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Treatment with donor-derived multiTAA-specific T cells as adjuvant therapy following HSCT for AML or MDS

Treatment with donor-derived multiTAA-specific T cells for relapsed/residual disease following HSCT for AML or MDS

The 5 dose levels are:

Dose Level 1: 5 x 10e6 cells/m2; Dose Level 2: 1 x 10e7 cells/m2; Dose Level 3: 2 x 10e7 cells/m2; Dose Level Four: 5 x 107 cells/m2; Dose Level Five: 1 x 108 cells/m2

The T cells are given from 30 days post-HSCT. They are administered by intravenous injection over 1-10 minutes through either a peripheral or central lie.

If patients with residual disease (Group B) have a partial response, complete response or stable disease, they will be eligible to receive up to 6 further doses of multiTAA-specific T cells at the same dose as the initial infusions (or below the patient's original dose can be administered) at least 4 weeks apart.

MultiTAA-specific T cells

Premal Lulla, MD

Catherine Robertson

This research study uses special blood cells called multiple tumor-associated antigen (TAA)-specific T cells (a new experimental therapy) to treat patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) which has come back, or may come back, or has not gone away after standard treatment, including an allogeneic hematopoietic stem cell transplant (HSCT).

The investigators have previously used this sort of therapy to treat Hodgkin or non-Hodgkin lymphomas that are infected with Epstein-Barr virus (EBV). EBV is found in cancer cells of up to half of all patients with Hodgkin 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. The investigators previously 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 the investigators found that giving these trained T cells causes a complete or partial response.

Other cancers express specific proteins that can be targeted in the same way. The investigators have been able to infuse such tumor-targeted cells into up to 10 patients with lymphoma who do not have EBV, and seen some complete responses. Importantly, the treatment appears to be safe. Therefore, the investigators now want to test whether the investigators can direct these special T cells against other types of cancers that carry similar proteins called tumor-associated antigens (TAAs). These proteins are specific to the cancer cell, so they either do not show up, or show up in low quantities, or normal human cells.

The investigators will grow T cells from patients' stem cell donors in the laboratory in a way that will train them to recognize the tumor proteins WT1, NY-ESO-1, PRAME, and Survivin, which are expressed on most AML and MDS cancer cells. The cells will be infused at least 30 days post-allogeneic stem cell transplant. In this study, the investigators want see whether these cells will be able to recognize and kill cancer cells that express these proteins. These donor-derived multiTAA-specific T cells are an investigational product not yet approved by the U.S. Food and Drug Administration

The purpose of this study is to find the largest safe dose of donor-derived tumor protein multiTAA-specific T cells for patients with AML or MDS.

To make donor derived multiTAA-specific T cells, the investigators will collect blood from the patient's stem cell donor, and mix the donor's T cells with small pieces of tumor proteins WT1, PRAME, NY-ESO-1, and Survivin. These protein fragments stimulate the donor T cells to grow and react against these proteins in such a way that they will recognize and kill cancer cells that express these proteins. Once sufficient numbers of multiTAA-specific T cells have been made, the investigators test them to make sure they target the patient's cancer cells, but not their normal healthy cells.

The multiTAA-specific T cells will be administered as a single intravenous (IV) infusion over 10 minutes. The patient's cancer will be assessed within 4 weeks prior to the T cell infusion, and then 4-6 weeks after the infusion. If at least 4 weeks after the infusion there is no change or a reduction in the number of cancer cells measured in the bone marrow, or a decline in cancer-specific markers in the blood, patients may receive up to six (6) additional doses of T cells at least 4 weeks apart. All of the treatments will be given by the Center for Cell and Gene Therapy at Houston Methodist Hospital or Texas Children's Hospital.

For at least 4 weeks after the infusion, patients may not receive any other anti-cancer treatments, such as radiation therapy, or chemotherapy. Patients who do receive any other therapies will be taken off treatment and will not be able to receive additional doses of T cells. However, drugs such as 5-azacytidine (Vidaza), decitabine (Dacogen), or lenalidomide (Revlimid) will be allowed during infusions.

