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Ondansetron

Azacitidine

BIRC5 protein, human

Antimetabolites

Enzyme Inhibitors

The first stage will be an "antigen-escalation" stage using a fixed total dose of cells (5 x 10\^6 cells/m\^2 x 2) to evaluate the safety of the T cells primed against PRAME pepmix, and then SSX pepmix, and then MAGE A4 pepmix, and then NY-ESO pepmix, and then SURVIVIN pepmix.

In the dose escalation stage, three dose levels will be studied. Patients in the dose escalation portion of the study will be entered and stratified separately to the following two groups:

Group A: Patients receiving CTLs as therapy for Hodgkin's or non-Hodgkin's lymphoma.

Group B: Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.

This phase will administer aza intravenously at a dose of 75 mg/m2 after premedication with an anti-emetic such as ondansetron po or IV (up to a maximum dose of 16 mg ondansetron or equivalent). This phase will determine whether infusion of TAA-specific T cells (at dose level 2 - 1x10\^7) targeting multiple tumor antigens in combination with azacytidine is safe, and whether CTL infusions (with or without azacytidine) increase the spectrum of epitopes/antigens targeted by endogenous T cells (epitope spreading).

This phase will give patients \< 18 years old two infusions (on Day 0 and Day 14) of multi-TAA specific T cells at a fixed dose of 1x10\^7 cells/m2. This phase will test the safety and efficacy of multiTAA-specific T cells in pediatric patients with active HL/NHL.

Antigen-Escalation Stage

Each patient will receive 2 injections at the same dose (5 x 10\^6 cells/m2), 28 days apart, according to the following schedules:

Schedule One:

* Day 0: PRAME-specific T cells
* Day 28: PRAME- and SSX-specific T cells

Schedule Two:

* Day 0: PRAME- and SSX-specific T cells
* Day 28: PRAME/SSX/MAGE-specific T cells

Schedule Three:

* Day 0: PRAME/SSX/MAGE-specific T cells
* Day 28: PRAME/SSX/MAGE/NY-ESO specific T cells

Schedule Four:

* Day 0: PRAME/SSX/MAGE/NY-ESO specific T cells
* Day 28: PRAME/SSX/MAGE/NY-ESO/Survivin-specific T cells

Antigen-Escalation Stage

Dose-Escalation Stage

Three different dosing schedules will be evaluated. Each patient will receive 2 injections at the same dose, 14 days apart, according to the following dosing schedules:

DL1: Day 0 and Day 14: 5 x 10\^6 cells/m\^2

DL2: Day 0 and Day 14: 1 x 10\^7 cells/m\^2

DL3: Day 0 and Day 14: 2 x 10\^7 cells/m\^2

Dose-Escalation Stage

Up to 15 patients will be treated with 3 cycles of aza at a dose of 75 mg/m2 I.V. administered for 5 days/cycle followed, within 28 days of the last aza dose, by two infusions (on Day 0 and Day 14) of multi-TAA specific CTLs at a fixed dose of 1x10\^7 cells/m2. If drug-related myelosuppression occurs aza dosing will be modified, according to the following:

1. ANC \>1,000 or Platelets \>50,000 (or any other grade I AE attributable to aza)

   Adjustment: None
2. ANC 500-1000 or Platelets 25,000-50,000 (or any other grade II-III AE attributable to aza)

   Adjustment: 50% dose reduction
3. ANC \<500 or any episode of febrile neutropenia or platelets \<25,000 or any episode of bleeding attributed to thrombocytopenia (or any other grade IV or higher AE attributable to aza)

Adjustment: Discontinue drug, can proceed with CTL infusion if eligible within 28 days of last aza infusion

azacytidine and multiTAA T cells Stage

Patients \< 18 years old will receive two infusions (on Day 0 and Day 14) of multi-TAA specific T cells at a fixed dose of 1x10\^7 cells/m2. We will enroll and infuse at least 5 adolescents on the pediatric arm before opening to all patients.

