0 x upper limit of normal (ULN) --Aspartate aminotransferase (AST) <= 5.0 x ULN --Creatinine <= 1.6 mg/dL --Total bilirubin <= 2.0 mg/dL, except in participants with Gilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL. -Four weeks must have passed after any prior systemic therapy for cancer, any investigational agents, surgical procedures, or limited field radiotherapy prior to randomization, as long as related major organ toxicities have recovered to grade 1 or less per Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. NOTE: Participants with adverse events Grade 2 that are deemed irreversible and stable and will not prevent administration of the study drug(s)/intervention or prevent compliance with the study requirements (e.g., alopecia, peripheral neuropathy, laboratory parameters not otherwise specified per the eligibility criteria) are an exception to this criterion and are eligible. -Ability of the participant to understand and the willingness to sign a written informed consent document. -Willing to sign a durable power of attorney. -Participants must be co-enrolled on protocols 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols), and 09-C-0161 (Follow-up Protocol for Subjects Previously Enrolled on NCI Surgery Branch Studies). EXCLUSION CRITERIA -Unequivocal radiographic evidence of residual tumor. -Participants with measurable disease per RECIST v1.1 criteria. -Any form of secondary immunosuppression. -Active or chronic infections requiring anti-microbial, anti-fungal, or anti-viral treatment. -Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and Acquired immunodeficiency syndrome [AIDS]). -History of major organ autoimmune disease. -Concurrent opportunistic infections. -History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin. -History of coronary revascularization or ischemic symptoms. -Left ventricular ejection fraction (LVEF) <= 45% for participants with a clinical history prompting cardiac evaluation (e.g., participants who are >= 65 years of age, or who have a ventricular arrhythmias, including but not limited to atrial fibrillation, ventricular tachycardia, heart block OR Participants < 65 years of age with cardiac risk factors [e.g., diabetes, hypertension, obesity]). -Forced expiratory volume in the first second (FEV1) <= 50% predicted for participants with a clinical history prompting pulmonary evaluation (e.g., a prolonged history of cigarette smoking [>= 20 pack-year smoking history within the past two years], symptoms of respiratory dysfunction, thoracic surgeries, or other clinical indications). -Positive beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in IOCBP at screening. -Uncontrolled intercurrent illness evaluated by medical history and physical exam that are not stable and would potentially increase the risk to the participant.
-Resected pancreas ductal adenocarcinoma (PDAC):
--Resected pancreas ductal adenocarcinoma
--If stage I-III has a history of detectable circulating tumor DNA (ctDNA) after resection/local treatment of all known disease.
OR
--If stage I-III, have a history of abnormally elevated cancer antigen (CA)19-9 at diagnosis (before surgery) AND a history of abnormally elevated post-operative CA19-9 measured at least 30 days after surgery AND a history of the relative increase of postoperative CA19-9 of 2.6-fold or more compared to the participant s post-operative baseline, as confirmed by two separate tests at least 3 weeks apart.
--Had metastatic disease (stage IV) at diagnosis and were down staged with chemotherapy and underwent resection.
-Colorectal liver, lung, and/or lymph node metastases (CRLM):
--Participants with stage IV colorectal cancer with metastases to the liver, lung, and/or lymph nodes that were completely treated with local therapy (resection, ablation, and/or radiotherapy).
--Must have a history of detectable ctDNA after resection/local treatment of all known disease.
-Gastrointestinal carcinoma (GIC):
--Participants with resected gastroesophageal cancer, hepatocellular cancer, cholangiocarcinoma, duodenal, small bowel, or primary colorectal cancer (i.e., pathologic stage I-III as distinguished from CRLM).
-Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology (LP).
-Must have a history of:
--KRAS G12D mutation plus HLA-A*11:01
--KRAS G12D mutation plus HLA-C*08:02
--KRAS G12V mutation plus HLA-C*01:02
--TP53 R175H mutation plus HLA-A*02:01.
-Treated with standard systemic and/or radiotherapy if indicated unless participant refusal or non-tolerance of the standard regimen. For example:
--Participants with PDAC should receive neoadjuvant or adjuvant chemotherapy (5-FU or gemcitabine-based).
