Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults With Blood Cancers Undergoing Donor Stem Cell Transplant

Status:Not yet recruiting
Conditions:Other Indications, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Hematology
Therapuetic Areas:Hematology, Oncology, Other
Age Range:Any - 22
Start Date:May 1, 2019
End Date:December 31, 2020
Contact:Marie Bleakley

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Multi-Center Phase II Randomized Controlled Trial of Naïve T Cell Depletion for Prevention of Chronic Graft-Versus-Host Disease in Children and Young Adults

This phase II trial studies how well naive T-cell depletion works in preventing chronic
graft-versus-host disease in children and young adults with blood cancers undergoing donor
stem cell transplant. This study is comparing naïve T-cell depletion transplantation to the
traditional stem cell transplantation. In these transplants, chemotherapy and total-body
radiotherapy ('conditioning') are used to kill residual leukemia cells and the patient's
normal blood cells, especially immune cells that could reject the donor cells. Following the
chemo/radiotherapy, blood stem cells from the donor are infused. These stem cells will grow
and eventually replace the patient's original blood system, including red cells that carry
oxygen to our tissues, platelets that stop bleeding from damaged vessels, and multiple types
of immune-system white blood cells that fight infections. Mature donor immune cells,
especially a type of immune cell called T lymphocytes (or T cells) are transferred along with
these blood-forming stem cells. T cells are a major part of the curative power of
transplantation because they can attack leukemia cells that have survived the chemo/radiation
therapy and also help to fight infections after transplantation. However, donor T cells can
also attack a patient's healthy tissues in an often-dangerous condition known as
Graft-Versus-Host-Disease (GVHD). Drugs that suppress immune cells are used to decrease the
severity of GVHD; however, they are incompletely effective and prolonged immunosuppression
used to prevent and treat GVHD significantly increases the risk of serious infections.
Removing all donor T cells from the transplant graft can prevent GVHD, but doing so also
profoundly delays infection-fighting immune reconstitution and eliminates the possibility
that donor immune cells will kill residual leukemia cells. Work in animal models found that
depleting a type of T cell, called naïve T cells or T cells that have never responded to an
infection, can diminish GVHD while at least in part preserving some of the benefits of donor
T cells including resistance to infection and the ability to kill leukemia cells. This
clinical trial studies how well the selective removal of naïve T cells works in preventing
GVHD after peripheral blood stem cell transplants compared to the subjects that receive
unmanipulated bone marrow transplants.

Participants are randomized to 1 of 2 arms. All participants receive 1 of 3 conditioning

CONDITIONING REGIMEN A: Participants undergo total body irradiation (TBI) twice daily (BID)
on days -10 to -7, then receive thiotepa intravenously (IV) over 4 hours once daily (QD) on
days -6 and -5, and fludarabine IV over 30 minutes once daily on days -6 to -2.

CONDITIONING REGIMEN B: Participants undergo TBI BID on days -8 to -5, then receive
fludarabine IV over 30 minutes QD on days -4 to -2, and cyclophosphamide IV over 1 hour QD on
days -3 and -2.

CONDITIONING REGIMEN C: Participants receive fludarabine IV over 30 minutes QD on days -6 to
-2, busulfan IV over 180 minutes QD on days -5 to -2, and undergo total body irradiation BID
on day -1.

ARM I: Participants receive naive T-cell depleted PBSCs on day 0.

ARM II: Participants receive unmanipulated T cell-replete BM on day 0.

GVHD PROPHYLAXIS: All participants receive tacrolimus IV beginning on day -1 and methotrexate
IV on days 1, 3, 6, and 11.

After completion of study treatment, participants are followed up periodically.

Inclusion Criteria:

- The patient must have one of the following diagnoses and be considered to be an
appropriate candidate for allogeneic HCT by the study site Principal Investigator

- Acute lymphoblastic leukemia (ALL) with < 5% marrow blasts.

- Acute myeloid leukemia (AML) with < 25% marrow blasts.

- Other acute leukemia (OAL) including but not limited to acute biphenotypic
leukemia (ABL), ambiguous lineage (ALAL), mixed phenotype acute leukemia (MPAL),
blastic plasmacytoid dendritic cell neoplasm (BPDCN), and acute undifferentiated
leukemia (AUL) with < 5% marrow blasts.

- Myelodysplastic syndrome (MDS) with excess blasts (EB-1 and EB-2) and has
received cytotoxic induction chemotherapy (excluding small molecule inhibitors
and de-methylating agents).

- Matched related donor (MRD) or matched unrelated donor (MUD) (defined as 8/8 match for
human leukocyte antigen [HLA]-A, -B, -C, -DRB1).