Pediatric multiTAA T cells Stage

Geoge Carrum, MD

Patients have a type of lymph gland disease called Hodgkin or non-Hodgkin lymphoma which has come back, or may come back, or has not gone away after treatment, including the standard treatment known for these diseases. This a research study using special immune system cells called tumor associated antigen (TAA)-specific cytotoxic T lymphocytes, a new experimental therapy.

This sort of therapy has been used previously to treat Hodgkin or non-Hodgkin lymphomas that show proof of infection with Epstein-Barr virus (EBV), the virus that causes infectious mononucleosis ("mono" or the "kissing disease"). EBV is found in cancer cells of up to half of all patients with Hodgkin's and non-Hodgkin lymphoma. This suggests that it may play a role in causing lymphoma. The cancer cells infected by EBV are able to hide from the body's immune system and escape being killed. Investigators tested whether special white blood cells, called T cells, that were trained to kill EBV-infected cells could affect these tumors, and in many patients it was found that giving these trained T cells caused a complete or partial response.

However, many patients do not have EBV in their lymphoma cells; therefore investigators now want to test whether it is possible to direct these special T cells against other types of proteins on the tumor cell surface with similar promising results. The proteins that will be targeted in this study are called tumor associated antigens (TAAs) - these are cell proteins that are specific to the cancer cell, so they either do not show or show up in low quantities on normal human cells.

In this study, we will target five TAAs which commonly show on lymphoma, called: NY-ESO-1, MAGEA4, PRAME, Survivin and SSX. This will be done by using special types of T cells called cytotoxic T lymphocytes (CTLs) generated in the lab.

In addition, some adult patients will receive a drug called azacytidine before giving the T cells. We hope that the combination helps the T cells work better.

The patient will give blood to make TAA-specific cytotoxic T cells in the lab. These cells will be grown and frozen. If the TAA-specific cytotoxic T cells can be made, the time from collection of the blood to manufacture of T cells for administration to the patient is about 1 to 2 months.

There are 4 stages of this study: an antigen-escalation phase, a dose-escalation stage, aza stage and pediatric patients stage.

The antigen-escalation phase will be first. Patients will receive TAA-specific T cells targeting first 1 and then 2 TAAs. Once this schedule proves safe, the next group of patients will receive TAA-specific T cells targeting first 2 and then 3 TAAs. This process will continue until all 4 levels are studied. This means that the final cohort of patients will receive TAA-specific T cells targeting first 4 and then 5 TAAs. If the side-effects are too severe, the number of TAAs being targeted will be lowered or the T cell injections will be stopped. Each patient will receive 2 infusions at the same dose 28 days apart

After the antigen-escalation phase, the dose-escalation phase will begin. Patients will be started on the lowest dose (1 of 3 different levels) of T cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 3 dose levels are studied. If the side-effects are too severe, the dose will be lowered or the T cell injections will be stopped. Each patient will receive 2 infusions at the same dose 14 days apart

After the dose escalation stage, adult patients will be enrolled on the aza stage where they will receive the drug aza followed by two infusions of T cells on dose level 2. Patients will be given 3 cycles of aza (administered daily through a vein for 5 days, every 28 days) followed by 2 doses of multiTAA-specific T cells administered 14 days apart. Before the patient is given the aza they will be given a drug to help prevent nausea and vomiting.

On the pediatric stage, pediatric patients will receive 2 infusions of T cells on dose level 2. The T cells will be given 14 days apart.

The cells will be injected by IV over 10 minutes. The patients may be pre-treated with acetaminophen (Tylenol) and diphenhydramine (Benadryl). Acetaminophen (Tylenol) and diphenhydramine (Benadryl) are given to prevent a possible allergic reaction to the T cell administration. If after the second infusion there is a reduction in the size of the patient's lymphoma on CT or MRI scan as assessed by a radiologist, the patient can receive up to six (6) additional doses of the T cells at monthly intervals if they wish. All of the treatments will be given by the Center for Cell and Gene Therapy at Houston Methodist Hospital or Texas Children's Hospital.

