Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations

This study is currently recruiting participants.
Verified March 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:
NCT01861106
First received: May 21, 2013
Last updated: April 8, 2014
Last verified: March 2014
  Purpose

Background:

- GATA2 deficiency is a disease caused by mutations in the GATA2 gene. It can cause different types of leukemia and other diseases. Researchers want to see if a stem cell transplant can be used to treat this condition. A stem cell transplant will give stem cells from a matching donor (related or unrelated) to a recipient. It will allow the donor stem cells to produce healthy bone marrow and blood cells that will attack the recipient s cancer cells.

Objectives:

- To see if stem cell transplants are successful at treating GATA2 mutations and related conditions.

Eligibility:

  • Recipients who are between 10 and 70 years of age and have GATA2 deficiency.
  • Donors who are between 6 and 70 years of age and are matched with the recipients.

Design:

  • All participants will be screened with a physical exam and medical history. Blood samples will be collected. Recipients will have imaging studies and other tests.
  • Donor participants will provide stem cells for the treatment. Filgrastim injections will allow these cells to be collected from the blood. In some cases, bone marrow donations will be needed to provide more stem cells.
  • Recipients will have chemotherapy or radiation to prepare for the transplant. On the day of the transplant, they will receive the donated stem cells.
  • Recipients will stay in the hospital until their condition is stable after transplant.
  • Frequent blood tests and scans will be required for the first 6 months after the transplant, followed by less frequent visits over time.

Condition Intervention Phase
GATA2
Immunodeficiency
MDS
Drug: Fludarabine(Fludara, Berlex Laboratories)
Drug: Busulfan (Busulfex)
Drug: Cyclophosphamide(CTX, Cytoxan)
Procedure: Total Body Irradiation (TBI)
Drug: Equine Anti-Thymocyte Globulin
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: Allogeneic Hematopoietic Stem Cell Transplant for Patients With Mutations in GATA2 or the MonoMAC Syndrome

Resource links provided by NLM:


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

Primary Outcome Measures:
  • To determine whether allogeneic HSCT approach results in engraftment and restores normal hematopoiesis by day + 100 in patients with mutations GATA2. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To determine the safety [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Immune reconstitution [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • To determine the incidence of acute and chronic graft-versus-host disease [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Overall survival, and disease-free survival. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 30
Study Start Date: April 2013
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group A
10/10 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: 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)
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: 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)
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 minutes once daily on days -6 and -5 (weight based dosing) or 50 mg/kg IV infusion over 2 hours on day -6 (weight based dosing) or 50/kg IV once daily x 2 doses on days +3 and +4
Procedure: Total Body Irradiation (TBI)
200 cGy on Day -1
Active Comparator: Group D
Umbilical Cord Blood 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 minutes once daily on days -6 and -5 (weight based dosing) or 50 mg/kg IV infusion over 2 hours on day -6 (weight based dosing) or 50/kg IV once daily x 2 doses on days +3 and +4
Procedure: Total Body Irradiation (TBI)
200 cGy on Day -1
Drug: Equine Anti-Thymocyte Globulin
30mg/kg IV (in the vein) once daily x 3 days on Days -6, -5, -4 (3 doses total)

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   6 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • ELIGIBILITY CRITERIA:

INCLUSION CRITERIA- Recipient

  1. Patient age of 10-70 years.
  2. Mutation in the GATA2 gene, or evidence of loss of expression of one allele of GATA2, by cDNA analysis performed by a CLIA certified laboratory, or the clinical syndrome of MonoMAC
  3. Clinical history of at least one life-threatening infection and/or MDS with International Prognostic Scoring System (IPSS) category of Intermediate-1 or High.
  4. 10/10 or 9/10 HLA-matched related or unrelated donor, 4/6 (or greater) matched umbilical cord blood (UCB) unit(s) with a total dose of greater than or equal to 3.5 times 10(7) TNC/kg, or a haploidentical related donor.
  5. Patients may have evidence of MDS with one or more peripheral blood cytopenias and greater than 5% blasts but less than 10% blasts in the bone marrow in the absence of filgrastim.
  6. Left ventricular ejection fraction > 40%, preferably by 2-D echo obtained within 28 days of enrollment
  7. Creatinine: Adult patients: less than or equal to 2.0 mg/dl and creatinine clearance greater than or equal to 30 ml/min; Pediatric patients( < 18 years old) creatinine < 1.5 mg/dL and a creatinine clearance > 30 mL/min/1.73m(2).
  8. Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST less than or equal to 5 times upper limit of normal
  9. Adequate central venous access potential.
  10. Written informed consent/assent obtained from patient/parent or legal guardian.
  11. Disease status: Patients are to be referred in remission for evaluation. Should a patient have progressive disease, or a donor becomes not available 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. HIV infection.
  2. 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 or Lead Associate Investigator.
  3. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
  4. Active infection refractory to antimicrobial therapy.
  5. Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI).
  6. Pregnant or lactating.
  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. 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. 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, 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, 4/6 (or greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5 times 10(7) TNC/kg, or haploidentical related donor.

INCLUSION CRITERIA- Matched Related Donor

  1. Related donor matched at 9/10 or 10/10 HLA-A, B, C, DR, and DQ loci by high resolution typing.
  2. Ability to give informed consent
  3. Age 6-70 years
  4. No history of life-threatening opportunistic infection
  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.
  8. No mutation in GATA2, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is required to have no clinical evidence of MonoMAC .

INCLUSIN CRITERIA- Matched Unrelated Donor

  1. Unrelated donor matched at 10/10 or 9/10 HLA-A, B, C, DRB1, and DQB1 loci by high resolution typing.
  2. Matched unrelated donors for pediatric recipients must be 18 years of age or older.
  3. The evaluation of donors shall be in accordance with existing NMDP Standard Policies and Procedures. General donor inclusion criteria specified in the NMDP Standards (19th Edition, Section 12.4).

INCLUSION CRITERIA- Haploidentical Related Donor

  1. A haploidentical donor is a related 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 (allelelevel) 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 6 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 6-70 years
  3. No history of life-threatening opportunistic infection
  4. 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.
  5. Haploidentical donors will undergo marrow harvest with general anesthesia. Subjects will undergo anesthesia consultation prior to enrollment. CD34 plus fraction will be determined.
  6. No mutation in GATA2, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is required to have no clinical evidence of MonoMAC

EXCLUSION CRITERIA- Matched Related Donor

  1. Age less than6 years or greater than 70 years.
  2. History of psychiatric disorder which in the opinion of the PI may compromise compliance with transplant protocol, or does not allow for appropriate informed consent.
  3. History of other medical conditions that in the opinion of PI constitute a contraindication to donation.
  4. 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. Risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient.
  5. 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.
  6. Mutation in GATA2, or evidence of loss of expression of one allele of GATA2 by cDNA analysis performed by a CLIA certified laboratory, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is excluded if he or she has the clinical syndrome of MonoMAC.

EXCLUSION CRITERIA- Matched Unrelated Donor

a) Failure to qualify as an NMDP donor as described in Section 12.4.

EXCLUSION CRITERIA- Haploidentical Related Donor

  1. Age less than 6 years or greater than 70.
  2. 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
  3. History of other medical conditions that in the opinion of PI constitute a contraindication to donation.
  4. 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.
  5. 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.
  6. Mutation in GATA2, or evidence of loss of expression of one allele of GATA2 by Cdna analysis performed by a CLIA certified laboratory, or in the case where the mutation in GATA2 has not been identified, but the recipient has the clinical syndrome of MonoMAC, the donor is required to have no clinical history of MonoMAC

INCLUSION CRITERIA- Umbilical Cord Blood Unit-HLA Typing and Dose

  1. At least an HLA UCB 4/6 match (Class I-A, B by low resolution, and Class II-DR by high resolution) to recipient. The following algorithm will be applied to determine if patient will receive single or double umbilical cord graft:
  2. For Single UCB SCT:

    • If 6/6 match the unit must have > 3 x 10(7) nucleated cells /kg of recipient body weight.
    • If 5/6 match the unit must have > 4 x 10(7) nucleated cells /kg of recipient body weight.
    • If 4/6 match the unit must have > 5 x 10(7) nucleated cells/kg of recipient body weight.

    Recipient body weight will be determined as per standard guidelines.

  3. If no single UCB with the above characteristics is available, a double UCB will be considered. Units will be selected with the following criteria:

    • Both units will be at least 4/6 match (Class I-A, B by low resolution, Class II-DR by high resolution) to recipient, and should be at least a 4/6 match (Class I-A, B by low resolution, Class II-DR by high resolution) to each other.
    • At least one UCB will have a minimum cell dose of 2.0 times 10(7) TNC/kg of recipient body weight.
    • The minimum combined dose of both units must be at least 3.5 times 10(7) TNC/kg of recipient body weight.
    • The smaller of the two units (UCB2) will have a minimum of 1.5 times 10(7) TNC/kg of recipient body weight.
    • The TNC of non-RBC reduced units will be dose corrected by -25% to allow for cell loss while washing the unit.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01861106

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    888-624-1937      
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: NCT01861106     History of Changes
Other Study ID Numbers: 130132, 13-C-0132
Study First Received: May 21, 2013
Last Updated: April 8, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Allogeneic Donors
Peripheral Blood Stem Cell
Immunodeficiency
Myelodysplasia
Haploidentical

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Immune System Diseases
Antilymphocyte Serum
Busulfan
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antirheumatic Agents

ClinicalTrials.gov processed this record on April 22, 2014