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

• Status: Recruiting
• Trial end date: 2023-12-31
• Target enrollment: 0
• Participant gender: All

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 5 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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Busulfan; Cyclophosphamide; Fludarabine; Fludarabine phosphate

Criteria

• INCLUSION CRITERIA - RECIPIENT:

• Age of 5-35 years

• Weight greater than or equal to 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.

• Adequate central venous access potential.

• 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.

EXCLUSION CRITERIA - RECIPIENT:

• 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 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.

• 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. Males 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.

INCLUSION CRITERIA - MATCHED RELATED DONOR:

• Related donors matched at HLA-A, B, C, DR, and DQ loci by high resolution typing (10/10 antigen/allele match) are acceptable donors. Alternatively, a 9/10 matched related donor can be used.

• Ability to give informed consent; for donors <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 a mental health specialist to participate.

• Age 2-60 years, and weight of greater than or equal to 15 kilograms.

• At least one normal DOCK8 allele demonstrated by a CLIA-certified lab.

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

• 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.

• 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. Filgrastim may be secreted in human milk, although its bioavailability from this source is not known.

• Matched related donors that will undergo marrow harvest with general anesthesia. Subjects will undergo anesthesia consultation, and meet criteria for eligibility/enrollment.

• Matched related donors that will have their cells collected via apheresis 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 subjects and age-appropriate questioning when indicated for pediatric subjects. CD34+ fraction will be determined..

INCLUSION CRITERIA - MATCHED UNRELATED DONOR:

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

• 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:

• 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 are 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. 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

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

• At least one normal DOCK8 allele demonstrated by a CLIA-certified lab in a sibling donor.

• No history of life-threatening opportunistic infections

• Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis (if applicable).

• 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.

• 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.

• 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 subjects and age-appropriate questioning when indicated for pediatric subjects.

• Adult related donors would be preferred over related donors who are minors.

• Subjects will undergo follow-up evaluation within 1 week of donation.

EXCLUSION CRITERIA-MATCHED RELATED DONOR:

• History of severe cutaneous viral infections with herpes simplex, herpes zoster, or molluscum contagiosum.

• HIV infection

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

• Other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident).

• History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-bycase 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 subject.

• 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.

• Other medical conditions that in the opinion of the PI constitute exclusion as a donor.

• Mutation of DOCK8 on both alleles.

EXCLUSION CRITERIA - MATCHED UNRELATED DONOR:

a) Failure to qualify as an NMDP donor.

EXCLUSION CRITERIA - HAPLOIDENTICAL RELATED DONOR:

• HIV infection

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

• 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

• Other medical contraindications that in the opinion of the PI constitute exclusion as a donor. History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-bycase 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 subject.

• 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.

• Mutation of DOCK8 on both alleles in a sibling donor.

Inclusion Criteria for Family Interviews:

• Parent/caregiver of a subject(s) who received a transplant for DOCK8 deficiency on this study.

• Transplant recipient greater than or equal to 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