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Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplant From A Haploidentical Donor For Patients With Acute Leukemia and Myelodysplasia


Phase 1
N/A
50 Years
Open (Enrolling)
Both
Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Myelodysplastic Syndrome, Leukemia

Thank you

Trial Information

Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplant From A Haploidentical Donor For Patients With Acute Leukemia and Myelodysplasia


Patients:

The major risk with using a stem cell donor who is not a perfect match for HLA antigens is
severe graft versus host disease (GVHD). GVHD is a condition that happens when the donor's
T-cells, immune system cells that are found in the transplanted stem cells, react against
cells of the patient receiving the transplant. This can cause serious and possibly
life-threatening side effects. Severe GVHD can also continue for a long time. This is
called "chronic GVHD." Chronic GVHD can result in skin, liver, and intestinal problems, as
well as other health-threatening complications.

In order to lower the risk of GVHD, the number of T-cells in the donated stem cells can be
lowered. T-cells are an important part of your immune system that can fight infections and
cancer cells. While lowering the number of T-cells has helped in lowering the chance of
GVHD from transplanting stem cells that do not match perfectly, it takes a long time to
build up the number of T-cells in your body again.

Researchers want to find out if treating the donated stem cells with anti-B7 antibodies,
before they are transplanted, can help lower the chance of GVHD and still help speed up the
process of building up your T-cells again. Anti-B7 antibodies are proteins that attach to
immune system cells and interfere with the immune response. This may help to keep the
transplanted T-cells from attacking the cells in your body.

Small groups of people will be enrolled in steps in this trial. The first group (up to 8
participants) will be given a certain number of anti-B7 antibody treated donor immune cells.
If they have few or manageable side effects, the next small group of people enrolled will
receive a higher number of donor immune cells. This increase in numbers with groups of
people will continue until the study doctors find the highest number of anti-B7 antibody
treated donor immune cells that can be given without causing severe or unmanageable side
effects.

The initial group of patients (3 to 5 patients) that enter this study will receive a very
small number of donor immune cells. This phase of the study will help the cell processing
laboratory determine if the techniques and procedures are working correctly before
proceeding to higher doses of immune cells for the next patients that will participate in
the study.

You will have a central venous catheter (CVC) inserted, so that daily blood draws and daily
medicine and fluids can be given without extra "needle sticks" or IV lines. The CVC is a
needle and tube that is inserted into a vein in your chest or back, that stays in the whole
time you are on treatment. You will be given a separate form that will explain this
procedure. Your surgeon and anesthesiologist will review this with you.

Your stem cell donor will be asked to sign a consent form, so that the stem cells can be
collected through a process called leukapheresis.

Once enough stem cells have been collected from your donor, you will begin treatment with
total body irradiation (TBI), followed by chemotherapy. This treatment is generally referred
to as either "conditioning" or "preparative" therapy. It is given in order to kill the
leukemia cells, as well as your own stem cells, and your immune cells. The TBI will be
given 2 times a day for 3 days, and will last 20-40 minutes each time. All of the
chemotherapy will be given intravenously (IV--through a needle in your vein), usually
through your CVC. You will receive the chemotherapy drug thiotepa once a day for 2 days,
fludarabine once a day for 5 days, and anti-thymocyte globulin (ATG) once a day for 4 days.
Methylprednisolone, a steroid drug, will be given with the ATG to lower the risk of any side
effects.

After the radiation and chemotherapy treatments, you will receive the transplant of your
donor's normal and T-cell depleted stem cells by IV or CVC. If some or all of the donor
cells are not used during the transplant, the leftover cells will be stored. The leftover
stored cells will be thrown away if your doctor decides you do not need them any more.
After 10 years, the Cell Processing Laboratory at M. D. Anderson will throw away any
remaining stored cells.

The stem cell transplant will have 2 parts: the first infusion of normal donor stem cells,
and then an infusion of stem cells treated with the anti-B7 antibodies.

In order to perform the treatment with anti-B7 antibodies, T-cells must be collected from
the blood of both the same person who donated the stem cells and either you or a family
member who shares some of your genetic tissue typing. If the cells come from your family
member, they will be collected 32 days after the transplant. If you are donating your own
cells for this purpose, they will be collected before the conditioning treatment starts, and
then the cells will be frozen, stored, and then thawed on Day 32 after transplant.

