C7R-GD2.CART Cells for Patients With Relapsed or Refractory Neuroblastoma and Other GD2 Positive Cancers (GAIL-N)

  • STATUS
    Recruiting
  • End date
    Dec 22, 2038
  • participants needed
    94
  • sponsor
    Baylor College of Medicine
Updated on 7 October 2022
platelet count
cancer
fludarabine
cytokines
breast cancer
liver disease
progressive disease
tumor cells
refractory neuroblastoma
metastatic uveal melanoma
refractory osteosarcoma

Summary

This study is for patients with neuroblastoma, sarcoma, uveal melanoma, breast cancer, or another cancer that expresses a substance on the cancer cells called GD2. The cancer has either come back after treatment or did not respond to treatment. Because there is no standard treatment at this time, patients are 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 gene into T cells that will make them recognize cancer cells and kill them. In our last clinical trial we made a gene called a chimeric antigen receptor (CAR) from an antibody that recognizes GD2, a substance found on almost all neuroblastoma cells (GD2-CAR). 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 GD2 positive tumor cells.

Therefore, in this study we will add a new gene to the GD2 T cells that can cause the cells to live longer. T cells need substances called cytokines to survive and the cells may not get enough cytokines after infusion. 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, 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 cancer.

Description

To prepare the 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 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 cancer 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. The assigned dose of cells is based on body weight and height.

In this study, patients will receive the GD2-C7R cells and may 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.

If the patient receives cyclophosphamide and fludarabine, these drugs 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 clinic for about 3 hours. If you tolerate the infusion without severe side effects you may receive another infusion one week later. In this case both infusion will be considered part of one dose. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital. The patient may 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 after the T cell infusion at weeks 1, 2, 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, if the patient's disease has not gotten worse, or if in the future it seems the patient might benefit AND the patient has not had a severe side effect caused by the infusion of the GD2-C7R T cells, the patient may be eligible to receive one additional dose of their T cells. The dose will be at the same dose level as the first infusion and separated by at least 6 weeks such that we can make sure the patient has no severe side effects between infusions. The second dose may consist of two infusions again if you received two infusions with the first dose. 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 imaging studies and/or bone marrow evaluation. We will use the imaging studies that have been used in the past to best assess the tumor (Computer Tomogram (CT) or Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET/CT), Bone Scan, and/or MIBG scan)
  • Pulmonary Function Tests (PFT) to see how well your lungs are working

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 routine imaging studies and/or bone marrow evaluation 6 weeks after the infusion (if the bone marrow showed tumor before the infusion).

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 repeat bone marrow 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.