In between the first and second T cell infusions and for 6 weeks after the last infusion, the patient should not receive any other anti-cancer treatments such as radiation therapy or chemotherapy. If the patient does receive any other therapies in-between the first and second infusion of T cells, they will be taken off treatment and will not be able to receive the second infusion of T cells.

MEDICAL TESTS BEFORE TREATMENT

* Physical exam.
* Blood tests to measure blood cells, kidney and liver function.
* Measurements of your tumor by routine imaging studies. We will use the imaging study that was used before to follow your tumor: CT, MRI, or PET.
* Pregnancy test if you are a female who can have children.

MEDICAL TESTS AFTER TREATMENT

- Imaging study 6 weeks after the 2nd TAA-CTL infusion.

To learn more about the way the T cells are working in the patient's body, an extra 20-40 mL (4-8 teaspoons) of blood will be taken before each cycle of aza (if applicable), 2 weeks after each cycle of aza (if applicable), before each T-cell infusion, and at Weeks 1, 2, 4 and 6. One additional blood sample might be drawn 3 to 4 days post the T-cell infusion; this is optional. Afterwards, blood will be collected at 3, 6, 9 and 12 months after the last infusion. The blood may be drawn from a central line at the time of the patient's regular blood tests. Investigators will use this blood to see how long the T cells last,and to look at the immune response to the patient's cancer.

Study Duration: Patients will be on active study participation for approximately one year. Patients who receive additional doses of the T cells as described above will be actively followed until 1 year after their last dose of T cells. Investigators will then remain in contact with patients once a year for up to 4 additional years (total of 5 years follow-up) in order to evaluate disease response long-term.

Administration of TAA-Specific CTLs; Hodgkin or Non-Hodgkin Lymphoma; TACTAL

Administration of Tumor-Associated Antigen (TAA)-Specific Cytotoxic T-Lymphocytes to Patients With Active or Relapsed Hodgkin or Non-Hodgkin Lymphoma

To determine the safety of 2 intravenous injections of autologous TAA-specific cytotoxic T lymphocytes (CTLs) in patients with Hodgkin or non-Hodgkin lymphoma.

To determine whether infusion of TAA-specific T cells targeting multiple tumor antigens in combination with azacytidine is safe

Information on the expansion, persistence and anti-tumor effects of the adoptively transferred tumor-specific CTLs will be analyzed for the immunological parameters based on multimer analysis, intracellular cytokine staining and ELIspot assays to assess the frequency of cells secreting γ-IFN using the descriptive statistics such as mean, median, standard deviation at each timepoint.

To determine whether CTL infusions increase the spectrum of epitopes/antigens targeted by endogenous T cells (epitope spreading).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Administration of TAA-Specific CTLs; Hodgkin or Non-Hodgkin Lymphoma; TACTAL	NCT01333046	Hodgkin Lymphom... Non-Hodgkin Lym... Hodgkin Disease	Antigen-Escalat... Dose-Escalation... azacytidine and... Pediatric multi...	18 Years -	Baylor College of Medicine
Administration of TAA-Specific CTLs; Hodgkin or Non-Hodgkin Lymphoma; TACTAL	NCT01333046	Hodgkin Lymphom... Non-Hodgkin Lym... Hodgkin Disease	Antigen-Escalat... Dose-Escalation... azacytidine and... Pediatric multi...	18 Years -	Baylor College of Medicine
Administration of TAA-Specific CTLs; Hodgkin or Non-Hodgkin Lymphoma; TACTAL	NCT01333046	Hodgkin Lymphom... Non-Hodgkin Lym... Hodgkin Disease	Antigen-Escalat... Dose-Escalation... azacytidine and... Pediatric multi...	18 Years -	Baylor College of Medicine

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