The donor immune cells and the cells from yourself or a family member who shares some of
your tissue typing will be taken to the laboratory where they will be mixed with anti-B7
antibodies on Day 32. The mixture will be kept in the laboratory for 3 days. Adding the
anti-B7 antibodies to this mixture of stem cells will keep certain interactions between the
two cell types from happening. Researchers believe this will "teach" the donor's immune
cells what kinds of cells to leave alone when those donor cells are put back into your body.
The anti-B7 antibodies will then be rinsed away from the mixture, and the cells will be
given to you by IV infusion on Day 35 after transplant. If the infusion needs to be put off
based on your medical condition, the cells will be collected on Day 39 and given on Day 42.

Throughout your stay in the hospital, which should be about 4-6 weeks, blood tests (about 4
teaspoons) and physical exams will often be performed. Depending on your clinical
condition, other tests, including radiologic scans and/or biopsies, may also be needed.
These will be discussed with you as needed.

After you are sent home from the hospital, you will be asked to come back to the clinic
several times. The frequency of visits will be determined in part by your clinical
condition. You may need to come as often as every day for about 3 months. At these visits,
a physical exam, blood tests (about 2 teaspoons), and a check-up for GVHD will be done.
Most of these tests will be related to your regular medical care, but some blood tests will
be related to the study only. Whenever possible, the study blood tests will be collected at
the same time as the blood being drawn for routine tests. Your size and your blood counts
will help the study staff decide the correct amount of blood to draw (no more than 6
teaspoons each time). These samples will be frozen and stored until they are used for study
tests.

You will be in the study for about 1 year. This time includes the screening visit, treatment
before the transplant, and follow-up visits after the transplant. After you are able to
return to your own home and own physicians, the study staff will contact you every 3 months
until 2 years after the transplant, to see how you are doing. You will be asked to return to
the program at about 6 months, 1 year, and 2 years after the transplant.

At these follow up visits, the study staff will collect information about you from doctors'
notes and medical records. This information will include any transplant side effects,
treatments, and information obtained from procedures, including lab tests, scans, and
biopsies. The study staff will collect your health information until the end of the
research. They may collect some follow-up information, such as your disease status, and
treatments that you receive, from your medical record even after your direct participation
in the research study ends.

This is an investigational study. The treatment in this study is authorized for use in
research only. Up to 40 patients will take part in this multicenter study. About 20 will
be enrolled at M. D. Anderson.

Peripheral Blood Mononuclear Cell (PBMC) Collection from Family Donors:

Your family member will receive a stem cell transplant with a certain type of cells called
lymphocytes removed. This is being done to help prevent graft-versus-host disease (GVHD) in
the patient, but it may also lower the ability of the donated stem cells to fight
infections.

The transplant treatment being used for your family member involves collecting stem cells
from the peripheral blood of the person in your family who is acting as the stem cell donor.
During the process of collecting these donor peripheral blood stem cells, large numbers of
T lymphocytes (or "T-cells") are also collected. Because these donor T-cells can cause GVHD
in the person receiving the transplant, the stem cells collected will be purified to lower
the number of T-cells. This may lower the risk of GVHD. This procedure is called T-cell
depletion.

The stem cells, minus the T-cells, will then be given to the patient. The side effect of
removing these T cells, however, is that there may be a higher risk of infection.
Researchers want to give the patient another infusion of extra blood cells containing
T-cells, about 5 weeks after the transplant. Before giving them these cells, the study
staff will add anti-B7 antibodies to them, to try to lower the chances that they will cause
GVHD when they are given. To change the cells this way, researchers need blood cells from a
family member, to mix with the donor's T-cells. You are being asked to provide these extra
cells, to be mixed with the anti-B7 antibodies.

If you decide to take part as a blood donor, you will first have a physical exam and blood
tests (less than 3 tablespoons) performed to make sure you are healthy enough to donate.
These blood tests include routine tests, tests of kidney and liver function, and other
tests, depending upon your health history. Women who are able to have children must have a
negative blood pregnancy test before donating blood in this study.

