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Pilot Study of Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant of DOCK8 Deficiency


Phase 1
10 Years
60 Years
Open (Enrolling)
Both
DOCK8 Deficiency

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Trial Information

Pilot Study of Matched Related and Unrelated Donor Hematopoietic Stem Cell Transplant of DOCK8 Deficiency


Background

Mutations in the dedicator of cytokinesis-8 (DOCK8) gene are responsible for a newly
described immunodeficiency disease characterized by a constellation of signs: severe
cutaneous and sinopulmonary infections with bacterial organisms; severe cutaneous viral
infections with Herpes simplex, Herpes zoster, Molluscum contagiosum, and Human Papilloma
Virus; a marked elevation in serum IgE levels and eosinophilia; and homozygous or compound
heterozygous mutations in the dedicator of cytokinesis 8 (DOCK8) gene. Patients with this
syndrome die from bacterial sepsis, squamous cell carcinomas, or hematological malignancies.
Hematopoietic stem cell transplantation (HSCT) represents a potentially life-saving
treatment for immunodeficiency diseases, such as DOCK8 deficiency. In this pilot study we
propose to evaluate the efficacy and safety of allogeneic HSCT for DOCK8 deficiency. We are
particularly interested in determining whether allogeneic HSCT reverses the lethal disease
phenotype in DOCK8 deficiency by reconstituting normal host defense. The development of
lethal squamous cell carcinomas and lymphomas arising from the immunodeficiency in DOCK8
deficiency supports therapeutic intervention before malignancy arises.

Objectives

- To determine whether allogeneic HSCT reconstitutes T-lymphocyte and B-lymphocyte cells
and myeloid cells with normal donor cells at Day +100 and reverses the clinical
phenotype of severe recurrent infections in patients with DOCK8 deficiency.

- To determine the safety of this allogeneic transplant regimen in DOCK8 deficiency by
assessing transplant related toxicity, the incidence of acute and chronic
graft-versus-host disease, immune reconstitution, overall survival, and disease-free
survival

Eligibility

Patients 10-60 years old with DOCK8 deficiency who have suffered two or more
life-threatening infections, or who have developed lymphoma or squamous cell carcinoma, and
have a 10/10 matched related donor, a 10/10 matched unrelated donor, or a 9/10 matched
unrelated donor (HLA -A, -B, -C, DRB1, and DQ by high resolution typing identified through
the National Marrow Donor Program), or a haploidentical donor

Design

DOCK8 deficiency patients with a 10/10 matched related or 10/10 matched unrelated donor will
receive a pre-transplant conditioning regimen consisting of fludarabine 40 mg/m2/day on days
-6, -5, -4, and -3, Busulfex 3.2 mg/kg IV every day for four days on -6, -5, -4, and -3, and
HT on day 0. Patients with DOCK8 deficiency and a 9/10 matched unrelated donor will receive
a pre transplant conditioning regimen consisting of fludarabine 40mg/m2/day on days -6, -5,
-4, and -3, and HSCT on day 0. Patients with a haploidentical donor will receive a reduced
intensity- conditioning regimen with cyclophosphamide 14.5 mg/kg on days -6 and -5,
fludarabine 30mg/m2 on days -6 to -2, and 200 cGy TBI on day -1. Donor bone marrow cells
will be infused on day 0. Post-transplant immunosuppression for graftversus- host-disease
(GVHD) prophylaxis will consist of methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 and
tacrolimus daily from day -3 until day +180. If there is no evidence of graftversus- host
disease and patients have achieved full donor chimerism, Tacrolimus will be tapered off
after day +180. Post- transplant immunosupression for graft-versus-host-disease prophylaxis
for recipents of haploidentical donors will consist of cyclophosphamide 50 mg/kg on days +3
and +4, along with sirolimus from day +5 to day 180, and tacrolimus from day +5 to day 180,
providing that there is no GVHD.

Inclusion Criteria


- INCLUSION CRITERIA:

Recipient:

1. Patient age of 10-60 years.

2. DOCK8 deficiency (documentation of DOCK 8 mutation acceptable from an outside
Laboratory) with the two criteria listed below:

1. Clinical history of two or more episodes of life-threatening or severely
disfiguring infection with opportunistic organisms, including severe recurrent
cutaneous and sinopulmonary infections with bacterial or fungal infection, or
viral infections with herpes simplex, herpes zoster, Molluscum contagiosum, or
human papilloma virus.

2. Homozygous or compound heterozygous mutations in the DOCK8 gene.

3. Available 10/10 HLA-matched related donor, 10/10 or 9/10 matched unrelated donor, or
a haploidentical donor.

4. Left ventricular ejection fraction > 50%, preferably by 2-D echo, or by MUGA, or
shortening fraction > 28% by ECHO, obtained within 28 days of enrollment.

