Clinical Trials /

C7R-GD2.CAR T Cells for Patients With GD2-expressing Brain Tumors (GAIL-B)

NCT04099797

Description:

This study is for patients with high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). Because there is no standard treatment for this cancer at this time, patients are being asked to volunteer in a gene transfer research study using special immune cells called T cells. T cells are a type of white blood cell that helps the body fight infection. 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. 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. We have found from previous research that we can put a new antibody gene into T cells that will make them recognize cancer cells and kill them. GD2 is a protein found on several different cancers. When we and other researchers tested DIPG/HGG cancer cells we found that many of these cancers also have GD2 on their surface. In a clinical trial for a different cancer in children (neuroblastoma), we made a gene called a chimeric antigen receptor (CAR) from an antibody that recognizes GD2. We put this gene into the patients' own T cells and gave them back to 11 neuroblastoma patients. We saw that the cells did grow for a while, but started to disappear from the blood after 2 weeks. We think that if T cells are able to last longer, they may have a better chance of killing tumor cells. In this study we will add a new gene to the GD2 T cells that can cause the cells to live longer. We know that T cells need substances called cytokines to survive. We have added the gene C7R that gives the cells a constant supply of cytokine and helps them to survive for a longer period of time. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and we think that it will allow the T cells to expand and stay longer in the body, and potentially kill cancer cells more effectively. The GD2.C7R T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of GD2-C7R T cells, and also to evaluate how long they can be detected in the blood and what affect they have on DIPG/HGG.

Related Conditions:
  • Anaplastic Astrocytoma
  • Diffuse Intrinsic Pontine Glioma
  • Glioblastoma
  • High-Grade Glioma, NOS
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: C7R-GD2.CAR T Cells for Patients With GD2-expressing Brain Tumors (GAIL-B)
  • Official Title: Phase I Study of Autologous T Lymphocytes Expressing GD2-specific Chimeric Antigen and Constitutively Active IL-7 Receptors for the Treatment of Patients With GD2-expressing Brain Tumors (GAIL-B)

Clinical Trial IDs

  • ORG STUDY ID: H-45668 GAIL-B
  • NCT ID: NCT04099797

Conditions

  • Diffuse Intrinsic Pontine Glioma
  • High Grade Glioma

Interventions

DrugSynonymsArms
CyclophosphamideCytoxanC7R-GD2.CAR T cells
FludarabineFludaraC7R-GD2.CAR T cells

Purpose

This study is for patients with high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). Because there is no standard treatment for this cancer at this time, patients are being asked to volunteer in a gene transfer research study using special immune cells called T cells. T cells are a type of white blood cell that helps the body fight infection. 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. 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. We have found from previous research that we can put a new antibody gene into T cells that will make them recognize cancer cells and kill them. GD2 is a protein found on several different cancers. When we and other researchers tested DIPG/HGG cancer cells we found that many of these cancers also have GD2 on their surface. In a clinical trial for a different cancer in children (neuroblastoma), we made a gene called a chimeric antigen receptor (CAR) from an antibody that recognizes GD2. We put this gene into the patients' own T cells and gave them back to 11 neuroblastoma patients. We saw that the cells did grow for a while, but started to disappear from the blood after 2 weeks. We think that if T cells are able to last longer, they may have a better chance of killing tumor cells. In this study we will add a new gene to the GD2 T cells that can cause the cells to live longer. We know that T cells need substances called cytokines to survive. We have added the gene C7R that gives the cells a constant supply of cytokine and helps them to survive for a longer period of time. In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and we think that it will allow the T cells to expand and stay longer in the body, and potentially kill cancer cells more effectively. The GD2.C7R T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of GD2-C7R T cells, and also to evaluate how long they can be detected in the blood and what affect they have on DIPG/HGG.

Detailed Description

      To prepare the DIPG/HGG specific T cells (GD2-C7R T cells), research staff will take some
      blood from the patient. We will grow the GD2.C7R T cells by infecting the T cells with a
      retroviral vector (a special virus that can carry a new gene into cells) containing one gene
      that can recognize and kill DIPG/HGG cells (GD2.CAR) and the new gene called C7R that will
      help these cells survive longer. After the new genes have been put into the T cells, the
      cells will be tested to make sure that they kill GD2-positive DIPG/HGG cells.

      Because we are growing the cells in the laboratory, we will also need to take blood to test
      for infectious viruses such as hepatitis and HIV (the virus that causes AIDS), and we will
      also ask patients to complete a questionnaire that is given to blood donors.

