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

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Brief Title

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

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 Relapsed or Refractory Neuroblastoma and Other GD2 Positive Solid Cancers(GAIL-N)

Brief 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.
    

Detailed 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. 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. 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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Determine maximum tolerated dose (MTD) of C7R-GD2.CART Cells

Secondary Outcome

 Determine Anti-tumor Responses

Condition

Relapsed Neuroblastoma

Intervention

C7R-GD2.CART cells

Study Arms / Comparison Groups

 Arm A: High-risk group of patients with lung metastases
Description:  Patients will be treated at 4 dose levels. At dose level 0, patients will only receive C7R-GD2.CART cells without lymphodepletion chemotherapy. 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.
Starting at dose level 1, the protocol is divided into two arms, a high-risk group of patients with lung metastases (Arm B) and a standard risk group of all other patients (Arm A). The standard risk Arm A includes osteosarcoma patients without pulmonary disease. Starting with dose level 1, each arm will undergo separate dose escalation.

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

94

Start Date

April 23, 2019

Completion Date

December 2037

Primary Completion Date

June 2022

Eligibility Criteria

        Procurement Inclusion Criteria:

          1. Evaluable neuroblastoma with persistent or relapsed disease

               1. Recurrent disease following completion of aggressive multi-drug frontline
                  therapy.

               2. Progressive disease during aggressive multi-drug frontline therapy.

               3. Primary resistant/refractory disease (less than partial response by INRC)
                  detected at the conclusion of at least 4 cycles of aggressive multi-drug
                  induction chemotherapy on or according to a standard high-risk treatment protocol

             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.

          2. Life expectancy of at least 12 weeks

          3. Karnofsky/Lansky score of 50% or greater

          4. Absence of human anti-mouse antibodies (HAMA) prior to enrollment (only in patients
             that have been previously treated with murine antibodies)

          5. Informed consent and assent (as applicable) obtained from parent/guardian and child

          6. Greater than 1 and less than 75 years of age

        Treatment Inclusion Criteria:

          1. Neuroblastoma with persistent or relapsed disease

               1. Recurrent disease following completion of aggressive multi-drug frontline
                  therapy.

               2. Progressive disease during aggressive multi-drug frontline therapy.

               3. Primary resistant/refractory disease (less than partial response by INRC)
                  detected at the conclusion of at least 4 cycles of aggressive multi-drug
                  induction chemotherapy on or according to a standard high-risk treatment
                  protocol.

             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.

          2. Life expectancy of at least 12 weeks

          3. Karnofsky/Lansky score of 50% or greater

          4. Patients must have an ANC ≥ 500, platelet count ≥ 20,000

          5. Pulse Ox ≥ 90% on room air

          6. 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)

          7. Total bilirubin less than 3 times the upper limit of normal

          8. 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.

          9. 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.

         10. Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who
             have received prior therapy with murine antibodies

         11. Patients must have autologous activated T-cells with ≥ 20% expressing GD2.CAR

         12. Informed consent and assent (as applicable) obtained from parent/guardian and child

         13. Greater than 1 and less than 75 years of age

        Procurement Exclusion Criteria:

          1. History of hypersensitivity to murine protein containing products (patients who have
             undergone desensitization and successful re-challenge without hypersensitivity
             reaction are eligible)

          2. Active autoimmune disease (requiring immunosuppressive treatment in the past 6 months)

          3. Primary brain tumor or known brain metastases (on evaluation by MIBG and/or PET if
             applicable, CT/MRI/LP not required)

        Treatment Exclusion Criteria

          1. Currently receiving other investigational drugs.

          2. Received any investigational immunotherapies or checkpoint inhibitors within 6 weeks.
             Immunotherapies include adoptive cell therapies, gene therapies, and tumor vaccines.

          3. History of hypersensitivity to murine protein containing products (patients who have
             undergone desensitization and successful re-challenge without hypersensitivity
             reaction are eligible).

          4. History of cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT.
             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.

          5. Evidence of tumor potentially causing airway obstruction

          6. Patients must not be pregnant, lactating, or unwilling to use birth control

          7. Patients must not be currently receiving immunosuppressive drugs such as
             corticosteroids (prednisone dose of > 0.25 mg/kg/day or equivalent), tacrolimus or
             cyclosporine

          8. Active autoimmune disease (requiring immunosuppressive treatment in the past 6 months)

          9. Primary brain tumor or known brain metastases (on evaluation by MIBG and/or PET if
             applicable, CT/MRI/LP not required)
      

Gender

All

Ages

1 Year - 74 Years

Accepts Healthy Volunteers

No

Contacts

Bilal Omer, MD, 832-824-6855, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03635632

Organization ID

H-42207 GAIL-N


Responsible Party

Principal Investigator

Study Sponsor

Baylor College of Medicine

Collaborators

 Center for Cell and Gene Therapy, Baylor College of Medicine

Study Sponsor

Bilal Omer, MD, Principal Investigator, Baylor College of Medicine


Verification Date

December 2020