5. Pulmonary Function Tests: Adult patients: Corrected DLCO diffusion capacity and FEV1
greater than or equal to 20% of expected value obtained within 28 days of enrollment.
Pediatric patients: DLCO corrected for hemoglobin and alveolar volume greater than or
equal to 20% of predicted.

6. Creatinine: Adult patients: less than or equal to 2.0 mg/dl and creatinine clearance
greater than or equal to 30 ml/min/1.73 m(2).

Pediatric patients (less than 18 years old): Creatinine less than or equal to 1.5 and
a creatinine clearance greater than or equal to 30 mL/min/1.73 m(2).

7. Serum total bilirubin < 2.5 mg/dl; serum ALT and AST less than or equal to 5 times
upper limit of normal.

8. Adequate central venous access potential.

9. Written informed consent/assent obtained from patient/parent or legal guardian.

10. Disease status: Patients are to be referred in remission for evaluation. Should a
patient have progressive disease or a donor not be available after enrollment, the
patient will be referred back to their primary hematologist-oncologist for treatment.
If this course of action is not in the best interest of the patient according to the
clinical judgment of the PI/LAI, then the patient may receive standard treatment for
the malignant disease under the current study. If under either of these settings, it
becomes apparent that the patient will not be able to proceed to transplant, then
he/she must come off study. Recipient-Subjects receiving a standard therapy will be
told about the therapy, associated risks, benefits alternatives of the proposed
therapy, and availability of receiving the same treatment elsewhere, outside of a
research protocol.

Matched Related Donor

1. Related donor matched at HLA-A, B, C, DR, and DQ loci by high resolution typing
(10/10 antigen/allele match) are acceptable donors.

2. Ability to give informed consent; for donors less than 18 years of age, he/she must
be the oldest eligible donor, their legal guardian must give informed consent, the
donor must give verbal assent, and he/she must be cleared by social work and mental
health specialist to participate.

3. Age 4-60 years, and weight of greater than or equal to 15 kilograms.

4. At least one normal DOCK8 allele by DNA sequencing by GeneDx.

5. Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

6. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
antibody negative.

7. A donor who is lactating must be willing and able to interrupt breast-feeding or
substitute formula feeding for her infant during the period of filgrastim
administration and for two days following the final dose.

Matched Unrelated Donor

1. Unrelated donor matched at 10/10 or 9/10 HLA-A, B, C, DR, and DQ loci by high
resolution typing.

2. The evaluation of donors shall be in accordance with existing NMDP Standard Policies
and Procedures. General donor inclusion criteria specified in the NMDP Standards

Inclusion Criteria- Haploidentical Related Donor

1. A haploidentical donor that shares one haplotype in common with the recipient such
that

HLA compatibility will be a minimum of 5 out of 10 HLA loci matched. The HLA loci to
be tested will be HLA A, B, Cw, DRB1, and DQB1. A minimum number of mismatches is
desirable; however if several options are available the selection of a donor will be
based on the loci where the mismatch occurs and the relative importance of its
potential immunological function. Donor-recipient pairs will initially be typed
molecularly to provide a low resolution typing (antigen-level) to aid in the
selection of the potential donor. Upon review of the familial inheritance pattern, a
qualified HLA staff member will review haplotype inheritance. High resolution
(allele-level) typing will be performed. Final selection of a donor will be in
consultation with NCI physicians and qualified HLA personnel. Haploidentical related
donors for pediatric recipients must be 15 years of age or older. If more than one
haploidentical related donor is available, we will evaluate each donor individually
according to overall health, ABO matching, CMV, etc. to select the donor

2. Age 15-60 years

3. No history of life-threatening opportunistic infection

4. Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

5. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
antibody negative. This is to prevent the possible transmission of these infections
to the recipient.

6. Haploidentical donors will undergo marrow harvest with general anesthesia. Subjects
will undergo anesthesia consultation, and meet criteria for eligibility/enrollment.
CD34+ fraction will be determined.

7. Subjects will also undergo the Donor Health History Screen to determine donor
eligibility using standard DTM criteria in the Dowling Apheresis Clinic by skilled
staff in the Blood Services Section for adult patients and age-appropriate
questioning when indicated for pediatric subjects.

8. Subjects will undergo follow-up history and physical examination within 1 week of
donation.

EXCLUSION CRITERIA:

Recipient

1. HIV infection.

2. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For
patients with a concomitant positive hepatitis B surface antigen, patients will
require a hepatology consultation. The risk-benefit profile of transplant and
hepatitis B will be discussed with the patient, and eligibility determined by the PI
and the protocol chairperson.