      The cells generated will be frozen and stored to give back to the patient. Because patients
      will have received cells with a new gene in them patients will be followed for a total of 15
      years to see if there are any long term side effects of gene transfer.

      Patients will be assigned a dose of GD2-C7R T cells. There is one dose where patients will
      only receive GD2 T cells without the C7R. The assigned dose of cells is adjusted based on
      body weight and height.

      In this study, patients will receive the GD2-(C7R) cells and also receive cyclophosphamide
      and fludarabine. These two drugs are standard chemotherapy medicines and may be given before
      the T cells to make space in the blood for the T cells to grow after receiving them.

      Cyclophosphamide and fludarabine will be given intravenously (through an i.v. needle inserted
      in a vein or your central line) for 2 days and then fludarabine alone on the third day.

      The patient will be given an injection of GD2-(C7R) T cells into the vein through an IV line
      at the assigned dose. Before receiving the T cell infusion, the patient may be given a dose
      of Benadryl (diphenhydramine) and Tylenol (acetaminophen). The infusion will take between 1
      and 10 minutes. We will then monitor the patient in the hospital for at least 3 days. The
      treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital.
      The patient will need to stay in Houston for up to 4 weeks after the infusion so we can
      monitor for side effects.

      The patient will have follow-up visits at weeks 1, 2, 3, 4, 6, and 8, then at months 3, 6, 9,
      and 12, and then twice a year for the next 4 years and annually for the next 10 years for a
      total of 15 years. The patient will also have scheduled disease evaluations after the T-cell
      injection at week 6 and then as clinically needed.

      After disease re-evaluation, the patient may be eligible to receive one additional dose of T
      cells if the following criteria are met: (1) The disease has not gotten worse and/or it seems
      the patient may benefit in the future from an additional dose. (2) The patient has not had a
      severe side effect caused by the infusion of GD2-C7R T cells. The dose will be at the same
      dose level as the first infusion and separated by at least 3 months such that we can make
      sure there are no severe side effects between infusions. If the patient receives an
      additional dose of GD2-(C7R) T-cells, then they will need to stay in Houston for up to 4
      weeks after the infusion as well so we can monitor for side effects.

      Medical tests before treatment--

      Before being treated, the patient will receive a series of standard medical tests:

        -  Physical exam

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

        -  Measurements of the tumor by routine MRI (Magnetic Resonance Imaging)

      Medical tests during and after treatment--

      The patient will receive standard medical tests when they are getting the infusions and
      afterwards:

        -  Physical exams

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

        -  Measurements of the tumor by MRI imaging studies and spinal fluid analysis 6 weeks after
           the infusion and repeat MRI imaging at 3 months.

      Spinal Fluid Tests: One spinal tap will be performed as part of the study. This procedure is
      usually done under general anesthesia in children. After the skin is numbed, a long needle is
      placed into the lower back to remove 1-2 ml of spinal fluid (less than half a teaspoon).

      To learn more about the way the GD2-(C7R) T cells are working and how long they last in the
      body, an extra amount of blood will be obtained on the day that chemotherapy starts, the day
      of the T-cell infusion(s) and at the end of the T-cell infusion(s), 1, 2, 4, 6 and 8 weeks
      after the T-cell infusion(s) and every 3 months for the 1st year, every 6 months for the next
      4 years and annually for the next 10 years. The amount of blood taken will be based on weight
      with up to a maximum of 60 mL (12 teaspoons) of blood to be obtained at any one time. For
      children, the total amount of blood drawn will not be more than 3 mL (less than 1 teaspoon)
      per 1 kg of body weight on any one day. This volume is considered safe, but may be decreased
      if the patient is anemic (has a low red blood cell count).

      During the time points listed above, if the GD2-(C7R) T cells are found in the patient's
      blood at a certain amount, an extra 5 mL (about 1 teaspoon) of blood may need to be collected
      for additional testing.

      If the patient has a procedure where tumor samples are obtained, like a spinal tap evaluation
      or tumor biopsy, we will request a sample to be used for research purposes.

      The patient will receive supportive care for any acute or chronic toxicities, including blood
      components or antibiotics, and other intervention as appropriate.
    

