Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 Deficiency

NCT01176006 | Active Not Recruiting Phase 2

• 2 other identifiers: 10017410-C-0174
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• DOCK8 deficiency is a genetic disorder that affects the immune system and can lead to severe recurrent infections and possible death from infections or certain types of cancers, including blood cancers. A stem cell transplant is a life-saving treatment for this condition. In this study we are evaluating the efficacy and safety of transplant from different donor sources for DOCK8 deficiency. The donors that we are using are matched siblings, matched unrelated donors, and half-matched donors, so called haploidentical related donors, such as mothers or fathers or half-matched siblings. Objectives:
• To determine whether transplant of bone marrow cells from different types of donors corrects DOCK8 deficiency. Eligibility:
• Donors: Healthy individuals between 2 and 60 years of age who are matched with a recipient.
• Recipient: Individuals between 4 and 35 years of age who have confirmed DOCK8 deficiency, have suffered at least one life-threatening infections, or have had certain viral related cancers of cancer and have a stem cell donor. Design:
• All participants will be screened with bloodwork, a physical examination and medical history.
• DONORS:
• -Donors who have donate bone marrow cells or blood stem cells will have a sample of blood/bone marrow stored to be compared with the recipients sample after transplant.
• RECIPIENTS:
• Recipients receiving 10/10 matched related or unrelated donors will receive 4 days of chemotherapy with busulfan and fludarabine to suppress their immune system and prepare them for the transplant. Donors receiving 9/10 matched related or unrelated donors as well as haploidentical related donors will receive 5 days chemotherapy with cyclophosphamide, fludarabine, and busulfan. They will also receive one dose of radiation to suppress their immune system and prepare them for the transplant.
• After the initial chemotherapy and radiation (if indicated), recipients will receive the donated stem cells as a single infusion.
• After the stem cell transplant, recipients will receive two days of a chemotherapy called cyclophosphamide on day's + 3 and + 4 followed by two drugs tacrolimus and mycophenolate to prevent graft versus host disease where the donor cells attack the patient's body. All patients will remain in the hospital for at least approximately 1 month, and will be followed with regular visits for up to 3 years with periodic visits thereafter to evaluate the success of the transplant and any side effects....

Conditions

DOCK8 Deficiency

Keywords

DOCK8; Molluscum; Transplant; Immunodeficiency

Outcome Measures

Primary Outcomes (1)

• Feasibility

  Number of severe recurrent infections in patients with DOCK8 post transplant compared to number of severe recurrent infections in patients with DOCK8 pre transplant

  1 year post transplant

Secondary Outcomes (2)

• Toxicity

  180 days post transplant

• Safety

  Overall and disease free survival

Study Arms (5)

Group A

ACTIVE COMPARATOR

10/10 HLA Matched Related or Unrelated Donor Transplant

Drug: Fludarabine(Fludara, Berlex Laboratories)

Group B

ACTIVE COMPARATOR

9/10 HLA Matched Related or Unrelated Donor Transplant

Procedure: Reduced-intensity hematopoietic stem cell; Drug: Fludarabine(Fludara, Berlex Laboratories); Drug: Cyclophosphamide(CTX, Cytoxan); Procedure: Total Body Irradiation (TBI); Drug: Busulfan (Busulfex)

Group C

OTHER

Donor (closed)

Procedure: Reduced-intensity hematopoietic stem cell; Procedure: Donor peripheral blood stem cell mobiliation and collection; Procedure: Bone Marrow Harvest Procedure

Group D

OTHER

Family Interview (closed)Participation in research interview

Procedure: Reduced-intensity hematopoietic stem cell

Group E

NO INTERVENTION

Patient and caregiver psychosocial and QOL assessments during HSCTParticipation in interview and questionnaires

Interventions

Bone Marrow Harvest Procedure PROCEDURE

Bone marrow from haploidentical related donors, and, in some cases, matched related donors will be harvested under routine conditions in the operating room. General or spinal anesthesia will be employed.

Group C

Reduced-intensity hematopoietic stem cell PROCEDURE

stem cell transplant

Group B; Group C; Group D

Fludarabine(Fludara, Berlex Laboratories) DRUG

40 mg/m2 IV (in the vein) over 30 minutes (in the vein) once daily on Days -6, -5, -4, and -3 or 30 mg/m2 IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2

Group A; Group B

Cyclophosphamide(CTX, Cytoxan) DRUG

14.5 mg/kg IV (in the vein) infusion over 30 min on days -6, and -5

Group B

Total Body Irradiation (TBI) PROCEDURE

200 cGy on Day -1

Group B

Busulfan (Busulfex) DRUG

3.2 mg/kg IV (in the vein) over 3 hours once daily on Days -6, -5, -4 and -3 (weight based dosing) or on days -4, -3 and -2

Group B

Donor peripheral blood stem cell mobiliation and collection PROCEDURE

Donors undergo peripheral blood stem cell (PBSC) collection by apheresis will have their CD34 cells mobilized into the blood with filgrastim (Neupogen, Amgen)