Your blood sample will also be tested for the human immunodeficiency virus (HIV), the virus
that causes AIDS. You have the right to know the results of this test, and you will be
notified privately if your HIV test is positive. What that test result means to you will be
explained by a member of the medical staff. If you are found to be HIV positive, you will
not be eligible to be a donor, as it may not be safe for the patient.

You will also be tested for syphilis, hepatitis, and other viral diseases that could be
passed on to the patient if you donate blood cells. You have the right to know the results
of these tests. Any unusual test results will be discussed with you by a member of the
medical staff.

If you are still able to take part in this study, the collection of circulating blood will
happen on Day 32 (in some cases, Day 39) after the patient's stem cell transplant. The
number of T-cells being given to your family member will be decided as he or she enters the
study. If your family member is being given a small or moderate number of T-cells, the
process of collecting blood immune cells from you will involve placement of an intravenous
(IV) needle into a vein in your arm and drawing blood. The amount of blood may be as little
as 2 tablespoons or as much as 7-12 tablespoons.

If your family member is receiving the largest possible number of T-cells, it is possible
that researchers will need to use a pheresis machine to collect enough blood immune cells
from you. Apheresis is a process used to collect blood cells and uses a technique very
similar to a platelet collection. Apheresis requires having an IV needle placed in each arm
before the procedure, or a central venous catheter (CVC) placed in a large vein by a
surgeon. If a CVC is needed, you will be given a separate informed consent document, which
will explain the procedure and its risks. The blood is drawn, processed in a machine that
separates out the cells that are needed, and the remaining blood parts are returned to you
through the second IV or the other port of the catheter. No medication is required before
this collection, and the procedure would be done on a single day.

Your participation will start with your screening tests, before the patient's transplant.
The blood cells will be collected on Day 32 (or 39) after the transplant. This will end
your participation on the main part of this study. You can stop your participation at any
time. Your doctor can also stop your participation in this study at any time, if it is in
your best interest to do so.

This is an investigational study. The treatment in this study is authorized for use in
research only. About 37 patients will take part in this study. About 20 will be enrolled
at M. D. Anderson.

Stem Cell Mobilization and Collection from Family Donors:

This study will look at the use of mismatched, related donors as the source of stem cells
and immune cells for transplantation for patients with acute leukemias or myelodysplastic
syndrome. You are being asked to donate blood stem cells and immune cells (T-lymphocytes,
also called T-cells).

The circulating blood contains stem cells that are the basis for both the blood and immune
systems. Drugs can be used to increase the number of these stem cells in the blood to high
enough numbers for transplantation. Stem cells will be taken from the circulating blood you
donate, and then will be given to your family member. Your healthy stem cells will replace
your family member's bone marrow to help fight his/her disease. During the process of blood
stem cell collection, large numbers of T-cells are also collected. Sometimes these immune
system cells will actually "attack" the person they're being given to. This is called
"graft versus host disease" (GVHD). Your blood stem cells will be purified, so that the
number of these T-cells are lowered. This will help lower the risk of GVHD. This is called
"T-cell depletion."

The second part of this study involves more donated blood cells from you and another donor.
Removing T-cells from the donated stem cells may raise the risk of the patient getting an
infection. To prevent this, you will be asked to donate more blood for stem cells about a
month after the first transplant. These stem cells will be mixed with T-cells from another
donor that have been treated with anti-B7 antibodies. Researchers want to find out if this
mixture will lower the risk of GVHD by "teaching" your T-cells not to attack the patient's
cells.

If you agree to take part in this study, you will have what are called "screening tests."
These tests will help the doctor decide if you are eligible to take part in this study. You
will have a physical exam and blood tests (less than 3 tablespoons) to make sure you are
healthy enough to donate. These blood tests will include routine tests, tests of your liver
and kidney function, and possibly other tests, based upon your health history. Women who
are able to have children must also have a negative blood pregnancy test before taking part
in this study.

