Expanded Access Protocol (EAP) Using the CliniMACS® Device for Pediatric Haplocompatible Donor Stem Cell Transplant



Status:Available
Conditions:Cancer, Osteoporosis, Blood Cancer, Infectious Disease, HIV / AIDS, Lymphoma, Orthopedic, Women's Studies, Anemia, Hematology
Therapuetic Areas:Hematology, Immunology / Infectious Diseases, Oncology, Rheumatology, Orthopedics / Podiatry, Reproductive
Healthy:No
Age Range:Any - 30
Updated:12/14/2018
Contact:Morton J. Cowan, MD
Email:mcowan@peds.ucsf.edu
Phone:415-476-2188

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An Expanded Access Study of the Feasibility of Using the CliniMACS® Device for CD34+ Cell Selection and T Cell Depletion for Graft-versus-Host Disease Prophylaxis in Alternative Donor Stem Cell Transplant Recipients

This protocol provides expanded access to bone marrow transplants for children who lack a
histocompatible (tissue matched) stem cell or bone marrow donor when an alternative donor
(unrelated donor or half-matched related donor) is available to donate. In this procedure,
some of the blood forming cells (the stem cells) are collected from the blood of a partially
human leukocyte antigen (HLA) matched (haploidentical) donor and are transplanted into the
patient (the recipient) after administration of a "conditioning regimen". A conditioning
regimen consists of chemotherapy and sometimes radiation to the entire body (total body
irradiation, or TBI), which is meant to destroy the cancer cells and suppress the recipient's
immune system to allow the transplanted cells to take (grow). A major problem after a
transplant from an alternative donor is increased risk of Graft-versus-Host Disease (GVHD),
which occurs when donor T cells (white blood cells that are involved with the body's immune
response) attack other tissues or organs like the skin, liver and intestines of the
transplant recipient. In this study, stem cells that are obtained from a partially-matched
donor will be highly purified using the investigational CliniMACS® stem cell selection device
in an effort to achieve specific T cell target values. The primary aim of the study is to
help improve overall survival with haploidentical stem cell transplant in a high risk patient
population by limiting the complication of GVHD.

Patients will be enrolled with alternative (mismatched/haplocompatible) related donors or
unrelated donors either for an initial transplant or as a rescue following rejection of a
previous graft or relapse following a previous transplant. For patients with mismatched
related donors, the majority of clinical experience has been with a T cell-depleted PBSC
product. Currently, no FDA-approved method for T cell depletion exists. Recent experience
with the CliniMACS® device has produced excellent results with a 70-75% survival in children,
many of whom were high risk patients.

Patients that receive transplants from unrelated donors usually receive stem cells that are
not T cell-depleted. However, this is associated with a high risk of GVHD. The excellent
results with mismatched related donor transplants justify expanding this approach to
unrelated donor transplant recipients if the HLA mismatch is sufficiently great. It is
anticipated that the use of the CliniMACS® device will result in a very low risk of GVHD
without the need for post-transplant immunosuppression. The outcomes in relatively small
studies for children receiving unrelated donor transplants using the CliniMACS® have been
comparable to or better than those receiving T replete transplants with post-transplant
immunosuppression.

This protocol will allow the use of patient-specific conditioning regimens. Some patients
have contraindications to certain components of the conditioning regimen used for our ongoing
study under BB-IND 8817 (CC# 01151). An example is a patient with pre-existing organ
dysfunction that would be better served by the use of a reduced intensity conditioning
regimen. Another example is a patient for whom total body irradiation is contraindicated due
to very young age or prior radiation therapy. Finally, patients who would be otherwise
eligible for the predecessor study but who do not have an eligible related donor or a closely
matched unrelated donor would be eligible for this study. The target CD3+ T cell dose that
will be given will be 3 x 10^4/kg. The UCSF 01151 protocol uses a dose of 3 x 10^4/kg. The T
cell dose in the graft is usually < 1 x 10^4/kg after processing and T cells are added to the
product.

