Study of People With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Gastrointestinal Neoplasm Clinical Trial

Official title: A Phase I/II Trial in Patients With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Status Withdrawn

Clinical Trial Summary

Background:

The gene CISH can weaken immune cells called lymphocytes. It is found in all cells of the body but it most negatively impacts lymphocytes. This study may help people with certain cancers.Lymphocyte cells will be taken from their tumors, the CISH gene will be removed from those cells, then the cells will be returned to the person. Researchers hope this process will help the cells work better and fight the tumors.

Objective:

To see if cells with the CISH gene removed are safe and shrink metastatic gastrointestinal epithelial tumors.

Eligibility:

People 18 70 years old with metastatic gastrointestinal epithelial cancer

Design:

Participants will be screened with physical exam, scans, and heart, lung, blood, and urine tests.

Participants will have cells collected in another protocol. They must tell their doctor of any antibiotic allergy.

The cells will be changed in a lab. Participants will stop therapy 4 6 weeks before getting the cells back.

Participants will have leukapheresis. Blood is sent by a needle in one arm into a machine that takes out the white blood cells. The blood is returned through a needle in the other arm.

Participants will have an IV catheter inserted in their upper chest to receive medicines and the cells.

Participants will stay in the hospital and:

• Have chemotherapy for 1 week

• Get the cells for about a half hour to a little over an hour

• Get a cell growth medicine about every 8 hours for up to 12 doses

• Get medicines to boost blood cells and fight side effects

• Recover for 1 3 weeks.

Participants will have 2 follow-up visits within 12 weeks of treatment, then a couple visits each year. They will repeat screening tests.

Clinical Trial Description

BACKGROUND:

• CISH (Cytokine-induced SH2 protein) is an important negative regulator of T-cell signaling. The knockout or knockdown of CISH in mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses compared to the wild-type anti-tumor lymphocytes.

• We have developed and optimized a CRISPR/Cas9 based strategy for highly efficient gene disruption in primary human T-cells without sacrificing cell viability or function.

• Thus, in this protocol we propose to disrupt the gene encoding CISH in lymphocytes from patients with metastatic cancers that are selected for anti-tumor activity.

OBJECTIVES:

Primary objectives:

• To determine the safety of the administration of mutation reactive autologous lymphocytes with knockout of the CISH gene in patients with refractory metastatic gastrointestinal epithelial cancer.

• To determine the response rate of the administration of mutation reactive TIL with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancers.

ELIGIBILITY:

• Age greater than or equal to 18 years and less than or equal to 70 years

• Evaluable metastatic gastrointestinal epithelial cancer refractory to standard chemotherapy

• Metastatic cancer lesions suitable for surgical resection for the preparation of TIL

• No allergies or hypersensitivity to high-dose aldesleukin administration

• No concurrent major medical illnesses or any form of immunodeficiency

DESIGN:

• Patients with evaluable metastatic gastrointestinal epithelial cancer will undergo a resection of tumor under the NCI Surgery Branch companion protocol 03-C-0277.

• The study will begin in a standard phase I dose-escalation. After the MTD cell dose has been determined, patients will be enrolled into the Phase II portion of the trial at the MTD established during the Phase I portion of the study.

• Patients will receive a non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of the CISH knockout lymphocytes plus IV aldesleukin.

• In the Phase II portion, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. If 0 or 1 of the first 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21

evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled.

• The objective will be to determine if the treatment regimen is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).

• Up to 60 patients may be enrolled over 5 years. ;

Related Conditions & MeSH terms

• Cancer of Gastrointestinal Tract
• Cancer, Gastrointestinal
• Digestive System Neoplasms
• Gastrointestinal Epithelial Cancer
• Gastrointestinal Neoplasm
• Gastrointestinal Neoplasms

• NCT number: NCT03538613
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• Start date: May 17, 2018
• Completion date: September 10, 2018