Your blood will be tested for the human immunodeficiency virus (HIV), the virus that causes
AIDS. You have the right to know the results of this test, and you will be notified
privately if your HIV test is positive. What that test result means to you will be
explained by a member of the medical staff. If you are found to be HIV positive, you will
not be eligible to be a donor as it may not be safe for the patient. You will also be
tested for syphilis, hepatitis, and other viral diseases that could be passed on to the
patient if you donate blood. You have the right to know the results of these tests. Any
abnormal test results will be discussed with you by a member of the medical staff.

If you are still eligible to take part in this study, you will begin drug treatment before
the stem cell collection. You will be asked to inject yourself each morning for 4-6 days
with a drug called filgrastim (G-CSF, Neupogen). Filgrastim is a protein that causes bone
marrow to make more stem cells. A nurse or other trained professional in the clinic will
teach you how to inject the Filgrastim under your skin.

The first dose of filgrastim must be given in the clinic, so that the study staff can watch
for any side effects. Blood samples (about 4 teaspoons) will be drawn on Day 4 of the
filgrastim injections, to check your white blood cell count level. These blood tests will
happen every day until the stem cell collections are done. Based on the results of these
blood tests, your dose of filgrastim may be changed.

On Day 4 or 5 of your filgrastim treatments, your blood stem cell collection will start.
Blood stem cells are collected using a process called apheresis. Apheresis uses a technique
very similar to a platelet collection. Apheresis requires having an IV needle placed in
each arm before the procedure, or a central venous catheter (CVC) placed in a large vein by
a surgeon. If a CVC is needed, you will be given a separate informed consent document,
which will explain the procedure and its risks. The blood is drawn, processed in a machine
that separates out the cells that are needed, and the remaining blood parts are returned to
you through the second IV or the other port of the catheter. The collection may take up to
4 days, though it usually takes 1-2 days to collect enough stem cells. If not enough cells
can be collected in this time, the study staff will look for another donor.

Your T-cells will later be collected on Day 32 after the patient's stem cell transplant.
Before you can donate T-cells, you will again go through the screening tests, and must not
have any infections or medical conditions that would be a health risk to the person
receiving your blood. About 2 tablespoons of blood will be drawn for these tests.

The number of T cells being given to your family member will be decided as they enter the
study. If your family member is being given a small or moderate number of T-cells, the
process of collecting blood immune cells from you will involve placement of an intravenous
(IV) needle into a vein in your arm and drawing blood. The amount of blood may be as little
as 4 tablespoons or as much as 7-12 tablespoons.

If your family member is receiving the largest possible number of T-cells, it is possible
that researchers will need to perform apheresis on you again, to collect enough blood immune
cells from you. However, you would not need to take any filgrastim or other drug before
this collection, and the apheresis would be limited to a single day.

If the stem cells do not grow well in the patient, the doctors may ask you for more stem
cells within the first months after the patient's treatment, in an effort to further improve
the growth of the stem cells and better treat the patient's disease.

You can stop your participation at any time. Tell the study doctor if you are thinking
about stopping or decide to stop. Your doctor can also stop your participation in this
study at any time, if it is in your best interest to do so.

This is an investigational study. Filgrastim is an FDA approved drug. Apheresis is a
standard procedure for some blood or platelet donors and stem cell donors. It is important
that you tell your study doctor if you have been injured because of taking part in this
study. About 37 patients will take part in this study. About 20 will be enrolled at M. D.
Anderson.


Inclusion Criteria:



1. Patients criteria for stem cell transplantation.

2. Cardiac function: left ventricular ejection fraction > 45%

3. Renal function: Serum creatinine < 2x upper limit of normal for age or if serum
creatinine elevated beyond normal, must have creatinine clearance or glomerular
filtration rate > 50% lower limit of normal for age

4. Hepatic function: AST/ALT < 3x upper limit of normal for age and bilirubin < 2.0
mg/dl. These criteria do not apply if liver is involved with disease.

5. Pulmonary function: Patient must have room air O2 saturation >95% and no clinical
evidence of pulmonary insufficiency unless the lungs are involved with disease.