Details
Condition Relapsed Neuroblastoma, Refractory Neuroblastoma, Relapsed Osteosarcoma, Relapsed Ewing Sarcoma, Relapsed Rhabdomyosarcoma, Uveal Melanoma, Phyllodes Breast Tumor
Treatment cyclophosphamide, Fludarabine, C7R-GD2.CART cells
Clinical Study IdentifierNCT03635632
SponsorBaylor College of Medicine
Last Modified on7 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Evaluable neuroblastoma with persistent or relapsed disease
Progressive disease during aggressive multi-drug frontline therapy
OR Relapsed or refractory osteosarcoma not responsive to standard treatment
OR Patients diagnosed with GD2 positive metastatic uveal melanoma and progressed after
at least one prior systemic treatment
OR GD2 positive breast cancer with metastatic or locally recurrent unresectable breast
cancer currently progressive after at least two prior lines of therapy in the advanced
setting. Patients with HER2+ disease must have failed two or more different anti-HER2
agents
OR Patients with other relapsed or refractory solid tumors not responsive to standard
treatment with confirmed expression of GD2 by immunohistochemistry testing
Life expectancy of at least 12 weeks
Karnofsky/Lansky score of 50% or greater
Absence of human anti-mouse antibodies (HAMA) prior to enrollment (only in patients
that have been previously treated with murine antibodies or testing pending)
Informed consent and assent (as applicable) obtained from parent/guardian and child
Greater than 1 and less than 75 years of age
Treatment Inclusion Criteria
Recurrent disease following completion of aggressive multi-drug frontline
Neuroblastoma with persistent or relapsed disease
therapy
Progressive disease during aggressive multi-drug frontline therapy
Primary resistant/refractory disease (less than partial response by INRC)
detected at the conclusion of at least 4 cycles of aggressive multi-drug
OR Relapsed or refractory osteosarcoma not responsive to standard treatment
induction chemotherapy on or according to a standard high-risk treatment
protocol
OR Patients diagnosed with GD2 positive metastatic uveal melanoma and progressed after
at least one prior systemic treatment
OR GD2 positive breast cancer with metastatic or locally recurrent unresectable breast
cancer currently progressive after at least two prior lines of therapy in the advanced
setting. Patients with HER2+ disease must have failed two or more different anti-HER2
agents
OR Patients with other relapsed or refractory solid tumors not responsive to standard
treatment with confirmed expression of GD2 by immunohistochemistry testing
Life expectancy of at least 12 weeks
Karnofsky/Lansky score of 50% or greater
Patients must have an ANC ≥ 500, platelet count ≥ 20,000
Pulse Ox ≥ 90% on room air
AST and ALT less than 5 times the upper limit of normal (less than 10 times upper
normal if uveal melanoma with metastatic liver disease)
Total bilirubin less than 3 times the upper limit of normal
Serum creatinine less than 3 times upper limit of normal. Creatinine clearance is
needed for patients with creatinine greater than 1.5 times upper limit of normal
At least 4 weeks from completion and recovered from acute effects of all prior
chemotherapy. If some effects of therapy have become chronic (i.e., treatment
associated thrombocytopenia), the patient must be clinically stable and meet all other
eligibility criteria. Maintenance therapy with non-investigational oral antineoplastic
drugs is allowed up to 48 hours prior to infusion
Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who
have received prior therapy with murine antibodies
Patients must have autologous activated T-cells with ≥ 20% expressing GD2.CAR
Informed consent and assent (as applicable) obtained from parent/guardian and child
Greater than 1 and less than 75 years of age

Exclusion Criteria

History of hypersensitivity to murine protein containing products (patients who have
undergone desensitization and successful re-challenge without hypersensitivity
reaction are eligible)
Active autoimmune disease (requiring immunosuppressive treatment in the past 6 months)
Primary brain tumor or known brain metastases (on evaluation by MIBG and/or PET if
applicable, CT/MRI/LP not required)
Treatment Exclusion Criteria
Currently receiving other investigational drugs
Received any investigational immunotherapies or checkpoint inhibitors within 6 weeks
Immunotherapies include adoptive cell therapies, gene therapies, and tumor vaccines
History of hypersensitivity to murine protein containing products (patients who have
Evidence of tumor potentially causing airway obstruction
undergone desensitization and successful re-challenge without hypersensitivity
Patients must not be pregnant, lactating, or unwilling to use birth control
reaction are eligible)
History of cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT
Active autoimmune disease (requiring immunosuppressive treatment in the past 6 months)
However, patients with cardiomegaly on imaging may be enrolled if they have an
assessment of cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting
protocol therapy that is within acceptable limits (LVSF>28% or LVEF>50%)
Additionally, patients with bilateral pulmonary infiltrates on imaging may be enrolled
if the lesions are not consistent with active neuroblastoma (i.e., negative on
functional imaging with PET or MIBG, or by pathologic assessment) or not bulky in
other diseases (< 5 cm for each lesion) and patient meet FiO2 criteria (>90% on room
air). Baseline pulmonary function testing is required in patients with bilateral
pulmonary infiltrates (except young children unable to undergo testing). Patients with
poor lung function based on PFT testing (Patients with FEV 1, FVC and DLCO/diffusion
capacity < 50%) will not be eligible for treatment on protocol. Patients with
intermediate function (FEV 1, FVC and DLCO/diffusion capacity ≥ 50% and < 70%
predicted) will require assessment by a pulmonologist prior to treatment
Patients must not be currently receiving immunosuppressive drugs such as
corticosteroids (prednisone dose of > 0.25 mg/kg/day or equivalent), tacrolimus or
cyclosporine
Primary brain tumor or known brain metastases (on evaluation by MIBG and/or PET if
applicable, CT/MRI/LP not required)
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