Trial Arms

NameTypeDescriptionInterventions
C7R-GD2.CAR T cellsExperimentalThis is a single arm study. Patients will be treated at 4 dose levels. At dose level 0, patients will only receive GD2.CART cells without C7R and they will receive lymphodepletion chemotherapy consisting of cyclophosphamide and fludarabine. Three patients will be evaluated and if safety is confirmed patients will be treated with lymphodepletion chemotherapy consisting of cyclophosphamide and fludarabine followed by C7R.GD2.CART cell infusion at 3 dose levels.
  • Cyclophosphamide
  • Fludarabine

Eligibility Criteria

        Procurement Inclusion Criteria:

          1. Patients with histologically confirmed, GD2-expressing newly diagnosed DIPG or HGG or
             confirmation of positive H3K27M mutation status if sufficient tissue for GD2 staining
             by IHC is not available.

          2. Tumors less than 5 cm in maximum dimension at enrollment

               1. Tumors with ≤25% increase in size (on any dimension) on MRI 4-8 weeks
                  post-radiotherapy remain eligible for study

               2. Tumors with >25% increase in size on post-radiation imaging may be reassessed
                  with repeat MRI in 4-6 weeks, and are eligible if tumor size is subsequently ≤
                  25% increased compared with time of diagnosis

          3. Measurable disease on at least 2 dimensions on MRI

          4. Age 12 months to 18 years

          5. Functional score (Karnofsky/Lansky) ≥ 50 expected at infusion

          6. Organ function:

               1. ANC > 1000 cells/ul

               2. Platelet count > 100,000 cells/ul

               3. Total bilirubin < 1.5x ULN

               4. ALT and AST < 5x ULN

               5. Serum creatinine or kidney within 2x ULN for age

        Procurement Exclusion Criteria:

          1. Patients who are pregnant or breast feeding

          2. Any patient with other risk factors for whom administration of investigational agent
             is deemed not in the patient's best interest, in the opinion of the investigator.

        Treatment Inclusion Criteria

          1. Patients with histologically confirmed, GD2-expressing newly diagnosed DIPG or HGG or
             confirmation of positive H3K27M mutation status if sufficient tissue for GD2 staining
             by IHC is not available.

          2. Tumors less than 5 cm in maximum dimension at enrollment

               1. Tumors with ≤25% increase in size (on any dimension) on MRI 4-8 weeks
                  post-radiotherapy remain eligible for study

               2. Tumors with >25% increase in size on post-radiation imaging may be reassessed
                  with repeat MRI in 4-6 weeks, and are eligible if tumor size is subsequently ≤
                  25% increased compared with time of diagnosis

          3. Measurable disease on at least 2 dimensions on MRI

          4. Central line (PICC or other) in place or planned to be placed

          5. Age 12 months to 18 years

          6. Functional score (Karnofsky/Lansky) ≥ 50

          7. Patients must have completed radiation therapy. Radiation therapy must be completed at
             least 4 weeks prior to administration of investigational agent

          8. Stable neurologic exam for 7 days prior to enrollment

          9. Stable or decreasing dose of steroids (max. allowable dose of dexamethasone is 0.1
             mg/kg/day over the past 7 days prior to infusion of investigational therapy)

         10. Organ function:

               1. ANC > 1000 cells/ul

               2. Platelet count > 100,000 cells/ul

               3. Total bilirubin < 1.5x ULN

               4. ALT and AST < 5x ULN

               5. Serum creatinine or kidney within 2x ULN for age

        Treatment Exclusion Criteria

          1. Patients who received any other forms of immunotherapy ≤ 42 days before administration
             of investigational agent

          2. Patients who received colony-stimulating factors within 14 days prior to
             administration of lymphodepletion

          3. Patients receiving any concurrent anti-cancer therapy

          4. Patients who are pregnant or breast feeding

          5. Any patient with other risk factors for whom administration of investigational agent
             is deemed not in the patient's best interest, in the opinion of the investigator.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) rate
Time Frame:4 weeks post T cell infusion
Safety Issue:
Description:DLT rate is defined as the proportion of subjects with DLT evaluated as per the NCI CTCAE v5.0 with the exception of CRS and neurological toxicities that are related to T cell infusions.

Secondary Outcome Measures

Measure:Response rate according to standard criteria
Time Frame:6 and 12 weeks post T cell infusion
Safety Issue:
Description:Anti-tumor response to (C7R)-GD2.CART cell therapy will be evaluated by Magnetic Resonance Imaging (MRI)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Baylor College of Medicine

Trial Keywords

  • Gene Therapy
  • CAR T-cells
  • chimeric antigen receptor
  • Brain Cancer
  • Immunotherapy
  • Glioma
  • Brain tumor

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