Group C

Eligibility Criteria

• Age: 4 Years - 120 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of 4-35 years
• Weight \>= 12 kilograms
• DOCK8 deficiency with the two criteria listed below:
• Clinical history of one 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.
• Homozygous or compound heterozygous mutations in the DOCK8 gene performed by a CLIA-certified laboratory
• Available 10/10 or 9/10 HLA-matched related or unrelated donor or a haploidentical related donor
• Left ventricular ejection fraction \> 40%, preferably by 2-D echo. If the subject has radiological evidence of aortic, renal artery, or coronary artery vasculitis, a left ventricular ejection fraction \>30% is acceptable.
• Pulmonary Function Tests: FEV1 \> 50% of expected
• Note: For children who are unable to cooperate for PFTs, the criterion is: No evidence of dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen therapy
• Creatinine: Subjects: less than or equal to 2.0 mg/dl or creatinine clearance greater than or equal to 30 ml/min/1.73 m\^2. Pediatric subjects (\<18 years old): Creatinine less than or equal to 1.5 mg/dl or a creatinine clearance of greater than or equal to 30 mL/min/1.73 m\^2.
• Serum total bilirubin \< 2.5 mg/dl; serum ALT and AST less than or equal to 5 times upper limit of normal.
• Subjects, parents/guardian(s), legally authorized representatives (LAR), or durable power of attorney must be able to give consent and sign the informed consent document
• Disease status: Subjects with malignancy are to be referred in remission for evaluation, except in the case of viral associated malignancies. Should a subject have progressive disease or a donor becomes unavailable after enrollment, the subject will be referred back to their primary hematologist-oncologist for treatment. If this course of action is not in the best interest of the subject according to the clinical judgment of the PI/LAI, then the subject may receive standard treatment for the malignant disease under the current study. If under either of these settings, it becomes apparent that the subject 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.

You may not qualify if:

• HIV infection.
• Chronic active hepatitis B. Subject may be hepatitis B core antibody positive. For subjects with a concomitant positive hepatitis B surface antigen, the risk-benefit profile of transplant and hepatitis B will be discussed with the subject, and eligibility determined by the PI and the protocol chairperson
• History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
• Active CNS involvement by malignancy (subjects with known positive CSF cytology or parenchymal lesions visible by CT or MRI). Except in the case of viral associated malignancies in which case the subject may benefit from the transplant to control the malignancy.
• Pregnant or lactating. The effects on human milk are also unknown and may be harmful to the infant; therefore, individuals who are nursing or plan to nurse a child must agree to discontinue/postpone nursing during the interval from study entry to one year post-transplant.
• Sexually active individuals capable of becoming pregnant who are unable or unwilling to use effective form(s) of contraception during time enrolled on 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. Individuals who can father children on the protocol must use an effective form of contraception at study entry, and for one year post-transplant. The effects of transplant, the radiation, and the medications used after transplant may be harmful to a fetus.
• Presence of active malignancy in another organ system other than the hematopoietic system, except when driven by viruses in which case the immune reconstitution after transplant may control the malignancy.
• No available 10/10 or 9/10 HLA-matched related or unrelated donor or haploidentical related donor.
• DONOR EVALUATION AND SELECTION CRITERIA:
• All donors will undergo suitability and eligibility determination according with current regulations of the field of hematopoietic cell transplantation. Related donor-recipient pairs will initially undergo low-resolution typing (antigen-level) to aid in the selection of a potential family donor and targeted sequencing of the DOCK8 gene. Heterozygous carriers of a DOCK8 mutation are suitable to donate. Upon review of the familial HLA inheritance pattern, confirmatory and high-resolution (allele-level) typing will be performed on potential fully matched and haploidentical related donors, respectively. Final selection of a related donor will be in consultation with qualified HLA personnel. Secondary donor characteristics as potential predictors of survival have been studied in large populations of donor/recipient pairs from US and European registries. Younger donor age and CMV seropositivity have been associated with improved survival. For the purposes of this study, overall donor health, younger age (\<35 years), CMV seropositivity and ABO matching will also impact selection when multiple donors related or unrelated of equal HLA matching degree are available.
• Parent/caregiver of a subject(s) who received a transplant for DOCK8 deficiency on this study.
• Transplant recipient \>= 18 who has undergone a transplant for DOCK8 deficiency on this study.
• Note: If a transplant recipient has completed follow-up or has come off study for any reason, re-enrollment will be permitted to complete the interview.
• Must be able to give consent and sign the informed consent document.
• Able to understand the English language

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Freeman AF, Yazigi N, Shah NN, Kleiner DE, Parta M, Atkinson P, Heller T, Holland SM, Kaufman SS, Khan KM, Hickstein DD. Tandem Orthotopic Living Donor Liver Transplantation Followed by Same Donor Haploidentical Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency. Transplantation. 2019 Oct;103(10):2144-2149. doi: 10.1097/TP.0000000000002649.

  PMID: 30720689 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Job Syndrome; Immunologic Deficiency Syndromes

Interventions

Cyclophosphamide; Whole-Body Irradiation; Busulfan

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Corina E Gonzalez, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2010
• First Posted: August 5, 2010
• Study Start: October 5, 2010
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 31, 2028
• Last Updated: May 1, 2026

Record last verified: 2026-04-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)