--Participants with CRLM should have received at least one line of 5FU-based chemotherapy (i.e., FOLFOX or FOLFIRI).
--Participants with resected stage III colon cancer should have received 5FU-based adjuvant therapy (i.e., FOLFOX or FOLFIRI).
-CRLM only: Participants with a history of brain metastases that have been treated with stereotactic radiosurgery or resection must be clinically stable for 3 months after treatment to be eligible.
-Age >= 18 years and <= 72 years.
-Clinical performance status of ECOG 0 or 1
-Individuals of child-bearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and up to and 12 months after the last dose of combined chemotherapy. Individuals that can father children must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 4 months after the last dose of study drugs. We also will recommend individuals that can father children with partners that can bear children ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals that can father
children must not freeze or donate sperm within the same period.
NOTE: IOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
-Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 4 months after the last dose of the study drug(s).
-Viral testing
--Seronegative for human immunodeficiency virus (HIV) antibody.
--Negative for hepatitis B (HBV) surface antigen (HbsAg), and seronegative for hepatitis C (HCV) antibody. If the HCV antibody test is positive, then the participant must be tested for the presence of antigen by RT-PCR and be HCV RNA negative to be eligible.
-Hematology
--Absolute neutrophil count (ANC) > 1000/mm^3 without the support of filgrastim
--White blood cells (WBC) >= 2500/mm^3
--Platelet count >= 80,000/mm^3
--Hemoglobin > 8.0 g/dL.
-Chemistry
--Alanine aminotransferase (ALT) <= 5.0 x upper limit of normal (ULN)
--Aspartate aminotransferase (AST) <= 5.0 x ULN
--Creatinine <= 1.6 mg/dL
--Total bilirubin <= 2.0 mg/dL, except in participants with Gilbert s Syndrome, who must have a total bilirubin < 3.0 mg/dL.
-Four weeks must have passed after any prior systemic therapy for cancer, any investigational agents, surgical procedures, or limited field radiotherapy prior to randomization, as long as related major organ toxicities have recovered to grade 1 or less per Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.
NOTE: Participants with adverse events Grade 2 that are deemed irreversible and stable and will not prevent administration of the study drug(s)/intervention or prevent compliance with the study requirements (e.g., alopecia, peripheral neuropathy, laboratory parameters not
otherwise specified per the eligibility criteria) are an exception to this criterion and are eligible.
-Ability of the participant to understand and the willingness to sign a written informed consent document.
-Willing to sign a durable power of attorney.
-Participants must be co-enrolled on protocols 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols), and 09-C-0161 (Follow-up Protocol for Subjects Previously Enrolled on NCI Surgery Branch Studies).
EXCLUSION CRITERIA
-Unequivocal radiographic evidence of residual tumor.
-Participants with measurable disease per RECIST v1.1 criteria.
-Any form of secondary immunosuppression.
-Active or chronic infections requiring anti-microbial, anti-fungal, or anti-viral treatment.
-Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and Acquired immunodeficiency syndrome [AIDS]).
-History of major organ autoimmune disease.
-Concurrent opportunistic infections.
-History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
-History of coronary revascularization or ischemic symptoms.
-Left ventricular ejection fraction (LVEF) <= 45% for participants with a clinical history prompting cardiac evaluation (e.g., participants who are >= 65 years of age, or who have a ventricular arrhythmias, including but not limited to atrial fibrillation, ventricular tachycardia, heart block OR Participants < 65 years of age with cardiac risk factors [e.g., diabetes, hypertension, obesity]).
-Forced expiratory volume in the first second (FEV1) <= 50% predicted for participants with a clinical history prompting pulmonary evaluation (e.g., a prolonged history of cigarette smoking [>= 20 pack-year smoking history within the past two years], symptoms
of respiratory dysfunction, thoracic surgeries, or other clinical indications).
-Positive beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in IOCBP at screening.
-Uncontrolled intercurrent illness evaluated by medical history and physical exam that are not stable and would potentially increase the risk to the participant.
Principal Investigator
Referral Contact
For more information: