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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01176006
First received: August 4, 2010
Last updated: June 6, 2014
Last verified: April 2014
  Purpose

Background:

- DOCK8 deficiency is a genetic disorder that affects the immune system and can lead to severe recurrent infections and possible death from blood poisoning or certain types of cancers, including blood cancers. Stem cell transplants from matching or closely related donors (allogenic stem cell transplants) may be a life-saving treatment for this condition. However, stem cell transplants can have serious complications, because they tend to be performed with very high doses of chemotherapy and/or radiation. Reduced-intensity stem cell transplants use smaller doses of radiation and chemotherapy to weaken but not completely eliminate the recipient s stem cells and immunity. Researchers are exploring whether reduced-intensity stem cell transplants in people with DOCK8 deficiency may decrease the chance of graft rejection and the overall side effects of the transplant.

Objectives:

- To evaluate the safety and effectiveness of reduced-intensity allogeneic stem cell transplant as a treatment for DOCK8 deficiency.

Eligibility:

  • Donors: Healthy individuals between 4 and 60 years of age who are matched with a recipient.
  • Recipient: Individuals between 10 and 60 years of age who have DOCK8 deficiency, have suffered two or more life-threatening infections, have either low white blood cell levels or have had certain types of cancer (lymphoma or squamous cell carcinoma), and have a stem cell donor.

Design:

  • All participants will be screened with a physical examination and medical history.
  • DONORS:
  • 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 are not eligible to receive filgrastim will provide the stem cells through bone marrow donation.
  • RECIPIENTS:
  • From 7 days before the stem cell transplant, recipients will be admitted to the inpatient unit of the National Institutes of Health Clinical Center and will receive regular doses of cyclophosphamide, fludarabine, and radiation to suppress their immune system and prepare them for the transplant.
  • From 3 days before the stem cell transplant, recipients will receive the drugs tacrolimus and sirolimus to help prevent complications from 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 and white blood cell transplant, recipients will remain in inpatient care for up to 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 Intervention Phase
DOCK8 Deficiency
Drug: Fludarabine(Fludara, Berlex Laboratories)
Drug: Cyclophosphamide(CTX, Cytoxan)
Procedure: Total Body Irradiation (TBI)
Drug: Equine ATG
Drug: Busulfan (Busulfex)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Related and Unrelated Donor Hematopoietic Stem Cell Transplant of DOCK8 Deficiency

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine the safety [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • To determine the incidence of acute and chronic graft-versus-host disease [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Immune reconstitution [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Overall survival, and disease-free survival. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 30
Study Start Date: July 2010
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A
Fludarabine+ Busulfan
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.
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: Equine ATG
ATG: 30 mg/kg IV once daily x 3 days on days -6, -5, and -4
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 C
Haploidentical Related Donor 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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   4 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA RECIPIENT:

    1. Patient age of 8-40 years.
    2. DOCK8 deficiency 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 performed by a CLIA-certified laboratory
    3. Available 10/10 or 9/10 HLA-matched related or unrelated donor or a haploidentical related donor.
    4. Left ventricular ejection fraction > 40%, preferably by 2-D echo, obtained within 28 days of enrollment.
    5. Pulmonary Function Tests: FEV1 greater than or equal to 20% of expected value obtained within 28 days of enrollment.
    6. 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 > 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 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:

  1. Patient age less than 8 years old or greater than 40 years old
  2. HIV infection.
  3. 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
  4. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
  5. 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.
  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 time enrolled on study and for 1 year posttransplant.

    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.

  8. 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.
  9. No available 10/10 or 9/10 HLA-matched related or unrelated donor or haploidentical donor.

INCLUSIONCRITERIA 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. Alternatively, a 9/10 matched related donor.

  2. 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.
  3. Age 4-60 years, and weight of greater than or equal to 15 kilograms.
  4. At least one normal DOCK8 allele demonstrated by a CLIA-certified lab.
  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. This is to prevent the possible transmission of these infections to the recipient.
  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. Filgrastim may be secreted in human milk, although its bioavailability from this source is not known.

2.4 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

2.5 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 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.
  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.
  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. Subjects will undergo follow-up evaluation within 1 week of donation.
  10. Adult related donors will be preferred over related donors who are minors.

EXCLUSION CRITERIA-MATCHED RELATED DONOR

  1. Patient age less than 4 years old or greater than 60 years old.
  2. History of severe cutaneous viral infections with herpes simplex, herpes zoster, or molluscum

    contagiosum.

  3. HIV infection.
  4. Chronic active hepatitis B. Donor may be hepatitis core antibody positive.
  5. Other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident).
  6. 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.
  7. 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.
  8. Other medical conditions that in the opinion of the PI constitute exclusion as a donor.
  9. Mutation of DOCK8 on both alleles.

EXCLUSION CRITERIA-MATCHED UNRELATED DONOR

a)Failure to qualify as an NMDP donor.

EXCLUSION CRITERIA- HAPLOIDENTICAL RELATED DONOR

  1. Age less than 4 years old or greater than 60 years old.
  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. 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-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.
  6. 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.
  7. Mutation of DOCK8 on both alleles.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01176006

Contacts
Contact: Dennis D Hickstein, M.D. (301) 594-1718 hicksted@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
Investigators
Principal Investigator: Dennis D Hickstein, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01176006     History of Changes
Other Study ID Numbers: 100174, 10-C-0174
Study First Received: August 4, 2010
Last Updated: June 6, 2014
Health Authority: United States: Federal Government

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

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

ClinicalTrials.gov processed this record on August 21, 2014