- Planned product type for infusion is PBSC or BM (i.e. not cord blood):

- For feasibility phase, planned product type for infusion must be PBSC.

- For RCT, planned product type must be PBSC or BM.

- Karnofsky or Lansky score >= 60%.

- Left ventricular ejection fraction (LVEF) at rest >= 40%.

- Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin)
>= 60% predicted by pulmonary function tests (PFTs)

* Patients who are unable to perform PFTs (age < 6 years or considered developmentally
incapable of PFTs): oxygen saturation (by oximetry) must be >= 92% on room air.

- Total bilirubin =< 2 x upper limit of normal (ULN) (unless value[s] > 2 x ULN are
disease- or medication-related).

* If value(s) are > 2 x ULN and not disease- or medication related, patient must be
evaluated by a gastrointestinal (GI) physician. If GI physician considers protocol
treatment to be contraindicated for the patient, the patient will not be eligible for
the study.

- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2 x ULN (unless
value[s] > 2 x ULN are disease- or medication-related).

* If value(s) are > 2 x ULN and not disease- or medication related, patient must be
evaluated by a gastrointestinal (GI) physician. If GI physician considers protocol
treatment to be contraindicated for the patient, the patient will not be eligible for
the study.

- Serum creatinine (SCr) within normal range for age. If SCr is outside normal range for
age, creatinine clearance (CrCl) > 40 mL/min/1.73m^2 must be obtained (measured by
24-hour [hr] urine specimen or nuclear glomerular filtration rate [GFR]).

- Age (Years): Maximum SCr (mg/dL)

- =< 5: 0.8

- 6-10: 1

- 11-15: 1.2

- > 15: 1.5

- Recipient informed consent/assent/legal guardian permission documentation must be

- DONOR: May be related (MRD) or unrelated (MUD) to the subject.

- DONOR: Must be matched to the subject at 8/8 HLA alleles (HLA-A, -B, -C, and -DRB1)

- DONOR: Be >=18 years of age.

- DONOR: Must be available to donate in the United States of America (USA) (i.e.
excludes international donors).

- DONOR: Must agree to donate BM or PBSC (i.e. agree to donate whichever product type is
requested) (applicable only to the RCT phase of this study)).


- Must give informed consent according to applicable National Marrow Donor Program
(NMDP) donor regulatory requirements.

- Must meet eligibility criteria as defined by the NMDP or be ineligible with
statement of urgent medical need.

- Tests must be performed using Food and Drug Administration (FDA) licensed,
cleared, and approved test kits in a Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratory.


- Must give informed consent using the Related Donor Informed Consent to
Participate in a Research Study form

- Must be negative for human immunodeficiency virus (HIV)-1, HIV-2, human
T-lymphotropic virus (HTLV)-1, HTLV-2, hepatitis B, hepatitis

- (serological and/or nucleic acid testing (NAT) and/or other approved testing)

- Must meet institutional donor eligibility criteria, or be ineligible with
statement that the donor is a first or second degree relative

- Tests must be performed using FDA licensed, cleared, and approved test kits
in a CLIA-certified laboratory.

Exclusion Criteria:

- Active central nervous system (CNS) disease. A patient may have a history of CNS
disease; however, any CNS disease must be cleared by the end of the pre-conditioning
evaluation time frame. If CNS disease is identified on the first cerebrospinal fluid
(CSF) evaluation within 30 days of the start of the preparative regimen a repeat
lumbar puncture (LP) with CSF evaluation must be performed and show no evidence of
disease in order for the patient to be eligible for the protocol.

- Patients on other experimental protocols for the prevention of GVHD.

- Patient body weight:

- Matched related donor (MRD): > 100 kg are ineligible

- Matched unrelated donor (MUD): > 75 kg must be discussed with the protocol PI
prior to enrollment.

- HIV-positive.

- Uncontrolled infections must be evaluated by an infectious disease physician and
considered suitable to undergo HCT by the study site PI, infectious disease physician
and protocol PI. Upper respiratory tract infection (URI) does not constitute an
uncontrolled infection in this context.

- Life expectancy < 3 months from disease other than acute leukemia or myelodysplastic
syndrome (MDS).

- Significant medical condition that would make recipient unsuitable for HCT.

- Prior allogeneic or autologous HCT.

- Females who are pregnant or breastfeeding.

- Patients of child bearing age who are presumed to be fertile and are unwilling to use
an effective birth control method or refrain from sexual intercourse during study
treatment and for 12 months following HCT.

- Known hypersensitivity to tacrolimus, fludarabine, or methotrexate (MTX).
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