Clinical Trials /

Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Patients With Pediatric Solid Tumors (GAP)

NCT02932956

Description:

This study enrolls patients who have GPC3-positive liver cancers currently. Patients may be considered if the cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study uses special immune system cells called GAP T cells, a new experimental treatment. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In preclinical studies, the investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33 that recognizes glypican-3, a proteoglycan found on solid tumors including pediatric liver cancers (GPC3-CAR). This study will test T cells genetically engineered with a GPC3-CAR (GAP T cells) in patients with GPC3-positive solid tumors. The GAP T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the biggest dose of GAP T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the GAP T cells will help people with GPC3-positive solid tumors. This study enrolls patients who have GPC3-positive liver cancers currently.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Patients With Pediatric Solid Tumors (GAP)
  • Official Title: Glypican 3-specific Chimeric Antigen Receptor Expressed in Autologous T Cells as Immunotherapy for Patients With Pediatric Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: H-39410- GAP
  • SECONDARY ID: GAP
  • NCT ID: NCT02932956

Conditions

  • Liver Cancer Pediatric

Interventions

DrugSynonymsArms
CytoxanCyclophosphamideGAP T cells + Fludarabine and Cytoxan
FludaraFludarabineGAP T cells + Fludarabine and Cytoxan

Purpose

This study enrolls patients who have GPC3-positive liver cancers currently. Patients may be considered if the cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study uses special immune system cells called GAP T cells, a new experimental treatment. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In preclinical studies, the investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33 that recognizes glypican-3, a proteoglycan found on solid tumors including pediatric liver cancers (GPC3-CAR). This study will test T cells genetically engineered with a GPC3-CAR (GAP T cells) in patients with GPC3-positive solid tumors. The GAP T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the biggest dose of GAP T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the GAP T cells will help people with GPC3-positive solid tumors. This study enrolls patients who have GPC3-positive liver cancers currently.

Detailed Description

      Approximately 24-30 subjects will participate in the treatment part of this study.

      Maximum of 180 mL of blood (not exceeding 3ml/kg/day) is collected from patients to grow the
      T cells and a retrovirus (a special virus that can insert the GPC3 CAR gene into the T cells)
      is used to genetically engineer them. After the CAR gene was put into the T cells, the
      investigators make sure that they are able to kill GPC3 positive solid tumor cells in the
      laboratory.

      LYMPHODEPLETION CHEMOTHERAPY:

      Several studies suggest that the infused T cells need room to be able to proliferate and
      accomplish their functions and that this may not happen if there are too many other T cells
      in circulation. Because of that, participants will receive treatment with cyclophosphamide
      (Cytoxan) and fludarabine for 3 days before receiving the T-cell infusion. These drugs will
      decrease the numbers of the participants' own T cells before the investigators infuse the GAP
      T CELLS.

      WHAT THE INFUSION WILL BE LIKE:

      After making these cells, they will be frozen. If the patient agrees to participate in this
      study, at the time the patient is scheduled to be treated, the cells will be thawed and
      injected into the patient over 5 to 10 minutes. The participant will receive the GAP T CELLS
      48 to 72 hours after completing the chemotherapy.

      This is a dose escalation study, which means that the investigators do not know the highest
      dose of GAP T cells that is safe. To find out, the investigators will give the cells to at
      least 3 participants at one dose level. If that is safe, the investigators will raise the
      dose given to the next group of participants. The dose each patient gets depends on how many
      participants get the agent before that patient and how they react. The investigator will tell
      each patient this information. This will help the participant think about possible harms and
      benefits. Since the treatment is experimental, what is likely to happen at any dose is not
      known.

      All of the treatments will be given by the Center for Cell and Gene Therapy at Texas
      Children's Hospital.

      Medical tests before treatment:

        -  Physical exam and History

        -  Blood tests to measure blood cells, kidney and liver function.

        -  Pregnancy test (if the participant is a female who can get pregnant)

        -  If the participant is infected with the hepatitis B virus (HBV) the investigators will
           do a test to measure the levels of the virus

        -  Measurements of the participant's tumor by scans and the tumor marker alfa-fetoprotein
           (AFP), if the participant's tumor produces this protein.

      Medical tests during and after treatment:

        -  Physical exams and History

        -  Blood tests to measure blood cells, kidney and liver function

        -  If the participant is infected with the hepatitis B virus (HBV) the investigators will
           repeat the test and monitor the levels of the virus

        -  Measurements of the participant's tumor by scans (4-6 weeks after the infusion) and AFP
           (if applicable at 1, 2, and 4 weeks after the infusion).

        -  Tumor biopsy between 2-4 weeks after the infusion and as clinically indicated
           thereafter. For additional clinically indicated tumor biopsies, investigators will ask
           for a portion of the sample for research.

      FOLLOW-UP STUDIES

      The investigators will follow the participant during and after the injections. To learn more
      about the way the T cells are working in the participant's body, up to 60 mL (upto 12
      teaspoons, no more than 3ml/kg/day) of blood will be taken from the participant before the
      chemotherapy, before the T-cell infusion, 1 to 4 hours after the infusion, 3 to 4 days after
      the infusion (this time point is optional ) at 1 week, 2 weeks, 4 weeks and 8 weeks after the
      injection, every 3 months for 1 year, every 6 months for 4 years and then every year for the
      next 10 years. Total participation time for this study will be 15 years.

      During the time points listed above, if the T cells are found in the participant's blood at a
      certain amount an extra 5 mL of blood may need to be collected for additional testing.

