Clinical Trials /

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

NCT04426669

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
  • Esophageal Carcinoma
  • Gallbladder Carcinoma
  • Gastric Carcinoma
  • Pancreatic Carcinoma
  • Small Intestinal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 2019LS002
  • NCT ID: NCT04426669
  • NCT ALIAS: NCT03538613

Conditions

  • 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
  • Stomach Cancer

Interventions

DrugSynonymsArms
CyclophosphamideCISH CRISPR TIL / Phase I Arm
FludarabineCISH CRISPR TIL / Phase I Arm
Tumor-Infiltrating Lymphocytes (TIL)CISH CRISPR TIL / Phase I Arm
AldesleukinInterleukin-2, IL-2CISH CRISPR TIL / Phase I Arm

Purpose

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.

Detailed Description

      Tumor Infiltrating Lymphocytes (TIL) have shown efficacy in certain cancers, principally in
      melanoma. Efficacy in more common solid tumors has been demonstrated via the selection of
      cancer neoantigen-specific TIL. Combination checkpoint inhibitor therapy has also been
      employed in an attempt to enhance the efficacy of these cell therapies. Genetic engineering
      of T cells to further increase anti-tumor activity is now possible.

      CISH (Cytokine-induced SH2 protein) is a novel intra-cellular immune checkpoint and an
      important negative regulator of T-cell signaling and function. The inhibition of CISH in
      mouse anti-tumor lymphocytes results in a marked increase in the ability of these lymphocytes
      to mediate tumor regression following administration to tumor bearing mice.

      Additionally, data in genetically-engineered, neoantigen-specific human T cells in which CISH
      was inhibited, showed enhanced TCR functional avidity and increased ability of these T cells
      to detect cancer specific mutations and mount robust polyfunctional cytokine immune responses
      against their cognate cancer antigens. Thus, these T cells appear to have a significant
      advantage in inducing anti-tumor responses compared to wild-type anti-tumor lymphocytes.

      The researchers have developed and optimized a CRISPR/Cas9 based strategy for precise and
      efficient genetic engineering in primary human T-cells without sacrificing cell viability or
      function.

      Thus, in this protocol, the researchers propose to inhibit the gene encoding the
      intra-cellular checkpoint target CISH in lymphocytes from patients with metastatic cancers
      that are selected for anti-tumor activity in order to evaluate the safety and efficacy of
      genetically engineered T cell therapy for solid tumors in the setting of novel checkpoint
      inhibition.
    

Trial Arms

NameTypeDescriptionInterventions
CISH CRISPR TIL / Phase I ArmExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine +escalating doses of CISH inactivated TIL + high-dose aldesleukin
  • Cyclophosphamide
  • Fludarabine
  • Tumor-Infiltrating Lymphocytes (TIL)
  • Aldesleukin
CISH CRISPR TIL / Phase II ArmExperimentalNon-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + MTD of CISH inactivated TIL
  • Cyclophosphamide
  • Fludarabine
  • Tumor-Infiltrating Lymphocytes (TIL)
  • Aldesleukin

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/ucm095
                  440.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 fibrillation, ventricular tachycardia, second- or
                  third-degree heart block, or have a history of ischemic heart disease and/or
                  chest pain. Patients < 65 years of age who present with cardiac risk factors
                  (e.g., diabetes, hypertension, obesity) may undergo cardiac evaluation as noted
                  above.

          -  Clinically significant patient history that in the judgment of the PI would compromise
             the patient's ability to tolerate high-dose aldesleukin.

          -  Documented FEV1 ≤ 50% predicted tested in patients with:

               -  A prolonged history of cigarette smoking (approximately 20 packs/year within the
                  past 2 years) and/or

               -  Symptoms of respiratory dysfunction

          -  Receiving any investigational agents.

        Confirmation of Eligibility Prior to CY/FU Start:

        Due to a 10-12 week or more delay between study enrollment and the start of study
        treatment, the following eligibility criteria must be met:

          -  Clinical performance status of ECOG 0 or 1

          -  Hematology within 7 days of starting lymphodepleting chemotherapy:

               -  Absolute neutrophil count > 1000/mm^3 without the support of filgrastim

               -  WBC ≥ 3000/mm^3

               -  Platelet count ≥ 100,000/mm^3

               -  Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cutoff.

          -  Adequate organ function within 7 days of starting lymphodepleting chemotherapy:

               -  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.

          -  Seronegative for HIV antibody, hepatitis B antigen, and hepatitis C antibody as tested
             within 3 months of beginning lymphodepleting chemotherapy. 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

          -  More than four weeks must have elapsed since the last dose of prior systemic therapy
             and the start of the lymphodepleting chemotherapy, and acute toxicities must have
             recovered to Grade 1 or less (except for toxicities such as alopecia or vitiligo).

          -  Sexually active females of child-bearing potential and males with female partners of
             child-bearing potential must agree to use effective contraception for the duration of
             study treatment starting with the 1st dose of fludarabine and for 4 months after the
             last dose of aldesleukin. Examples of effective contraception includes an IUD or
             implant plus a condom. Women of non-childbearing potential are defined as those who
             have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian
             function due to ovarian failure or surgical removal of the ovaries. A woman also is
             presumed to be infertile due to natural causes if she has been amenorrheic for > 12
             months and/or has an FSH > 40 IU/L.

          -  Negative pregnancy test within 7 days of starting lymphodepleting chemotherapy in
             women of childbearing potential.

          -  No change in medical status or social situation that would make study participation
             not in the best interest of the patient in the opinion of the enrolling investigator.

          -  Continues to agree 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 signed the study treatment consent form within 28 days prior to the start of
             the lymphodepleting chemotherapy.
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:28 Days Post IL-2
Safety Issue:
Description:Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:2 Years or Disease Progression
Safety Issue:
Description:Progression-Free Survival (PFS) of patients with metastatic gastrointestinal cancers treated using the autologous lymphocytes
Measure:Overall Survival (OS)
Time Frame:2 Years or Disease Progression
Safety Issue:
Description:Overall Survival (OS) of patients with metastatic gastrointestinal cancers treated using the autologous lymphocytes
Measure:Toxicity profiles resulting from treatment using these engineered tumor-infiltrating lymphocytes
Time Frame:2 Years or Disease Progression
Safety Issue:
Description:Incidence of targeted toxicities events

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Intima Bioscience, Inc.

Trial Keywords

  • Adoptive Cell Therapy, Immunotherapy, Gene Therapy, CISH checkpoint, CRISPR

Last Updated

June 9, 2020