Gastrointestinal CancerPhase 1/2NCT03745326

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

A Phase 1/2 study testing Cyclophosphamide, Fludarabine and Aldesleukin in people with Gastrointestinal Cancer and Pancreatic Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 72 years
Conditions the study is for: Gastrointestinal Cancer, Pancreatic Cancer, Gastric Cancer
What is being tested?: Cyclophosphamide, Fludarabine and Aldesleukin
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 5 participants
Where: 1 siteUnited States
Study dates: 16 May 2019to 23 Aug 2022
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 72 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

None listed.

Who cannot join

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
Concurrent systemic steroid therapy.
Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.

Show all 10Show fewer

History of coronary revascularization or ischemic symptoms.
For select patients with a clinical history prompting cardiac evaluation: last known left ventricular ejection fraction (LVEF) less than or equal to 45%.
For select patients with a clinical history prompting pulmonary evaluation: known forced expiratory volume at one second (FEV1) less than or equal to 50%.
Patients who are receiving any other investigational agents.

Trial locations and contacts

1 site in 1 country.

United States1 site

National Institutes of Health Clinical Center
Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

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.

Read the detailed description

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.

Conditions: Gastrointestinal Cancer, Pancreatic Cancer, Gastric Cancer, Colon Cancer, Rectal Cancer
Being tested: Cyclophosphamide, Fludarabine, Aldesleukin, anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL), EKG
Keywords: Immunotherapy, Cell Therapy, KRAS, HRAS, NRAS
Medical subject headings: Gastrointestinal Neoplasms, Pancreatic Neoplasms, Stomach Neoplasms, Colonic Neoplasms, Rectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CyclophosphamideDrug
Also called Cytoxan, Neosar
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.
FludarabineDrug
Also called Fludara
Days -7 to -3: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
AldesleukinDrug
Also called Interleukin- 2
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).
anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL)Biological
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).
EKGDiagnostic test
Also called Electrocardiogram
Baseline within 14 days prior to preparative regimen
CTDiagnostic test
Also called Computed tomography
Within 6 weeks and post treatment follow-up
MRIDiagnostic test
Also called Magnetic resonance imaging
Within 6 weeks and post treatment follow-up
PETDiagnostic test
Also called positron emission tomography
Within 6 weeks and post treatment follow-up
Chest x-rayDiagnostic test
Also called Chest XR
Baseline within 14 days prior to preparative regimen
PhotographyOther
Within 6 weeks and post treatment follow-up

Study groups in NCT03745326
Study group	Role	What they receive
Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen	Experimental	Cohort 1, Arm 1. Participants enrolled with measurable, metastatic, or unresectable malignancy expressing G12D mutated KRAS. Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12(G12D) murine T-cell receptor (mTCR) peripheral blood lymphocytes (PBL) + highdose aldesleukin. Receives: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin; Biological: anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL); Diagnostic Test: EKG; Diagnostic Test: CT; Diagnostic Test: MRI; Diagnostic Test: PET; Diagnostic Test: Chest x-ray; Other: Photography
Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen	Experimental	Cohort 2a: Participants with a diagnosis of pancreatic cancer. Cohort 2b: Participants with a diagnosis other than pancreatic cancer. Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + maximum tolerated dose (MTD) of anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12(G12D) murine T-cell receptor (mTCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin. Receives: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin; Biological: anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL); Diagnostic Test: EKG; Diagnostic Test: CT; Diagnostic Test: MRI; Diagnostic Test: PET; Diagnostic Test: Chest x-ray; Other: Photography

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

16 May 201923 Aug 2022

First posted19 Nov 2018
Study start16 May 2019
Primary completion23 Aug 2022
Study completion23 Aug 2022

Why it stopped: Study was closed due to lack of accrual and study outcomes overlapped with another protocol's eligibility.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Gastrointestinal CancerStudies of the same condition, open and under way.
More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Enrolment: 5 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03745326
Sponsor's protocol ID: 190017
Other IDs: 19-C-0017
Status last verified: May 2026
First submitted: 16 Nov 2018
Last updated: 19 May 2026
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. All collected IPD will be shared with collaborators under the terms of collaborative agreements.

Publications

Abrams SI, Khleif SN, Bergmann-Leitner ES, Kantor JA, Chung Y, Hamilton JM, Schlom J. Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. Cell Immunol. 1997 Dec 15;182(2):137-51. doi: 10.1006/cimm.1997.1224.
PubMed 9514698
Davis JL, Theoret MR, Zheng Z, Lamers CH, Rosenberg SA, Morgan RA. Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. Clin Cancer Res. 2010 Dec 1;16(23):5852-61. doi: 10.1158/1078-0432.CCR-10-1280.
PubMed 21138872
Wang QJ, Yu Z, Griffith K, Hanada K, Restifo NP, Yang JC. Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. Cancer Immunol Res. 2016 Mar;4(3):204-14. doi: 10.1158/2326-6066.CIR-15-0188. Epub 2015 Dec 23.
PubMed 26701267

