A Phase II Study of Adjuvant Immunotherapy Targeting KRAS G12D, KRAS G12V, or TP53 R175H for Participants With Advanced Gastrointestinal Malignancies

NCT06690281 | Withdrawn Phase 2 FDA Drug

• 2 other identifiers: 10001870001870-C
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Background: 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.

Conditions

Gastrointestinal Carcinoma; Pancreatic Cancer; Hepatocellular Cancer; Cholangiocarcinoma; Duodenal Cancer; Colorectal Cancer; Small Bowel Cancer; Metastatic Cancers

Keywords

KRAS Mutations; Cell Therapy; Gene Therapy; Tp53 Mutations; Immunotherapy; KRAS G12D; KRAS G12V; Tp53; R175H

Outcome Measures

Primary Outcomes (1)

• Recurrence free survival (RFS)

  RFS will be assessed with tumor markers and radiographic findings in each group and reported using the Kaplan-Meier method with 95% confidence intervals on the median RFS in each group.

  12 weeks then every 3 months x 3, every 6 months after that until progression or 5 years since randomization.

Secondary Outcomes (2)

• Overall survival (OS)

  12 weeks then every 3 months x 3, every 6 months after that until progression or 5 years since randomization. After progression contact with participants every 6 months until the first of death or 5 years after randomization.

• Safety

  until 6 months after the last dose of study agents

Study Arms (2)

1/ TCR T-cells and aldesleukin

EXPERIMENTAL

Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + TCR T cells + aldesleukin

Biological: KRAS TCR-Transduced PBL; Drug: Aldesleukin; Drug: Fludarabine; Drug: Cyclophosphamide

2/ No cellular therapy

NO INTERVENTION

Surveillance and follow-up

Interventions

KRAS TCR-Transduced PBL BIOLOGICAL

Day 0: Cells will be infused intravenously (IV) over 20-30 minutes (2-4 days after the last dose of fludarabine)

1/ TCR T-cells and aldesleukin

Aldesleukin DRUG

Aldesleukin 600,000 IU/kg 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 3 doses)

1/ TCR T-cells and aldesleukin

Fludarabine DRUG

Days -7 to -3: Fludarabine 25 mg/m\^2/day IVPB daily over 30 minutes for 4 days

1/ TCR T-cells and aldesleukin

Cyclophosphamide DRUG

Days -7 and -6: Cyclophosphamide 30 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 7.5 mg/kg/day over 1 hour x 2 days

1/ TCR T-cells and aldesleukin

Eligibility Criteria

• Age: 18 Years - 72 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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).
• 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
• KRAS G12D mutation plus HLA-C\*08:02

You may not qualify if:

• 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.
• 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 history of ischemic heart disease, chest pain, or clinically significant atrial and/or 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Pancreatic Neoplasms; Liver Neoplasms; Cholangiocarcinoma; Duodenal Neoplasms; Colorectal Neoplasms; Neoplasms

Interventions

aldesleukin; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Liver Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Duodenal Diseases; Intestinal Diseases; Colonic Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Nicholas D Klemen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2024
• First Posted: November 15, 2024
• Study Start: September 9, 2025
• Primary Completion: September 9, 2025
• Study Completion: September 9, 2025
• Last Updated: September 11, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be shared after reaching the primary endpoint per the identified timeframe.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)