Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System



Status:Active, not recruiting
Conditions:Cancer, Other Indications, Blood Cancer, Lymphoma, Hematology
Therapuetic Areas:Hematology, Oncology, Other
Healthy:No
Age Range:18 - 74
Updated:6/9/2018
Start Date:October 30, 2007
End Date:December 2018

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Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders

Background:

Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of
suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling
and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing
chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the
patients immune system attacks the transplanted donor cells.

This study will try to improve the results of SCT from unrelated HLA-matched donors using
targeted immune-depleting chemotherapy to bring the cancer under control before
transplantation and to lower the chance of graft rejection, followed by reduced-intensity
transplant chemotherapy to make the procedure less toxic.

Objectives:

To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed
by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood
and immune system.

To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD.
Both regimens have been successful in preventing GVHD, but they work by different mechanisms
and affect the rebuilding of the immune system after the transplant.

Eligibility:

People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune
system who do not have a suitable HLA-matched sibling.

Design:

All patients receive chemotherapy before transplant to treat the cancer and suppress immune
function.

All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine
for 4 days before SCT to prepare for the transplant.

Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as
follows:

- Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus
methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the
SCT and continues for 6 months following SCT.

- Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1
day before SCT and continuing for 6 months.

Patients receive the donors stem cells and immune cells 2 days after completing the
conditioning regimen.

Patients are followed at the clinic regularly for the first 6 months after SCT, and then less
often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood
draws, and other tests to monitor disease status.

A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

Background:

- The major limitations to the broader applicability of allogeneic hematopoietic stem cell
transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and
therapy-related toxicities which include delayed and incomplete immune reconstitution
and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment
of donor chimerism was essential for an optimal graft-versus-tumor effect, we have
employed a strategy of targeted immune depleting chemotherapy prior to reduced-intensity
allogeneic HSCT. It is our intent to investigate this approach in the setting of human
leukocyte-antigen (HLA)-matched unrelated donors in a pilot manner.

- A clearly superior GVHD prophylaxis regimen has not been established in the unrelated
donor transplant setting. The best results that have been reported are with the
combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus,
methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are
biologically distinct and potentially have markedly different effects upon immune
reconstitution that have not been well studied. In addition, neither of these regimens
has been assessed for their effects on chronic GVHD using the National Institutes of
Health (NIH) Consensus Conference Criteria. It is our intent to study the effects that
these two regimens have on immune reconstitution and chronic GVHD in the setting
sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT
from HLA-matched unrelated donors.

Objectives:

- Primary objectives:

1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS
and AC, on immune reconstitution in patients receiving targeted-immune depletion
and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of
a comprehensive assessment of immune reconstitution, the primary immunologic
endpoint will be the determination of cluster of differentiation 4 (CD4)+ T cell
receptor V BETA repertoire by complementarity determining region 3 (CDR3)
spectratyping at 3 months post-transplant.

2. to assess overall safety of these two regimens in this setting, as determined by
engraftment, acute GVHD, early and late treatment-related mortality, and overall
survival.

3. to determine and monitor incidence, organ severity and overall severity of chronic
GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and
staging criteria and preliminarily validate those tools for use in clinical
practice and trials.

- Secondary objectives include further assessment of immune reconstitution, study of
engraftment kinetics, and assessment of those patients who receive higher doses of
anthracyclines for long and short term toxicities

Eligibility:

- Adults (18-74 years) with advanced or high risk hematologic malignancies including acute
myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome
(MDS), chronic lymphocytic leukemia (CLL), non-hodgkin lymphoma (NHL), hodgkin lymphoma
(HL), chronic myelogenous leukemia (CML), multiple myeloma, and myeloproliferative
disorder (MPD) who lack a suitable HLA matched sibling.

- An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by
high resolution typing, identified through the National Marrow Donor Program.

- Life expectancy of at least 3 months, Eastern Cooperative Oncology Group (ECOG) less
than or equal to 2 and relatively normal major organ functions.

Design:

- Patients will receive disease-specific induction chemotherapy (etoposide, prednisone,
vincristine, cyclophosphamide and doxorubicin (EPOCH-fludarabine (F)/rituximab (R) or
fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)) prior to
transplant for disease control and immune depletion. If disease is controlled (greater
than partial response (PR)) and immune depletion objectives have been met, patients may
forgo induction chemotherapy and move forward to the transplant conditioning regimen.

- All patients will receive an identical conditioning regimen consisting of
cyclophosphamide 1200 mg/m(2)/day intravenous (IV) for 4 days and fludarabine 30
mg/m(2)/day for 4 days.

- Patients will be stratified according to degree of HLA-match and randomized at the time
of enrollment to one of two GHVD prophylaxis regimens:

- Group 1: Tacrolimus starting 3 days before stem cell transplant (SCT), and
continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus
sirolimus starting 3 days before the SCT and continues for 6 months following SCT.

- Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine
starting 1 day before SCT and continuing for 6 months.

- A maximum of 105 patients will be enrolled and randomly assigned to the two arms in
order to yield 44 patients per arm (88 total patients) who are able to be evaluated for
development of severe chronic GVHD.

- ELIGIBILITY CRITERIA RECIPIENT ON STANDARD CARE THERAPY:

- The patient is 18-74 years of age.

- The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74
years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National
Marrow Registry or Other Available Registry if they are between the ages of 18-74.

- The patient currently does not meet the protocol s eligibility/enrollment criteria for
any reason.

- There is a high likelihood that the patient, in the opinion of the principal
investigator (PI) or lead associate investigator (LAI), will meet the protocols
eligibility/enrollment criteria to proceed to transplant after standard therapy is
completed.

- The patient or legal guardian is able to give informed consent.

EXCLUSION CRITERIA RECIPIENT ON STANDARD CARE THERAPY:

- Human immunodeficiency virus (HIV) infection. There is theoretical concern that the
degree of immune suppression associated with the treatment may result in progression
of HIV infection.

- Pregnant or lactating. Patients of childbearing potential must use an effective method
of contraception. The effects of the chemotherapy, the subsequent transplant and the
medications used after the transplant are highly likely to be harmful to a fetus. The
effects upon breast milk are also unknown and may be harmful to the infant.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
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mi
from
Bethesda, MD
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