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

• ClinicalTrials.gov Identifier: NCT04099797
• Recruitment Status: Recruiting
• First Posted: September 23, 2019
• Last Update Posted: March 9, 2023
• Sponsor: Baylor College of Medicine
• Collaborators: Center for Cell and Gene Therapy, Baylor College of Medicine; The Faris Foundation
• Information provided by (Responsible Party): Bilal Omer, Baylor College of Medicine

Study Description

Brief Summary:

This study is for patients with high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG) or medulloblastoma or another rare brain cancer that expresses GD2. Because there is no standard treatment 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 help 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 cancer patients. 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 study for neuroblastoma in children, 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 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 studies using T cells some researchers 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 brain cancer.

Condition or disease	Intervention/treatment	Phase
Diffuse Intrinsic Pontine Glioma; High Grade Glioma; Embryonal Tumor; Ependymal Tumor	Genetic: (C7R)-GD2.CART cells	Phase 1

Detailed Description:

To prepare the brain cancer 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 brain cancer 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 brain cancer cells.

All patients on this study are required to have an Ommaya catheter in place prior to treatment as a precaution. This is a special catheter that leads to the tumor, the cavity left in the brain after surgical removal of the tumor, or into the fluid-filled space in the brain. If a patient does not have such a catheter already, one will need to be placed to allow for his/her treatment on this study. Catheter placement is done by a surgeon. Patients who had a VP shunt placed for other clinical reasons are also eligible.

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 a 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 5 days. If the first infusion is tolerated well, a second infusion may be given 5 to 12 days after initial infusion and patient will be monitored in the hospital for at least one additional day. 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 from the first infusion so we can monitor for side effects and will be readmitted to the hospital if patient develops a fever.

If patient is receiving a split dose of the cells, the patient will be monitored at least 5 days after the infusion of the first half-dose and at least 1 day after the second half-dose and until resolution of CRS. If patient develops fevers after discharge from the hospital within the safety observation period of 4 weeks, patient will be readmitted to the hospital for close monitoring for at least one night.

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 4 to 6 and then as clinically needed.

After disease re-evaluation, the patient may be eligible to receive up to three additional cycles of T cells (with up to two infusions each cycle) 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 (optional): Spinal fluid may be drawn from the patient's existing Ommaya reservoir or VP shunt (if clinically feasible) at week 2 and between week 6 and week 8 and possibly other timepoints if helpful for clinical care. This procedure can be done at the bedside under local anesthesia and 1-2 ml of spinal fluid (less than half a teaspoon) will be removed. Additional spinal fluid may be removed if the pressure inside the brain is elevated. Additionally, spinal fluid may be removed for clinical reasons, for example testing for a possible infection.

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 blood is collected 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: February 3, 2020
• Estimated Primary Completion Date: February 2025
• Estimated Study Completion Date: February 2039

Arms and Interventions

Arm

Intervention/treatment

Experimental: C7R-GD2.CAR T cells; This is a single arm study. Patients will be treated at 3 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 dose levels 1 and 2. Dose level 2 is split into two equal half-doses of 15 million cells/m2 to decrease peak inflammation. The second half-dose will be given at least 5 days after the initial half-dose and will be delayed if CRS or ICANS of Grade 2 or higher is present.

Genetic: (C7R)-GD2.CART cells; Dose level 0: 1 x 10^7 GD2.CART cells single transduced without C7R with lymphodepletion chemotherapy; Dose Level 1: 1 x 10^7 C7R-GD2.CART cells with lymphodepletion chemotherapy; Dose Level 2: 3 x 10^7 C7R-GD2.CART cells with lymphodepletion chemotherapy

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicity (DLT) rate [ Time Frame: 4 weeks post T cell infusion ]
   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 :

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

Eligibility Criteria

• Ages Eligible for Study: 12 Months to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. Newly diagnosed is defined as prior to radiographic progression or recurrence OR Recurrent or refractory intracranial embryonal tumor, HGG or ependymal tumor with confirmed GD2-expression (or H3K27M+ for HGG) Examples of embryonal tumors include: medulloblastoma, "PNET", AT/RT

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 21 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. Newly diagnosed is defined as prior to radiographic progression or recurrence OR Recurrent or refractory intracranial embryonal tumor, HGG or ependymal tumor with confirmed GD2-expression (or H3K27M+ for HGG) Examples of embryonal tumors include: medulloblastoma, "PNET", AT/RT

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) and Ommaya reservoir or VP shunt in place or planned to be placed
5. Age 12 months to 21 years
6. Functional score (Karnofsky/Lansky) ≥ 50
7. Completed standard of care radiation therapy. If bevacizumab was administered for management of radiation necrosis, 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.

Contacts and Locations

Contacts

Contact: Bilal Omer, MD; 832-824-6855; bomer@bcm.edu

Contact: David Allen; 832-824-4391; dlallen@bcm.edu

Locations

United States, Texas

Texas Children's Hospital; Recruiting

Houston, Texas, United States, 77030

Contact: Bilal Omer, MD 832-824-6855 bomer@bcm.edu

Contact: David Allen 832-824-4391 dlallen@bcm.edu

Sponsors and Collaborators

Baylor College of Medicine

Center for Cell and Gene Therapy, Baylor College of Medicine

The Faris Foundation

Investigators

• Principal Investigator: Bilal Omer, MD; Baylor College of Medicine

More Information

• Responsible Party: Bilal Omer, Assistant Professor, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT04099797
• Other Study ID Numbers: H-45668 GAIL-B
• First Posted: September 23, 2019
• Last Update Posted: March 9, 2023
• Last Verified: March 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bilal Omer, Baylor College of Medicine:

DIPG; Gene Therapy; CAR T-cells; chimeric antigen receptor; Brain Cancer; Immunotherapy; Glioma; Brain tumor; ETMRs; Medulloepithelioma; Atypical teratoid/rhabdoid tumors

Additional relevant MeSH terms:

Neoplasms; Glioma; Brain Neoplasms; Diffuse Intrinsic Pontine Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Stem Neoplasms; Infratentorial Neoplasms