This is a dose escalation study, which means that at the beginning, patients will be started on the lowest dose (1 of 5 different levels) of T cells. Once that dose level proves safe, the next group of patients will be started at the next highest dose. This process will continue until all 5 dose levels have been studied. If side-effects are too severe, the dose will be lowered or the T cells injections will be stopped.

MEDICAL TESTS BEFORE TREATMENT:

Before being treated, patients will undergo a series of standard medical tests:

* Measurement of AML/MDS (done by bone marrow biopsy or tests on blood or other tissues)
* Pregnancy test, if patient is a female who can have children.

MEDICAL TESTS DURING TREATMENT

Patients will undergo standard medical tests on the day of infusion:

* Physical exam.
* Blood test to measure blood cells, kidney and liver function.

MEDICAL TESTS AFTER TREATMENT:

* Blood tests to measure blood cells, kidney and liver function on week 4.
* Measurement of AML/MDS 4-6 weeks after the T cells infusion and 8-12 weeks after the infusion (done by bone marrow biopsy and tests done on your blood or other tissues).

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 the infusion, and at weeks 1, 2, 4 and 8. Afterwards, blood will be collected at 3, 6, 9 and 12 months after the infusion. Blood should come from the central intravenous line, and should not require extra needle sticks. 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. Investigators will also look at this in bone marrow and other tissue samples collected from the patient at the time points stated above (pre-infusion, 4 - 6 weeks and 8 - 12 weeks post infusion).

Patients will be followed for up to one year from the date of the last T cell infusion, so that the investigators can learn more about the way the T cells are working, how long the T cells last in the body, and to assess the immune response to the cancer. Patients who receive additional doses of T cells will undergo the same tests and evaluations performed for each dose as described above.

Patients will then be contacted once a year for up to 4 additional years (total of 5 years follow-up) to evaluate their disease response long-term.

Administration of Donor Multi TAA-Specific T Cells for AML or MDS (ADSPAM)

Administration of Donor Derived Multi-Tumor-Associated Antigen (TAA)- Specific T Cells to Patients With AML or MDS (ADSPAM)

Maximum tolerated dose (MTD) of multiTAA-specific T cells among the five pre-specified dose levels.

To obtain information on the anti-tumor effects of adoptively transferred donor-derived multiTAA-specific T cells in patients with AML or MDS.

To obtain information on the expansion and persistence of adoptively transferred donor-derived multiTAA-specific T cells in patients with AML or MDS.

The Methodist Hospital Research Institute

Center for Cell and Gene Therapy, Baylor College of Medicine

American Society for Blood and Marrow Transplantation (ASBMT)

Cancer Prevention Research Institute of Texas

Baylor College of Medicine

Assistant Professor

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Pancreatic Cancer

Patients with locally advanced or metastatic pancreatic adenocarcinoma who are responding following 3 cycles of first line chemotherapy will receive 6 infusions with a fixed dose of multiTAA specific T cells beginning on the 4th week of the 4th cycle of chemotherapy. MultiTAA T cell infusions will occur on day 21 (a chemotherapy "off" week) of each chemotherapy cycle starting on chemotherapy cycle 4.

Patients with locally advanced or metastatic pancreatic adenocarcinoma who have failed first line chemotherapy or are intolerant or ineligible to receive standard of care chemotherapy will be evaluated in the clinic and receive 6 infusions (administered at monthly intervals) with a fixed dose of multiTAA specific T cells.

Patients with resectable pancreatic adenocarcinoma following completion of neoadjuvant chemotherapy, radiotherapy or combination. These patients will receive 6 infusions with a fixed dose of multiTAA specific T cells. One infusion will occur 4 weeks prior to surgical resection (with an option to infuse up to one week earlier) and after the completion of all pre-operative chemotherapy and/or radiation. The subsequent 5 infusions will occur at monthly intervals beginning 8 weeks post-surgery. Following surgery all patients will additionally receive 3 months of standard of care (SOC) chemotherapy starting week 9 after surgery. Hence, SOC chemo will occur weeks 9-11, 13-15, and 17-19 post-surgery and multiTAA T cell infusions will occur at weeks 8, 12, 16, 20, and 24 post-surgery.