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 19 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients
ClinicalTrials.gov ID: NCT03745326
Acronym / sponsor ID: 190017
Conditions: Gastrointestinal Cancer, Pancreatic Cancer, Gastric Cancer, Colon Cancer, Rectal Cancer
Keywords: Immunotherapy, Cell Therapy, KRAS, HRAS, NRAS
Phase: Phase 1/2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Study was closed due to lack of accrual and study outcomes overlapped with another protocol's eligibility.
Enrolment: 5 participants (actual)
Lead sponsor: National Cancer Institute (NCI)US National Institutes of Health
Study start: 16 May 2019 (actual)
Primary completion: 23 Aug 2022 (actual)
Study completion: 23 Aug 2022 (actual)
First posted: 19 Nov 2018 (actual)
Results: Posted 19 May 2026

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Background:

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.

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.

Detailed description

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 design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen	Experimental	Drug: Cyclophosphamide, Drug: Fludarabine, Drug: Aldesleukin, Biological: anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL), Diagnostic Test: EKG, Diagnostic Test: CT, Diagnostic Test: MRI, Diagnostic Test: PET, Diagnostic Test: Chest x-ray, Other: PhotographyCohort 1, Arm 1. Participants enrolled with measurable, metastatic, or unresectable malignancy expressing G12D mutated KRAS. Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12(G12D) murine T-cell receptor (mTCR) peripheral blood lymphocytes (PBL) + highdose aldesleukin.
Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen	Experimental	Drug: Cyclophosphamide, Drug: Fludarabine, Drug: Aldesleukin, Biological: anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL), Diagnostic Test: EKG, Diagnostic Test: CT, Diagnostic Test: MRI, Diagnostic Test: PET, Diagnostic Test: Chest x-ray, Other: PhotographyCohort 2a: Participants with a diagnosis of pancreatic cancer. Cohort 2b: Participants with a diagnosis other than pancreatic cancer. Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + maximum tolerated dose (MTD) of anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12(G12D) murine T-cell receptor (mTCR) peripheral blood lymphocytes (PBL) + high-dose aldesleukin.

Who may qualify

Ages: 18 to 72 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (0 listed)

Key exclusion criteria (10 listed)

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
Concurrent systemic steroid therapy.
Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
CyclophosphamideAlso: Cytoxan, NeosarDays -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.	Drug	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
FludarabineAlso: FludaraDays -7 to -3: Fludarabine 25 mg/m^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.	Drug	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
AldesleukinAlso: Interleukin- 2Aldesleukin 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).	Drug	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
anti-Kirsten rat sarcoma virus (KRAS) Glycine(G) to Aspartic Acid(D) substitution at codon 12 peripheral blood lymphocytes (PBL)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).	Biological	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
EKGAlso: ElectrocardiogramBaseline within 14 days prior to preparative regimen	Diagnostic test	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
CTAlso: Computed tomographyWithin 6 weeks and post treatment follow-up	Diagnostic test	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
MRIAlso: Magnetic resonance imagingWithin 6 weeks and post treatment follow-up	Diagnostic test	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
PETAlso: positron emission tomographyWithin 6 weeks and post treatment follow-up	Diagnostic test	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
Chest x-rayAlso: Chest XRBaseline within 14 days prior to preparative regimen	Diagnostic test	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen
PhotographyWithin 6 weeks and post treatment follow-up	Other	Arm 1/Phase I Non-myeloablative, Lymphodepleting Preparative Regimen, Arm 2/Phase II Non-myeloablative, Lymphodepleting Preparative Regimen

Primary outcome

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
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
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.
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
Time frame: At the time of cell infusion and end two weeks after cell infusion, an average of one month
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.
Phase II: Percentage of Participants With a Clinical Response (Complete Response (CR) + Partial Response (PR) Reported With 80% Confidence Interval
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
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).
Phase II: Percentage of Participants With a Clinical Response (Complete Response (CR) + Partial Response (PR) Reported With 95% Confidence Interval
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
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).

Results and safety

Results posted to the registry on 19 May 2026, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Arm 1/Phase 1 Dose Level 1x10^8 Total Cell Dose	1	1
Arm 1/Phase 1 Dose Level 3x10^8 Total Cell Dose	0	0
Arm 1/Phase 1 Dose Level 1x10^9 Total Cell Dose	0	0
Arm 1/Phase 1 Dose Level 3x10^9 Total Cell Dose	0	0
Arm 2/Phase II Maximum Tolerated Dose	0	0

