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

Plain English Summary

A Study of Metastatic Gastrointestinal Cancers Treated With Tumor Infiltrating Lymphocytes in Which the Gene Encoding the Intracellular Immune Checkpoint CISH Is Inhibited Using CRISPR Genetic Engineering is a Phase 2 clinical trial sponsored by Intima Bioscience, Inc. studying Gastrointestinal Epithelial Cancer, Gastrointestinal Neoplasms, Cancer of Gastrointestinal Tract, Cancer, Gastrointestinal, Gastrointestinal Cancer, Colo-rectal Cancer, Pancreatic Cancer, Gall Bladder Cancer, Colon Cancer, Esophageal Cancer. This trial tests a new type of cell therapy that uses a patient's own immune cells (tumor-infiltrating lymphocytes) that have been genetically modified to better fight cancer. It is for patients with advanced gastrointestinal cancers that have spread and have not responded to standard treatments. Participation involves a procedure to collect tumor cells, genetic modification of immune cells in a lab, and then infusion of these modified cells back into the patient, along with chemotherapy and a growth factor. Alternative treatments may include other types of chemotherapy, targeted therapies, or immunotherapy, depending on the specific cancer and prior treatments. The trial aims to enroll 23 participants.

Official Summary

A clinical trial to assess the safety and efficacy of genetically-engineered, neoantigen-specific Tumor Infiltrating Lymphocytes (TIL) in which the intracellular immune checkpoint CISH has been inhibited using CRISPR gene editing for the treatment of Gastro-Intestinal (GI) Cancer.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients with metastatic gastrointestinal epithelial cancer that has progressed after at least one prior standard treatment can join. Patients must have measurable tumors, with at least one tumor large enough to be used for generating the therapy and another to monitor response. Certain brain metastases may be allowed if they are small, asymptomatic, and stable after treatment. Patients must be between 18 and 70 years old, have good general health, and have adequate organ function and blood counts. They must also be free of certain infections like HIV and Hepatitis B/C. This trial is studying Gastrointestinal Epithelial Cancer, Gastrointestinal Neoplasms, Cancer of Gastrointestinal Tract, Cancer, Gastrointestinal, Gastrointestinal Cancer, Colo-rectal Cancer, Pancreatic Cancer, Gall Bladder Cancer, Colon Cancer, Esophageal Cancer, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcomes measure how safe the treatment is and how well it works by looking at the maximum dose tolerated and the changes in tumor size over time, indicating if the engineered cells are ef The specific primary outcome measures are: Maximum tolerated dose (MTD) (28 Days Post IL-2); Preliminary efficacy of tumor reactive autologous lymphocytes with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancers: changes in diameter (Every 4 Weeks for the first three months, then every 8 weeks thereafter, up to 2 years); Safety of tumor reactive autologous lymphocytes with knockout of the CISH gene - Incidence of Adverse Events (2 Years or Disease Progression). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial explores a novel approach to cancer treatment by genetically engineering a patient's own immune cells to specifically target and destroy gastrointestinal tumors, potentially filling a gap f Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Gastrointestinal Epithelial Cancer, Gastrointestinal Neoplasms, Cancer of Gastrointestinal Tract, Cancer, Gastrointestinal, Gastrointestinal Cancer, Colo-rectal Cancer, Pancreatic Cancer, Gall Bladder Cancer, Colon Cancer, Esophageal Cancer, where improved treatment options are needed.

Investor Insight

This trial represents an early-stage investment in a cutting-edge cell therapy technology (CRISPR-edited TILs) for a significant market (GI cancers), with potential for high impact if successful, thou Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and benefits of this experimental treatment, including the procedures involved and potential side effects. Be prepared for a multi-step process involving surgery or biopsy, a hospital stay for chemotherapy and cell infusion, and regular follow-up appointments for monitoring. You will need to stay within a one-hour drive of the study center for a period after treatment for close monitoring. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 23 participants

Interventions

• DRUG: Cyclophosphamide — Day -6 and Day -5: Cyclophosphamide 60 mg/kg/dose as a 2 hour intravenous infusion with Mesna 15 mg/kg/dose, 1st dose prior to Cyclophosphamide infusion then at 3,6,9 and 12 hours later.
• DRUG: Fludarabine — Day -7 to Day -3 : Fludarabine 25 mg/m\^2/dose as a 1 hour intravenous infusion per institutional guidelines once a day for 5 doses beginning on Day -7. Fludarabine will be started approximately 1 to 2 hours after the cyclophosphamide on Day -6 and Day -5.
• BIOLOGICAL: Tumor-Infiltrating Lymphocytes (TIL) — Day 0 : Each bag of autologous CISH inactivated TIL for infusion will be administered intravenously (IV) on the Patient Care Unit over 10-20 minutes at assigned dose level.
• DRUG: Aldesleukin — Days 1-4 : Aldesleukin at 720,000 U/kg as an intravenous infusion, every 8 -12 hours but, no more than 24 hours apart as tolerated for up to 6 doses.

