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

  • STATUS
    Recruiting
  • End date
    Dec 1, 2028
  • participants needed
    70
  • sponsor
    National Cancer Institute (NCI)
Updated on 22 October 2022
platelet count
antibiotics
cancer
fludarabine
cyclophosphamide
filgrastim
absolute neutrophil count
systemic therapy
lung cancer
KRAS
NRAS
metastasis
oxaliplatin
gemcitabine
EGFR
leucovorin
irinotecan
metastatic colorectal cancer
bevacizumab
cancer treatment
antibiotic
amino acids
cancer chemotherapy
hepatitis b antigen
immunoglobulin
5-fluorouracil
pancreatic cancers

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. It is called gene transfer using anti-KRAS G12D mTCR cells.

Objective

To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink.

Eligibility

Adults ages 18-70 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 a 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.

Description

Background
  • We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of 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 PBL.
  • In co-cultures with HLA-A11:01+ target cells expressing this mutated oncogene, mTCR transduced T-cells lyse target cells and secrete IFN-y 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 RAS G12D mutation.
    Eligibility
  • Patients must be/have:
  • Age greater than or equal to 18 years and less than or eqaul to 70 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-CD3 (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 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.

Details
Condition Gastrointestinal Cancer, Pancreatic Cancer, Gastric Cancer, Colon Cancer, Rectal Cancer
Treatment aldesleukin, cyclophosphamide, Fludarabine, anti-KRAS G12D mTCR PBL
Clinical Study IdentifierNCT03745326
SponsorNational Cancer Institute (NCI)
Last Modified on22 October 2022

Eligibility

How to participate?

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Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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