6. Patients with acute myelogenous leukemia (AML): induction failure with < 3 induction
courses, >/= second or greater complete remission (CR) (defined as <5% blasts in bone
marrow and no active extramedullary disease) , CR1 with high risk features defined as
history of induction failure, 5q- or monosomy 7 cytogenetic findings;

7. Patients wih acute lymphocytic leukemia (ALL): >/= second or greater CR (defined as
<5% blasts in bone marrow and no active extramedullary disease), CR1 with high risk
features defined as history of induction failure or Ph+ or t(4;11) on cytogenetic
analysis or any infant with MLL rearrangements on cytogenetic analysis;

8. Patients with myelodysplastic syndrome (MDS): refractory anemia (RA) with excess
blasts (EB) with intermediate (INT)-1, INT-2 or high International Prognosis Score
System (IPSS) score, RAEB in transformation (iT) with INT-1, INT-2 or high IPSS score
and patients with RA and INT-2 IPSS score

9. Patients lacking a suitably matched family donor defined by genotypic or phenotypic
identity for >/= 5/6 A, B, DR loci

10. Patients lacking an immediately available genotypically matched (6/6) unrelated
marrow donor or umbilical cord blood donor with suitable cell dose after a search of
greater than or equal to 2 months OR patients whose medical condition is at high risk
of deteriorating or whose disease is at high risk of progression during a donor
search

11. Patients must have a healthy family member donor who must be at least genotypically
HLA-A, B, C, DR haploidentical to the patient.

12. Donors must sign voluntary, written informed consent OR in the case of minor donors
such consent must be signed by the parent or guardian and assent will be requested as
age appropriate.

13. Donors must be capable of undergoing leukapheresis, have adequate venous access and
be willing to undergo placement of a central venous catheter should leukapheresis via
peripheral access be inadequate.

14. Note that satisfactory mobilization of donor peripheral blood stem cells (PBSC) to
meet protocol criteria must take place prior to initiation of conditioning of the
patient.

15. Donors must be informed that they would be requested to undergo a second donation of
PBSC or a BM harvest should the patient fail to demonstrate sustained engraftment
after HSCT

16. Donors must meet all the medical criteria for blood product donation, including
negative test for HIV, freedom from other active infection, absence of medical
condition posing a health risk to donation of PBSC or function of the graft.

17. To provide a source of peripheral blood mononuclear cells to serve as allosensitizers
patients must EITHER: (a) have a parent disparate with the donor for the haplotype
shared by the patient and parent but not shared by the patient and donor; OR (b) be
able to donate sufficient autologous cells by peripheral blood draw or unstimulated
leukapheresis

18. Female patients of child-bearing age must have a negative pregnancy test and be using
an form of contraception considered effective and medically acceptable by the
investigator.

19. Voluntary written informed consent. Children will be asked for assent wherever age
appropriate.

Exclusion Criteria:

1. Active infection. Freedom from active infection is defined as: absence of an
infectious diagnosis or (in patients who have had a recent positive infectious
diagnosis) the resolution of fever, documentation of negative cultures or antigen
testing, continuation or completion of a course of appropriate therapy, and presence
of stable to resolving clinical symptoms.

2. Evidence of HIV infection or known HIV positive serology

3. Presence of active CNS disease

4. ALL patients who relapse with isolated extramedullary disease after completion of
treatment

5. Any prior stem cell transplant

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Feasibility of delayed infusion of ex vivo anergized donor PBMC after CD34 selected megadose HSCT

Outcome Time Frame:

Day 0 and Day +35 or 42+ (day of infusion of anergized cells)

Safety Issue:

Yes

Principal Investigator

Eva Guinan, M.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

2005-0695

NCT ID:

NCT00475384

Start Date:

June 2006

Completion Date:

Related Keywords:

  • Acute Myelogenous Leukemia
  • Acute Lymphocytic Leukemia
  • Myelodysplastic Syndrome
  • Leukemia
  • Acute Myelogenous Leukemia
  • Acute Lymphocytic Leukemia
  • Myelodysplastic Syndrome
  • Stem Cell Transplant
  • Haploidentical Donor
  • Leukemia
  • Fludarabine
  • Total Body Irradiation
  • Thiotepa
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Childrens Hospital Los AngelesLos Angeles, California  90027
Dana Farber Cancer InstituteBoston, Massachusetts  02115
UT MD Anderson Cancer CenterHouston, Texas  77030
University of Florida Shands HospitalGainesville, Florida  32610-0278