Primary Outcomes

• Maximum tolerated dose (MTD) (28 Days Post IL-2)
• Preliminary efficacy of tumor reactive autologous lymphocytes with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancers: changes in diameter (Every 4 Weeks for the first three months, then every 8 weeks thereafter, up to 2 years)
• Safety of tumor reactive autologous lymphocytes with knockout of the CISH gene - Incidence of Adverse Events (2 Years or Disease Progression)

Secondary Outcomes

• Progression-Free Survival (PFS) (2 Years or Disease Progression)
• Overall Survival (OS) (2 Years or Disease Progression)
• Toxicity profiles resulting from treatment using these engineered tumor-infiltrating lymphocytes (2 Years or Disease Progression)

Full Eligibility Criteria

Inclusion Criteria:

* Diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease following at least one first line standard therapy. When available, archived tissue from original diagnosis will be obtained for research related testing.
* Must have measurable disease per RECIST 1.1 with at least one lesion identified as resectable for TIL generation (minimum volume of tumor tissue required is 1 cm\^2 as single mass or fragments) and at least one other lesion meeting the RECIST criteria for measurable to serve as an indicator of disease response. The location of the tumor for TIL generation and method used to obtain (i.e. laparoscopy, endoscopic ultra sound, etc.) will be determined based on an individual patient's disease.
* 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 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible. Patients must not be receiving systemic steroids.
* Brain metastases are assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
* Age ≥ 18 years and ≤ 70 years.
* Clinical performance status of ECOG 0 or 1.
* Serology testing within 3 months of study enrollment (tumor collection):

  * Seronegative for HIV antibody. (The investigational treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immunocompetence and thus may be less responsive to the study treatment and more susceptible to its toxicities.)
  * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
  * Seronegative for anti-HBc, HBV/HCV/HIV-1 NAT, anti-HTLV-I/II, anti-T.cruzi, West Nile Virus NAT, anti-CMV, and RPR. (Note: Other blood viral testing may be required as updated on the FDA website: https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm095440.htm#approved)
* Hematology within 14 days of study enrollment:

  * Absolute neutrophil count \> 1000/mm\^3 without the support of filgrastim
  * WBC ≥ 3000/mm\^3
  * Platelet count ≥ 75,000/mm\^3
  * Hemoglobin \> 8.0 g/dl. Subjects may be transfused to reach this cutoff.
* Adequate organ function within 14 days of study enrollment defined as:

  * Serum ALT and AST ≤ 5.0 x ULN
  * Serum creatinine ≤ 1.6 mg/dl
  * Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dl.
* More than four weeks must have elapsed since prior systemic therapy at the time the patient receives the preparative regimen, and acute toxicities must have recovered to Grade 1 or less (except for toxicities such as alopecia or vitiligo). Disease appropriate standard therapy is permitted between tumor collection and start of the fludarabine and cyclophosphamide. Investigational therapy is prohibited.

Note: Patients may have undergone minor surgical procedures within the 3 weeks of the start of preparative therapy as long as all toxicities have recovered to Grade 1 or less.

* Willing to undergo outpatient non-mobilized leukapheresis (3 hour collection) prior to the tumor collection
* Agrees to remain in the Twin Cities metropolitan area (within 1 hour drive of the University of Minnesota) after the CISH KO TILs infusion through the End of Treatment visit (Day 28)
* Voluntary written consent prior to the performance of any research related procedures

Exclusion Criteria:

* Pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Women of childbearing potential (defined as menses within previous 12 month and/or FSH ≤ 40 IU/L) must have a negative pregnancy test (serum or urine) within 7 days of enrollment. A repeat negative pregnancy test is required within 7 days of beginning the preparative chemotherapy.
* Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
* Concurrent opportunistic infection (The treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune-competence may be less responsive to the treatment and more susceptible to its toxicities).
* Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active major medical illnesses.
* Concurrent systemic steroid therapy.
* History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
* History of coronary revascularization or ischemic symptoms.
* Documented LVEF ≤ 45% tested in patients:

  * Age ≥ 65 years and/or
  * With clinically significant atrial and/or ventricular arrhythmias, including but not limited to: atrial fibrillat

Trial Locations

• Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States

Frequently Asked Questions

Related Conditions

• Gastrointestinal Epithelial Cancer
• Gastrointestinal Neoplasms
• Colo-rectal Cancer
• Pancreatic Cancer
• Gall Bladder Cancer
• Colon Cancer
• Esophageal Cancer
• Gastric Cancer
• Small Intestine Cancer
• Hepatobiliary Tract Cancer

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