      The investigators will use this blood to look for the frequency and activity of the cells
      that the investigators have given; that is, to learn more about the way the T cells are
      working and how long they last in the body. The investigators will also use this blood to see
      if there are any long-term side effects of putting the new gene (chimeric antigen receptor,
      CAR) into the cells. In addition to the blood draws, because the participants have received
      cells that have had a new gene put in them, the participants will need to have long term
      follow up for 15 years so the investigators can see if there are any long-term side effects
      of the gene transfer.

      Once a year, the participants will be asked to have their blood drawn and answer questions
      about their general health and medical condition. The investigators may ask the participants
      to report any recent hospitalizations, new medications, or the development of conditions or
      illness that were not present when the participants enrolled in the study and may request
      that physical exams and/or laboratory tests be performed if necessary.

      When tumor biopsy is performed for clinical reasons the investigators will request permission
      to obtain excess sample to learn more about the effects of the treatment on the participant's
      disease.

      In the event of death, the investigators will request permission to perform an autopsy to
      learn more about the effects of the treatment on the participant's disease and if there were
      any side effects from the cells with the new gene.

      In addition, the investigators would like to ask for participant permission to use tumor
      biopsy for research purposes only. Associated risk with the biopsy will be discussed with
      each participant in detail in a procedure specific consent form. The investigators will test
      the sample to see if the GAP T cells can be found in the tumor and what effect they had on
      the tumor cells.

      If participants develop a second abnormal cancer growth, significant blood or nervous system
      disorder during the trial, a biopsy sample of the tissue will be tested.
    

Trial Arms

NameTypeDescriptionInterventions
GAP T cells + Fludarabine and CytoxanExperimentalGPC3-Car (GAP T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.
  • Cytoxan
  • Fludara

Eligibility Criteria

        Procurement Eligibility

        Inclusion Criteria:

          -  Relapsed or refractory GPC3-positive liver cancer

          -  Age ≥ 1 year and ≤ 21 years (NOTE: The first 3 patients on this study will be between
             the ages of 15-21 years)

          -  Lansky or Karnofsky score ≥60%

          -  Life expectancy ≥16 weeks

          -  Child-Pugh-Turcotte score <7 (for patients with hepatocellular carcinoma only)

          -  Informed consent explained to, understood by and signed by patient/guardian.
             Patient/guardian given copy of informed consent

        Exclusion Criteria:

          -  History of hypersensitivity reactions to murine protein-containing products OR
             presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who
             have received prior therapy with murine antibodies)

          -  History of organ transplantation

          -  Known HIV positivity

          -  Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus
             infections)

          -  Severe previous toxicity from cyclophosphamide or fludarabine

        Treatment Eligibility

        Inclusion Criteria:

          -  Age ≥ 1 year and ≤ 21 years (NOTE: The first 3 patients on this study will be between
             15-21 years)

          -  Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular
             carcinoma only)

          -  Life expectancy of ≥ 12 weeks

          -  Lansky or Karnofsky score ≥ 60%

          -  Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only)

          -  Adequate organ function:

               -  Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min

               -  serum AST< 5 times ULN

               -  total bilirubin < 3 times ULN for age

               -  INR ≤1.7 (for patients with hepatocellular carcinoma only)

               -  absolute neutrophil count > 500/microliter

               -  platelet count > 25,000/microliter (can be transfused)

               -  Hgb ≥7.0 g/dl (can be transfused)

               -  pulse oximetry >90% on room air

          -  Recovered from acute toxic effects of all prior chemotherapy and investigational
             agents before entering this study

          -  Sexually active patients must be willing to utilize one of the more effective birth
             control methods for 3 months after the T-cell infusion.

          -  Informed consent explained to, understood by and signed by patient/guardian.
             Patient/guardian given copy of informed consent

        Exclusion Criteria

          -  Pregnancy or lactation

          -  Uncontrolled infection

          -  Systemic steroid treatment (greater than or equal to 0.5 mg prednisone
             equivalent/kg/day, dose adjustment or discontinuation of medication must occur at
             least 24 hours prior to CAR T cell infusion)

          -  Known HIV positivity

          -  Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus
             infections)

          -  History of organ transplantation

          -  History of hypersensitivity reactions to murine protein-containing products OR
             presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who
             have received prior therapy with murine antibodies)

          -  Severe previous toxicity from cyclophosphamide or fludarabine

        GPC3 expression will be evaluated by standard immunohistochemistry (IHC). A tumor is
        considered GPC3 positive, when the staining is Grade 2 (>25% positive tumor cells) or above
        with an intensity score of 2 or above on a scale of 0 to 4.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Patients with Dose Limiting Toxicity
Time Frame:6 weeks
Safety Issue:
Description:A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the GPC3-CAR T cells. Specifically those which are Grade 5; non-hematologic Grade 3-4 not returning to Grade 2 within 72 hours; Grade 2-4 allergic reaction; Hematologic Grade 4 that fails to return to Grade 2 or baseline (whichever is more severe) within 14 days; all grade 4 CRS and neurologic toxicities and grade 3 CRS and neurologic toxicities that fail to return to Grade 1 within 7 days.

Secondary Outcome Measures

Measure:Percent of Patients with best response as either complete remission or partial remission
Time Frame:6 weeks
Safety Issue:
Description:Response rates will be estimated as the percent of patients whose best response is either complete remission or partial remission by combining the data from the two patients. To compare with historical data, a 95% confidence interval will be calculated for the response rate.
Measure:Median T cell persistence
Time Frame:15 years
Safety Issue:
Description:as measured by PCR

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Baylor College of Medicine

Trial Keywords

  • GPC3-CAR T cells
  • GPC3
  • Glypican
  • Liver cancer

Last Updated