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

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ClinicalTrials.gov Identifier: NCT01176006
Recruitment Status : Recruiting
First Posted : August 5, 2010
Last Update Posted : August 9, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

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 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 40 years of age who have DOCK8 deficiency, have suffered one or more 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 a physical examination and medical history.
  • DONORS:

    • Donors will donate bone marrow cells or blood stem cells. If donating blood stem cells, donors will receive injections of filgrastim to release stem cells into the blood. After 5 days of filgrastim injections, donors will have apheresis to donate stem cells and white blood cells that are present in the blood.
    • Donors who provide the stem cells through bone marrow donation will have their bone marrow cells harvested in the operating room.
  • RECIPIENTS:

    • Recipients receiving 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 haploidentical related donors will receive two doses of chemotherapy with cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and one dose of radiation to suppress their immune system and prepare them for the transplant.
    • After the initial chemotherapy and radiation, recipients will receive the donated stem cells as a single infusion. Recipients may also receive white blood cells from their stem cell donor to encourage acceptance of the stem cells.
    • 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 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

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated 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 of DOCK8 Deficiency
Study Start Date : July 29, 2010
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Active Comparator: Group A
10/10 HLA Matched Related Donor 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 Donor 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

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.




Primary Outcome Measures :
  1. Feasability [ Time Frame: 1 year post transplant ]
    Number of severe recurrent infections in patients with DOCK8 post transplant compared to number of severe recurrent infections inpatients with DOCK8 pre transplant


Secondary Outcome Measures :
  1. Safety [ Time Frame: 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 graftversus- host disease, immune reconstitution, overall survival, and disease-free survival

  2. Toxicity [ Time Frame: 180 days post transplant ]
    To determine whether posttransplant cyclophosphamideresults in a lower incidence of gradeIII-IV acute and chronic GVHDcompared to standard methotrexateand tacrolimus in 10/10 matchedrelated and unrelated donor recipients.



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Ages Eligible for Study:   2 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA - RECIPIENT:
  • Patient age of 5-35 years.

Weight greater than 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, obtained within 28 days of enrollment. If the patient has radiological evidence of aortic, renal artery, or coronary artery vasculitis, a left ventricular ejection fraction >30% is acceptable.
  • Pulmonary Function Tests: FEV1 greater than or equal to 50% of expected value obtained within 28 days of enrollment.

    --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: Patients: 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 patients (<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.
  • Patients, parents/guardian(s), legally authorized representatives (LAR), or durable power of attorney must be able to give consent and sign the informed consent document. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those greater than 12 years of age, when appropriate.
  • Disease status: Patients with malignancy are to be referred in remission for evaluation, except in the case of viral associated malignancies. Should a patient have progressive disease or a donor becomes unavailable 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.

EXCLUSION CRITERIA - RECIPIENT:

  • HIV infection.
  • 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
  • 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 (patients 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 patient 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. CD34+ fraction will be determined.
  • 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 patients and age-appropriate questioning when indicated for pediatric subjects.

INCLUSION CRITERIA - 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 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
  2. Age 4-60 years and weight of greater than or equal to 15 kilograms.
  3. At least one normal DOCK8 allele demonstrated by a CLIA-certified lab in a sibling donor.
  4. No history of life-threatening opportunistic infections
  5. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis (if applicable).
  6. 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.
  7. 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.
  8. 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.
  9. Adult related donors would be preferred over related donors who are minors.
  10. 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 patient.
  • 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 patient.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01176006


Contacts
Contact: Nirali N Shah, M.D. (240) 760-6970 shahnn@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Nirali N Shah, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01176006     History of Changes
Other Study ID Numbers: 100174
10-C-0174
First Posted: August 5, 2010    Key Record Dates
Last Update Posted: August 9, 2018
Last Verified: June 4, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
DOCK8
Molluscum
Transplant
Immunodeficiency

Additional relevant MeSH terms:
Cyclophosphamide
Busulfan
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists