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Soft Tissue Sarcoma

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Cyclophosphamide

Fludarabine

Fludarabine phosphate

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THIS ARM IS CLOSED

Dose Level 1: 1x10\^4 cells/m2

Dose Level 2: 3x10\^4 cells/m2

Dose Level 3: 1x10\^5 cells/m2 (NOT BEING USED)

Dose Level 4: 3x10\^5 cells/m2 (NOT BEING USED)

Dose Level 5: 1x10\^6 cells/m2

Dose Level 6: 3x10\^6 cells/m2

Dose Level 7: 1x10\^7 cells/m2

Dose Level 8: 3x10\^7 cells/m2

Dose Level 9: 1x10\^8 cells/m2

Autologous HER2-specific T cells+fludarabine:

Dose Level 9A: fludarabine followed by 1x10\^8 cells/m\^2

Autologous HER2-specific T cells+fludarabine+cyclophosphamide:

Dose Level 9B: fludarabine + cyclophosphamide followed by 1x10\^8 cells/m\^2

Dose Level 9C: fludarabine + cyclophosphamide followed by 1x10\^8 cells/m\^2 CAR positive cells/m\^2

Each patient will receive one intravenous injection of autologous HER2-specific T cells at one of the dose levels. If the patient has stable disease or a reduction in the size of the tumor they can receive additional doses of HER2-specific T cells at 6 to 12 weeks intervals-each of which will consist of the same cell number as their HER2-specific T-cell injection. For the first two subsequent HER2-specific T-cell infusions, patients will be able to receive additional lymphodepleting chemotherapy according to their dose levels.

Autologous HER2-specific T cells

Fludarabine will be administered for 5 days prior to the T cells

The dose:

\>10 kg: 25 mg/m2/day;

\<10 kg: 1 mg/kg/day IV over 30 minutes

Cyclophosphamide will be administered for 2 days.

Fludarabine and cyclophosphamide will be given for 2 days, followed by fludarabine alone for the next 3 days, followed by 2 days of rest, before the T cells will be administered.

Cyclophosphamide Dose:

30 mg/kg/day IV over 1 hour (with Mesna and IV hydration)

Fludarabine Dose:

\>10 kg: 25 mg/m2/day; \<10 kg: 1 mg/kg/day IV over 30 minutes

Patient will receive one intravenous injection of autologous CAR T cells at dose level 9C. Further CAR T-cell dose escalation at dose level 9C will be done using the lymphodepletion schema as in dose level 9B.

Autologous CAR Positive T cells

Nabil M Ahmed, MD

Patients have a type of cancer called sarcoma. Because there is no standard treatment for the patients cancer at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from diseases caused by germs or toxic substances. They work by binding those germs or substances, which stops them from growing or exerting their toxic effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with germs. Both antibodies and T cells have been used to treat patients with cancers: they both 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. We now want to see if we can put a new gene in these cells that will let the T cells recognize and kill sarcoma cells. The new gene that we will put in makes an antibody specific for HER2 (Human Epidermal Growth Factor Receptor 2) that binds to sarcoma cells. In addition it contains CD28, which stimulated T cells and make them last longer. 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. Giving chemotherapy before a T cell infusion is called lymphodepletion since the chemotherapy is specifically chosen to decrease the number of lymphocytes in the body. Decreasing the number of patient's lymphocytes first should allow the T cells we infuse to expand and stay longer in your body, and potentially kill cancer cells more effectively. We will use fludarabine or the combination of cyclophosphamide and fludarabine as the chemotherapy agents for lymphodepletion. Cyclophosphamide and fludarabine are the chemotherapy agents most commonly used for lymphodepletion in immunotherapy clinical trials. The purpose of this study is to find the largest safe dose of chimeric T cells, and to see whether this therapy might help patients with sarcoma. Another purpose is to see if it is safe to give HER2-CD28 T cells after lymphodepleting chemotherapy.

Because the cells have a new gene in them the patient will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.

When the patient is enrolled on this study, they will be assigned a dose of HER2-CD28 T cells. Depending on which dose level they are assigned, they will receive one of the following:

HER2-CD28 T cells and fludarabine (patient will receive fludarabine for 5 days followed by injection of HER2-CD28 T cells)

OR

HER2-CD28 T cells, fludarabine and cyclophosphamide (patient will receive fludarabine and cyclophosphamide for 2 days, fludarabine alone for an additional 3 days, and 2 days of rest before receiving the HER2-CD28 T cells.).

The HER2-CD28 T cells will be given into the vein through an IV line. The injection will take between 1 and 10 minutes. The patient will be followed in the clinic after the injection for 1 to 4 hours.

Each patient will be followed for 6 weeks after the T-cell infusion for evaluation of toxicity. They will have standard tests and procedures as well as research blood draws.

If the patient has stable disease (the tumor did not grow) or there is a reduction in the size of the tumor on imaging studies after the T-cell infusion, they can receive additional doses of the T cells at 6 to 12 weeks intervals. For the first two subsequent HER2-specific T-cell infusions, patients will be able to receive additional lymphodepleting chemotherapy according to their dose levels.

Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma

Administration of Her2 Chimeric Antigen Receptor Expressing T Cells for Subjects With Advanced Sarcoma (HEROS)

To determine the safety of one intravenous injection of autologous T cells expressing HER2-specific chimeric antigen receptor (CAR) in patients with advanced HER2-positive sarcoma.

To determine the safety of one intravenous injection of 1x10\^8/m\^2 autologous T cells after lymphodepleting chemotherapy.

To assess the in vivo expansion and persistence of infused T cells using immunoassays and transgene detection

To assess the anti-tumor effects of the infused HER2-specific T cells

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma	NCT00902044	Sarcoma	Autologous HER2... Fludarabine Cyclophosphamid... Autologous CAR ...	-	Baylor College of Medicine
Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma	NCT00902044	Sarcoma	Autologous HER2... Fludarabine Cyclophosphamid... Autologous CAR ...	-	Baylor College of Medicine
Her2 Chimeric Antigen Receptor Expressing T Cells in Advanced Sarcoma	NCT00902044	Sarcoma	Autologous HER2... Fludarabine Cyclophosphamid... Autologous CAR ...	-	Baylor College of Medicine

Spots Global Cancer Trial Database for autologous car positive t cells