Primary outcome: 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

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. Number. Unit: toxicities

Measure	Dose Level 1x10^8 Total Cell Dose: Grade 2 Toxicity n = 1	Dose Level 1x10^8 Total Cell Dose: Grade 3 Toxicity n = 1	Dose Level 3x10^8 Total Cell Dose: Grade 1 Toxicity n = 1	Dose Level 3x10^8 Total Cell Dose: Grade 2 Toxicity n = 1	Dose Level 3x10^8 Total Cell Dose: Grade 3 Toxicity n = 1	Dose Level 3x10^8 Total Cell Dose: Grade 4 Toxicity n = 1	Dose Level 3x10^8 Total Cell Dose: Grade 5 Toxicity n = 1	Dose Level 1x10^9 Total Cell Dose: Grade 1 Toxicity n = 1	Dose Level 1x10^9 Total Cell Dose: Grade 2 Toxicity n = 1	Dose Level 1x10^9 Total Cell Dose: Grade 3 Toxicity n = 1	Dose Level 1x10^9 Total Cell Dose: Grade 4 Toxicity n = 1	Dose Level 1x10^9 Total Cell Dose: Grade 5 Toxicity n = 1	Dose Level 3x10^9 Total Cell Dose: Grade 1 Toxicity n = 2	Dose Level 3x10^9 Total Cell Dose: Grade 2 Toxicity n = 2	Dose Level 3x10^9 Total Cell Dose: Grade 3 Toxicity n = 2	Dose Level 3x10^9 Total Cell Dose: Grade 4 Toxicity n = 2	Dose Level 3x10^9 Total Cell Dose: Grade 5 Toxicity n = 2
Serious - Bronchopulmonary hemorrhage	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Serious - Diarrhea	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Serious - Disease progression	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Serious - Metabolism and nutrition disorders - Other, specify: Failure to thrive	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Serious - Pelvic pain	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Non-Serious - Abdominal distension	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Non-Serious - Alopecia	1	0	0	1	0	0	0	0	1	0	0	0	0	1	0	0	0
Non-serious - Anemia	0	3

Primary outcome: 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

Time frame: At the time of cell infusion and end two weeks after cell infusion, an average of one month. Number. Unit: percentage of participants

Measure	Dose Level 1x10^8 Total Cell Dose n = 1	Dose Level 3x10^8 Total Cell Dose n = 1	Dose Level 1x10^9 Total Cell Dose n = 1	Dose Level 3x10^9 Total Cell Dose n = 2
Grade 3 Serious Diarrhea	0	0	0	50.0
Any Grade 4 Serious Event	0	0	0	0
Any Grade 5 Serious Event	0	0	0	0

Population analysed: All participants will be evaluable for toxicity from the time of their first treatment with cyclophosphamide.

Primary outcome: Phase II: Percentage of Participants With a Clinical Response (Complete Response (CR) + Partial Response (PR) Reported With 80% Confidence Interval

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. Number. Unit: percentage of participants

Population analysed: This outcome was not done. No participants were enrolled on Arm 2/Phase 2 because the study was closed due to lack of accrual and the study outcomes overlapped with another protocol's eligibility. Participants did not complete Phase 1 thus Phase 2 did not start.

Primary outcome: Phase II: Percentage of Participants With a Clinical Response (Complete Response (CR) + Partial Response (PR) Reported With 95% Confidence Interval

Adverse events

Time frame: All-Cause Mortality was monitored/assessed an average of 8.4 months. Adverse events were monitored/assessed 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, for an average of 8.4 months.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Dose Level 1x10^8 Total Cell Dose	1 of 1 (100%)	1 of 1 (100%)	0 of 1
Dose Level 3x10^8 Total Cell Dose	0 of 1 (0%)	1 of 1 (100%)	0 of 1
Dose Level 1x10^9 Total Cell Dose	0 of 1 (0%)	1 of 1 (100%)	0 of 1
Dose Level 3x10^9 Total Cell Dose	1 of 2 (50%)	2 of 2 (100%)	1 of 2

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 May 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 9514698Abrams SI, Khleif SN, Bergmann-Leitner ES, Kantor JA, Chung Y, Hamilton JM, Schlom J. Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations. Cell Immunol. 1997 Dec 15;182(2):137-51. doi: 10.1006/cimm.1997.1224.
Background: PubMed 21138872Davis JL, Theoret MR, Zheng Z, Lamers CH, Rosenberg SA, Morgan RA. Development of human anti-murine T-cell receptor antibodies in both responding and nonresponding patients enrolled in TCR gene therapy trials. Clin Cancer Res. 2010 Dec 1;16(23):5852-61. doi: 10.1158/1078-0432.CCR-10-1280.
Background: PubMed 26701267Wang QJ, Yu Z, Griffith K, Hanada K, Restifo NP, Yang JC. Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors. Cancer Immunol Res. 2016 Mar;4(3):204-14. doi: 10.1158/2326-6066.CIR-15-0188. Epub 2015 Dec 23.
NIH Clinical Center Detailed Web PageLink provided by the sponsor.
Individual participant dataSharing planned: Yes. All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. All collected IPD will be shared with collaborators under the terms of collaborative agreements.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

James C Yang, M.D. principal investigator

National Cancer Institute (NCI)

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 19 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 May 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (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). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03745326, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 May 2026.