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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT01176006

Collaborator

(none)

Enrollment

Location

Arms

158.9

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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 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.

Condition or Disease	Intervention/Treatment	Phase
DOCK8 Deficiency	Procedure: Reduced-intensity hematopoietic stem cell Drug: Fludarabine(Fludara, Berlex Laboratories) Drug: Cyclophosphamide(CTX, Cytoxan) Procedure: Total Body Irradiation (TBI) Drug: Busulfan (Busulfex) Procedure: Donor peripheral blood stem cell mobiliation and collection Procedure: Bone Marrow Harvest Procedure	Phase 2

Detailed Description

Background

Mutations in the Dedicator of Cytokinesis-8 (DOCK8) gene are responsible for an immunodeficiency disease characterized by: severe cutaneous and sinopulmonary infections with bacterial organisms; extensive cutaneous viral infections with Herpes simplex, Herpes zoster, Molluscum contagiosum, and Human Papilloma Virus; a marked elevation in serum IgE levels and eosinophilia; homozygous or compound heterozygous mutations in the dedicator of cytokinesis 8 (DOCK8) gene. Patients with DOCK8 deficiency die from severe infections, squamous cell carcinomas, or hematological malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially life-saving treatment for immunodeficiency diseases such as DOCK8 deficiency. In this study, we will evaluate the efficacy and safety of allogeneic HSCT for DOCK8 deficiency. We are particularly interested in determining whether allogeneic HSCT using different donor sources and conditioning regimens 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 overt malignancy arises.

Objective

To determine whether allogeneic HSCT reconstitutes T-lymphocyte and B-lymphocyte cells and myeloid cells with normal donor cells at one year post-transplant and reverses the clinical phenotype of severe recurrent infections in subjects with DOCK8 deficiency.

Eligibility

Subjects 5-35 years old with DOCK8 deficiency who have suffered one 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, a 9/10 matched related donor a 9/10 matched unrelated donor, or a haploidentical related donor.

Design

Subjects with a 10/10 matched related or unrelated donor will receive a pre-transplant conditioning regimen consisting of fludarabine 40 mg/m2/day on days -6, -5, -4, and -3, and busulfan IV (dose based on pharmacokinetic levels) every day for 4 days on days -6, -5, -4, and -3. Donor hematopoietic stem cells will be infused on day 0.

Subjects with a 9/10 matched related, 9/10 matched unrelated, or a haploidentical related donor will receive a pre-transplant conditioning regimen consisting of cyclophosphamide 14.5 mg/kg on days -6 and -5, fludarabine 30 mg/m2/day on days -6, -5, -4, -3 and -2, busulfan IV (dose based on pharmacokinetic levels) once daily for three days on -4, -3 and -2, and 200 cGy TBI on day -1. Donor hematopoietic stem cells will be infused on day 0. Post-transplant immunosuppression for graft-versus-host-disease (GVHD) prophylaxis for recipients of 9/10 matched related or unrelated donors will consist of cyclophosphamide 50 mg/kg IV once daily for two days on day s +3 and +4, along with mycophenolate mofetil from day +5 to day +35 and tacrolimus from day +5 to day 180. If there is no evidence of graft-versus-host disease, tacrolimus will be stopped at approximately day+180.

All subjects will receive post-transplant immunosuppression for graft-versus-host-disease (GVHD) prophylaxis for recipients of 10/10 matched related and unrelated donors will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to day +35 and tacrolimus from day +5 to approximately day 180. If there is no evidence of graft-versus-host disease, tacrolimus will be stopped at approximately day +180.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Related and Unrelated Donor Hematopoietic Stem Cell Transplant for DOCK8 Deficiency

Actual Study Start Date :

Oct 5, 2010

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group A 10/10 HLA Matched Related or Unrelated Donor Transplant	Procedure: Reduced-intensity hematopoietic stem cell stem cell transplant Drug: Fludarabine(Fludara, Berlex Laboratories) 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 Drug: Busulfan (Busulfex) 3.2 mg/kg IV (in the vein) over 2 hours once daily on Days -6, -5, -4 and -3 (weight based dosing) or on days -4, -3 and -2
Active Comparator: Group B 9/10 HLA Matched Related or Unrelated Donor Transplant	Procedure: Reduced-intensity hematopoietic stem cell stem cell transplant Drug: Fludarabine(Fludara, Berlex Laboratories) 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 Drug: Cyclophosphamide(CTX, Cytoxan) 14.5 mg/kg IV (in the vein) infusion over 30 min on days -6, and -5 Procedure: Total Body Irradiation (TBI) 200 cGy on Day -1 Drug: Busulfan (Busulfex) 3.2 mg/kg IV (in the vein) over 2 hours once daily on Days -6, -5, -4 and -3 (weight based dosing) or on days -4, -3 and -2
Other: Group C Donor	Procedure: Reduced-intensity hematopoietic stem cell stem cell transplant Procedure: Donor peripheral blood stem cell mobiliation and collection Donors undergo peripheral blood stem cell (PBSC) collection by apheresis will have their CD34 cells mobilized into the blood with filgrastim (Neupogen, Amgen) Procedure: Bone Marrow Harvest 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.
No Intervention: Group D Family Interview

Outcome Measures

Primary Outcome Measures

Feasibility [1 year post transplant]
Number of severe recurrent infections in patients with DOCK8 post transplant compared to number of severe recurrent infections in patients with DOCK8 pre transplant

Secondary Outcome Measures

Toxicity [180 days post transplant]
To determine whether post-transplant cyclophosphamide results in a lower incidence of grade III-IV acute and chronic GVHD compared to standard methotrexate and tacrolimus in 10/10 matched related and unrelated donor recipients.
Safety [Overall and disease free survival]
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 Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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:

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.