Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors

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Brief Title

Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in T Cells for Pediatric Solid Tumors

Official Title

Interleukin-15 Armored Glypican-3-specific Chimeric Antigen Receptor Expressing Autologous T Cells as Immunotherapy for Children With Solid Tumors

Brief Summary

      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 AGAR 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 (a tiny part of
      what makes-up DNA and carries your traits) into T cells that will make them recognize cancer
      cells and kill them. In the lab, investigators made several genes called a chimeric antigen
      receptor (CAR), from an antibody called GPC3. The antibody GPC3 recognizes a protein found
      solid tumors including pediatric liver cancers. This CAR is called GPC3-CAR. To make this CAR
      more effective, investigators also added a gene that includes IL15. IL15 is a protein that
      helps CAR T cells grow better and stay in the blood longer so that they may kill tumors
      better. The mixture of GPC3-CAR and IL15 killed tumor cells better in the laboratory when
      compared with CAR T cells that did not have IL15 .This study will test T cells that
      investigators made (called genetic engineering) with GPC3-CAR and the IL15 (AGAR T cells) in
      patients with GPC3-positive solid tumors such as yours.

      T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug
      called AP1903. The investigators will insert the iCasp9 and IL15 together into the T cells
      using a virus that has been made for this study. The drug (AP1903) is an experimental drug
      that has been tested in humans with no bad side-effects. The investigators will use this drug
      to kill the T cells if necessary due to side effects.

      This study will test T cells genetically engineered with a GPC3-CAR and IL15 (AGAR T cells)
      in patients with GPC3-positive solid tumors.

      The AGAR 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 AGAR 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 AGAR T
      cells will help people with GPC3-positive solid tumors.
    

Detailed Description

      Approximately 15-24 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 increase in
      numbers/multiply 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
      lymphodepletion chemotherapy. This chemotherapy means the participant will receive both
      cyclophosphamide (Cytoxan) and fludarabine. Participants will receive these drugs 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 AGAR 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 AGAR 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. Tumor markers are molecules in
           the blood that are higher when a person has certain cancers

      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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Number of Patients with Dose Limiting Toxicity

Secondary Outcome

 Percent of Patients with best response as either complete remission or partial remission

Condition

Liver Cancer

Intervention

AGAR T cells

Study Arms / Comparison Groups

 AGAR T cells + Fludarabine and Cytoxan
Description:  GPC3-CAR and the IL15 (AGAR T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Genetic

Estimated Enrollment

24

Start Date

August 2021

Completion Date

January 2040

Primary Completion Date

February 2025

Eligibility Criteria

        Procurement Eligibility

        Inclusion Criteria:

          -  Relapsed or refractory GPC3-positive* solid tumors (currently only enrolling liver
             tumors)

          -  Age ≥ 1 year and ≤ 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

          -  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.
      

Gender

All

Ages

1 Year - 21 Years

Accepts Healthy Volunteers

No

Contacts

Andras Heczey, MD, (832) 824-4233, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04377932

Organization ID

H-47757 AGAR


Responsible Party

Principal Investigator

Study Sponsor

Baylor College of Medicine

Collaborators

 Center for Cell and Gene Therapy, Baylor College of Medicine

Study Sponsor

Andras Heczey, MD, Principal Investigator, Baylor College of Medicine


Verification Date

July 2021