Inclusion Criteria:

- >2 months - 30 years

- Patient must have a malignant or non-malignant disease that can benefit from
alternative stem cell transplantation according to standard practice guidelines for
including patients for transplant as outlined in UCSF Pediatric BMT Standard Operating
Procedure (SOP) #206.04. Examples include acute and chronic leukemias, myelodysplastic
syndrome, lymphoma, severe acquired and congenital cytopenias, white and red blood
cell abnormalities, inborn errors of metabolism and immunodeficiencies. Patient with
Fanconi's Anemia will be eligible regardless of match with donor.

- Patients with acute leukemia (AML excepted) or lymphoma must be in remission at the
time of transplant.

- Patients must lack a healthy human leukocyte antigen (HLA)-identical related donor.

- Recipient or authorized guardian must sign informed consent for this study.

- If recipient is female and of child-bearing age, negative pregnancy test.

- Patient must have a healthy, willing mismatched related or an unrelated donor who is:

- Able to receive G-CSF +/- Plerixafor and undergo apheresis either through
placement of catheters in antecubital veins or a temporary central venous
catheter,

- For Related donor: sibling, half-sibling, parent, cousin, aunt, uncle or
grandparent will all be considered eligible.

- For Related donor: HLA antigen genotypic match ≥ 4/8 and ≤ 7/8 (haplocompatible).

- For unrelated donor: 6/8 or 7/8 HLA antigen match (if two mismatches, they must
be at different loci).

- Complete medical history, physical and screening for infectious diseases that are
acceptable for donation.

- If donor is female and of child-bearing age, negative pregnancy test.

- Absence of anti-HLA antibodies in recipient directed against donor antigens.

- Donor must be willing to sign informed consent for this study. If donor is < 18
years of age, donor must be willing to give assent and parents willing to sign
informed consent.

- Be suitable for an autologous gene-modified transplant:

- Using either bone marrow or cytokine-mobilized peripheral blood stem cells
(PBSC).

- Patient or authorized guardian must sign informed consent for this study.

- For unrelated donors: Per New Algorithm, Jan. 14, 2016, effective immediately, NMDP/Be
The Match is adopting a revised algorithm for determining if a donor is a research
subject on their recipient's research protocol: The NMDP will inform the donor of the
activities and the use of donor's apheresis product to be used in this study and
obtain written consent from the donor. Transplant centers are sent documentation of
the donor consent to participate in the research support activities. (The revised
algorithm can be found on the "Be the Match Clinical Network")

- Criteria to consider when choosing among related haplo donors:

- CMV positive donor is preferred over other factors. CMV negative donor can be
used ONLY if recipient is CMV negative.

- HLA disparity i.e. 2 Ag mismatch preferred over 3 Ag mismatch; Drβ1 match
preferred over class I match; HLA-C matched preferred over A and B match.

- KIR mismatch in GVH direction is preferred for patients with malignant disorders

- ABO compatibility

- Age ≥ 2 months

Exclusion Criteria:

- Patient with an anticipated life expectancy of < 1 month

- Active infectious hepatitis or cytomegalovirus (CMV) disease (organ involvement)

- Human immunodeficiency virus (HIV) or Human T-lymphotropic virus (HTLV-I/II) infection

- Cardiac ejection fraction < 45%; can be lower if patient is not in clinical cardiac
failure and a reduced intensity conditioning regimen is used.

- Creatinine clearance <60 ml/min/1.72 m2; can be lower if a reduced intensity
conditioning regimen is used.

- Pulmonary diffusion capacity (corrected for hemoglobin), forced expiratory volume in
one second (FEV1), or forced vital capacity (FVC) <60% of predicted or oxygen
saturation (O2 sat) > 94% on room air if unable to perform pulmonary function tests
(PFTs); can be lower if a reduced intensity conditioning regimen is used.

- Serum alanine aminotransferase (ALT) > 5 x upper limit of normal (can be up to 10x
upper limit of normal if a reduced intensity conditioning regimen is used) or
bilirubin > 2.

- Performance score (Lansky/Karnofsky) < 50

- Any condition that compromises compliance with the procedures of this protocol, as
judged by the principal investigator.
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