3. History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent.

4. Active infection that is not responding to antimicrobial therapy.

5. Active CNS involvement by malignancy (patients with known posititve CSF cytology or
parenchymal lesions visible by CT or MRI).

6. Pregnant or lactating. The effects on breast-milk are also unknown and may be harmful
to the infant; therefore, women should not breast feed during the interval from study
entry to one year post-transplant.

7. Sexually active individuals capable of becoming pregnant who are unable or unwilling
to use effective form(s) of contraception during the time enrolled on the study and
for 1 year post-transplant. Effective forms of contraception include one or more of
the following: intrauterine device (IUD), hormonal (birth control pills, injections,
or implants), tubal ligation/hysterectomy, partner's vasectomy, barrier methods,
(condom, diaphragm, or cervical cap), or abstinence. Males on the protocol must use
an effective form of contraception at study entry, and for one year posttransplant.
The effects of transplant, the radiation, and the medications used after transplant
may be harmful to a fetus.

8. Presence of active malignancy in another organ system other than the hematopoietic
system.

9. No available 10/10 HLA-matched related donor, 10/10 or 9/10 matched unrellated donor.

Matched Related Donor

1. History of severe cutaneous viral infections with herpes simplex, herpes zoster, or
molluscumm contagiosum.

2. Hyper IgE > 3 times the upper limit of normal.

3. HIV infection.

4. Chronic active hepatitis B. Donor may be hepatitis core antibody postitive.

5. History of psychiatric disorder which in the opinion of the PI may compromise
compliance with transplant protocol, or which does not allow for appropriate informed
consent.

6. History of hypertension that is not controlled by medication, stroke, or severe heart
disease. Individuals with symptomatic angina will be considered to have severe heart
disease and will not

be eligible to be a donor.

7. Other medical contraindications to stem cell donation

8. History of prior malignancy.

9. Donors must not be pregnant.

10. Thrombocytopenia (platelets less than 150,000 per microl) at baseline evaluation.

11. Donors receiving experimental therapy or investigational agents.

12. Sensitivity to filgrastim or to E. coli-derived recombinant protein products.

13. History of autoimmune disorders, including rheumatic diseases and thyroid disorders.

14. History of documented deep vein thrombosis or pulmonary embolism.

Matched Unrelated Donor

Failure to qualify as an NMDP donor

Exclusion Criteria

Haploidentical donor

1. Age less than 15 years.

2. HIV infection

3. Chronic active hepatitis B. Donor may be hepatitis core antibody positive.

4. History of psychiatric disorder which in the opinion of the PI may compromise
compliance with transplant protocol, or which does not allow for appropriate informed

5. History of hypertension that is not controlled by medication, stroke, or severe heart
disease.

Individuals with symptomatic angina will be considered to have severe heart disease
and will not be eligible to be a donor.

6. Other medical contraindications to stem cell donation (i.e. severe atherosclerosis,
autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular
accident) (Anderlini, Korbling et al. 1997).

7. History of prior malignancy. However, cancer survivors who have undergone potentially
curative therapy may be considered for stem cell donation on a case-by-case basis.
The risk/benefit of the transplant and the possibility of transmitting viable tumor
cells at the time of transplantation will be discussed with the patient.

8. Donors must not be pregnant. Pregnancy is an absolute contraindication under this
protocol.

The effects of cytokine administration on a fetus are unknown. Donors of childbearing
potential must use an effective method of contraception. Effective forms of
contraception include one or more of the following: intrauterine device (IUD),
hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy,
partner's vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or
abstinence.

9. Thrombocytopenia (platelets less than 150,000 per ?l) at baseline evaluation.

10. Donors receiving experimental therapy or investigational agents.

11. Sensitivity to filgrastim or to E. coli-derived recombinant protein products.

12. History of autoimmune disorders, with the exception of thyroid disorders

13. History of documented deep vein thrombosis or pulmonary embolism

14. Mutation on both alleles of the DOCK8 gene

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:

To determine whether reduced-intensity allogeneic (HSCT) reconstitutes T-lymphocyte, B-lymphocyte, and NK cell populations with normal donor cells and reverses the clinical phenotype of severe recurrent in patients with DOCK8.

Outcome Time Frame:

2 years

Safety Issue:

No

Principal Investigator

Dennis D Hickstein, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

100174

NCT ID:

NCT01176006

Start Date:

July 2010

Completion Date:

Related Keywords:

  • DOCK8 Deficiency
  • DOCKS
  • Molluscum
  • Transplant
  • Immunodeficiency

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892