Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients
2 other identifiers
interventional
110
1 country
1
Brief Summary
Background: A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells. Objective: To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors. Eligibility: Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors. Design: In another protocol, participants will: Be screened Have cells harvested and grown Have leukapheresis In this protocol, participants will have the procedures below. Participants will be admitted to the hospital. Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest. A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter. For up to 3 days, participants will get a drug to make the cells active. A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin. Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests. Participants will take an antibiotic for at least 6 months. Participants will have visits every few months for 2 years, and then as determined by their doctor. Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn. Participants will have blood collected over several years.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1 pancreatic-cancer
Started Sep 2017
Longer than P75 for phase_1 pancreatic-cancer
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
June 16, 2017
CompletedFirst Posted
Study publicly available on registry
June 19, 2017
CompletedStudy Start
First participant enrolled
September 21, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
June 29, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
June 29, 2028
April 24, 2026
November 26, 2025
9.8 years
June 16, 2017
April 23, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Response rate
Percentage of patients who have a clinical response (PR+CR) to treatment (objective tumor regression)
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
Frequency and severity of treatment-related adverse events
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
From time of cell infusion to two weeks after cell infusion
Study Arms (2)
1/Phase I
EXPERIMENTALNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + escalating doses of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
2/Phase II
EXPERIMENTALNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of anti-KRAS G12V mTCR PBL + high-dose aldesleukin
Interventions
Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.
Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.
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).
Aldesleukin 720,000 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 9 doses).
Eligibility Criteria
You may qualify if:
- Measurable (per RECIST V1.1 criteria, metastatic, or unresectable malignancy expressing G12V mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. Patients shown to have tumors expressing G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope.
- Patients must be HLA-A\*11:01 positive as confirmed by the NIH Department of Transfusion Medicine.
- Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.
- Patients must have:
- previously received standard systemic therapy for their advanced cancer and have been either non-responders or have recurred, specifically:
- Patients with metastatic colorectal cancer must have had at least two systemic chemotherapy regimens that include 5FU, leucovorin, bevacizumab, oxaliplatin, and irinotecan (or similar agents), or have contraindications to receiving those medications.
- Patients with pancreatic cancer must have received gemcitabine, 5FU, and oxaliplatin (or similar agents), or have contraindications to receiving those medications.
- Patients with non-small cell lung cancer (NSCLC) must have had appropriate targeted therapy as indicated by abnormalities in ALK, EGFR, or expression of PDL- 1. Other patients must have had platinum-based chemotherapy.
- Patients with ovarian cancer or prostate cancer must have had approved first-line chemotherapy.
- declined standard treatment
- Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients
- with surgically resected brain metastases are eligible.
- Age greater than or equal to 18 years and less than or equal to 72 years.
- Clinical performance status of ECOG 0 or 1
- Patients must be willing to practice birth control from the time of enrollment on this study and 12 months after the last dose of combined chemotherapy for women and for 4 months after treatment for men.
- +19 more criteria
You may not qualify if:
- Large volume pulmonary irradiation.
- 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.
- History of coronary revascularization or ischemic symptoms
- For select patients with a clinical history prompting cardiac evaluation: last known LVEF less than or equal to 45%.
- For select patients with a clinical history prompting pulmonary evaluation: known FEV1 less than or equal to 50% or DLCO less than 60%.
- Patients who are receiving any other investigational agents.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Related Publications (3)
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.
PMID: 21138872BACKGROUNDWang 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.
PMID: 26701267BACKGROUNDAbrams 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.
PMID: 9514698BACKGROUND
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
James C Yang, M.D.
National Cancer Institute (NCI)
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
June 16, 2017
First Posted
June 19, 2017
Study Start
September 21, 2017
Primary Completion (Estimated)
June 29, 2027
Study Completion (Estimated)
June 29, 2028
Last Updated
April 24, 2026
Record last verified: 2025-11-26
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, ICF
- Time Frame
- Clinical data will be available during the study and indefinitely.
- Access Criteria
- Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
All IPD recorded in the medical record will be shared with intramural investigators upon request.