Each patient will receive 6 infusions of multiTAA T cells at a fixed cell dose (1 x 10\^7 cells/m2) at the times specified in the group description. The expected volume of infusion will be 1 to 10 cc.

multiTAA specific T cells

Anne Leen, PhD

Benjamin Musher, MD

Status - CLOSED TO PATIENT ENROLLMENT (CNPE)

Patients who have pancreatic cancer that has come back or has not gone away after treatment, including the standard treatment for this disease or patients who are not eligible for or have elected not to receive standard of care chemotherapy, and patients who will have surgery after treatment for pancreatic cancer are eligible for this study. This is a research study using special immune system cells called tumor-associated antigen (TAA)-specific cytotoxic T lymphocytes, a new experimental therapy.

The proteins that are targeted in this study are called tumor-associated antigens (TAAs). These are cell proteins that are specific to the cancer cell. They do not show, or they show up in low quantities, on normal human cells. In this study, five common TAAs will be targeted. They are called NY-ESO-1, MAGEA4, PRAME, Survivin and SSX2. On a different study, patients have been treated and so far this treatment has shown to be safe.

Investigators now want to try this treatment in patients with pancreatic cancer.

These TAA-specific cytotoxic T lymphocytes (TAA-CTLs) are an investigational product not approved by the Food and Drug Administration.

\*Arm A and Arm B are closed to new patient enrollment.\*

Status - CLOSED TO PATIENT ENROLLMENT (CNPE)

The patient will give blood to make TAA-Specific cytotoxic T cells in a lab. These cells well 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.

The cells will be infused by intravenous infusion (IV) into the patient over 1-10 minutes. The patient 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 TAA-CTL administration.

Patients will be given up to six doses of TAA-CTLs at monthly intervals. The treatments will be given by the Center for Cell and Gene Therapy at Houston Methodist Hospital (HMH).

MEDICAL TESTS BEFORE TREATMENT:

* Physical exam.
* Blood tests to measure blood cells, kidney and liver function.
* Measurements of the patient's tumor by routine imaging studies and/or blood tests. The study will use the imaging study that was used before to follow the patient's tumor: CT, MRI, or PET.
* Blood test to check for pregnancy for female patients who can have children

MEDICAL TESTS DURING TREATMENT:

Standard medical tests will be conducted on the day of the second and subsequent infusions:

* Physical exams prior to each T cell infusion
* Blood tests to measure blood cells, kidney and liver function.

MEDICAL TESTS AFTER TREATMENT:

- Measurements the patient's tumor by routine imaging studies and/or blood tests done as per standard of care.

To learn more about the way the TAA-CTLs are working in patient's body, an extra 20-40 mL (4-8 teaspoons) of blood will be taken before the infusion, at Weeks 1 and 2 after each infusion and at weeks 4, 6 and 8 and months 3, 6, 9 and 12 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 TAA-CTLs last, and to look at the immune system response to the patient's cancer.

Study Duration: Patients will be active participants in this study for approximately one year after their last dose. Investigators will contact patients once a year for up to 4 additional years (total of 5 years follow-up) in order to evaluate disease response long-term.

\*Arm A and Arm B are closed to new patient enrollment.\*

This study is designed as a fixed-dose pilot study to evaluate the safety and feasibility and efficacy of up to 6 intravenous infusions of multiTAA-specific T cells in pancreas cancer patients with metastatic, locally advanced unresectable, or resectable disease.

TAA Specific Cytotoxic T Lymphocytes in Patients With Pancreatic Cancer

Tumor-Associated Antigen (TAA) Specific Cytotoxic T Lymphocytes Administered in Patients With Pancreatic Cancer

To determine the safety of up to 6 intravenous infusions of multiTAA-specific T cells in pancreatic cancer patients with metastatic, locally advanced unresectable, or resectable disease.

To determine the feasibility of completing a total of 6 intravenous infusions of multiTAA-specific T cells to pancreatic cancer patients with metastatic, locally advanced unresectable, or resectable disease

To evaluate the progression-free of patients after multiTAA-specific T cell infusions

To evaluate the overall survival of patients after multiTAA-specific T cell infusions

Pancreatic Cancer Action Network

The V Foundation for Cancer Research

Harris County Hospital District

Adverse event data collection is still ongoing and will be updated upon study completion to include any additional adverse event data.

Patients with locally advanced or metastatic pancreatic adenocarcinoma who are responding following 3 cycles of first line chemotherapy will receive 6 infusions with a fixed dose of multiTAA specific T cells beginning on the 4th week of the 4th cycle of chemotherapy. MultiTAA T cell infusions will occur on day 21 (a chemotherapy "off" week) of each chemotherapy cycle starting on chemotherapy cycle 4.

multiTAA specific T cells: Each patient will receive 6 infusions of multiTAA T cells at a fixed cell dose (1 x 10\^7 cells/m2) at the times specified in the group description. The expected volume of infusion will be 1 to 10 cc.

Group A

Patients with locally advanced or metastatic pancreatic adenocarcinoma who have failed first line chemotherapy or are intolerant or ineligible to receive standard of care chemotherapy will be evaluated in the clinic and receive 6 infusions (administered at monthly intervals) with a fixed dose of multiTAA specific T cells.

multiTAA specific T cells: Each patient will receive 6 infusions of multiTAA T cells at a fixed cell dose (1 x 10\^7 cells/m2) at the times specified in the group description. The expected volume of infusion will be 1 to 10 cc.

Group B

Patients with resectable pancreatic adenocarcinoma following completion of neoadjuvant chemotherapy, radiotherapy or combination. These patients will receive 6 infusions with a fixed dose of multiTAA specific T cells. One infusion will occur 4 weeks prior to surgical resection (with an option to infuse up to one week earlier) and after the completion of all pre-operative chemotherapy and/or radiation. The subsequent 5 infusions will occur at monthly intervals beginning 8 weeks post-surgery. Following surgery all patients will additionally receive 3 months of standard of care (SOC) chemotherapy starting week 9 after surgery. Hence, SOC chemo will occur weeks 9-11, 13-15, and 17-19 post-surgery and multiTAA T cell infusions will occur at weeks 8, 12, 16, 20, and 24 post-surgery.

multiTAA specific T cells: Each patient will receive 6 infusions of multiTAA T cells at a fixed cell dose (1 x 10\^7 cells/m2) at the times specified in the group description. The expected volume of infusion will be 1 to 10 cc.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Administration of Donor Multi TAA-Specific T Cells for AML or MDS (ADSPAM)	NCT02494167	Acute Myeloid L... Myelodysplastic...	MultiTAA-specif...	-	Baylor College of Medicine
TAA Specific Cytotoxic T Lymphocytes in Patients With Pancreatic Cancer	NCT03192462	Pancreatic Canc...	multiTAA specif...	18 Years -	Baylor College of Medicine
TAA Specific Cytotoxic T Lymphocytes in Patients With Pancreatic Cancer	NCT03192462	Pancreatic Canc...	multiTAA specif...	18 Years -	Baylor College of Medicine
Administration of Donor Multi TAA-Specific T Cells for AML or MDS (ADSPAM)	NCT02494167	Acute Myeloid L... Myelodysplastic...	MultiTAA-specif...	-	Baylor College of Medicine
Administration of Donor Multi TAA-Specific T Cells for AML or MDS (ADSPAM)	NCT02494167	Acute Myeloid L... Myelodysplastic...	MultiTAA-specif...	-	Baylor College of Medicine

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