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High Dose Peripheral Blood Stem Cell Transplantation With Post Transplant Cyclophosphamide for Patients With Chronic Granulomatous Disease

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ClinicalTrials.gov Identifier: NCT02629120
Recruitment Status : Suspended
First Posted : December 14, 2015
Last Update Posted : September 27, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:
Chronic granulomatous disease (CGD) affects white blood cell function. Currently, the only curative treatment is bone marrow transplant to replace the abnormal stem cells with new ones (donor cells) capable of making a normal immune system. Transplant problems include graft versus host disease (GvHD) and graft rejection. With GvHD, donor cells attack the recipient s normal tissue. Researchers want to use preparation drugs and a high cell dose to increase graft success. They want to use 2 immunosuppressive drugs (cyclophosphamide and sirolimus) to lessen the risk of GvHD.

Condition or disease Intervention/treatment Phase
X-Linked Chronic Granulomatious Disease Drug: Campath Drug: Busulfan Other: allogeneic peripheral blood allograft infusion Drug: cyclophosphamide Early Phase 1

Detailed Description:

Chronic Granulomatous Disease (CGD) is an inherited disorder resulting from a failure to produce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, necessary for protection against a number of infectious organisms. Patients are subject to recurrent infections and inflammatory complications. The current management of these participants is limited to close surveillance for infections, administration of prophylactic antimicrobials, and rapid and aggressive treatment of suspected and documented infections with broad-spectrum antibiotics. Although often effective, these treatments can require long hospitalizations, impacting on the overall quality of life significantly, and lead to significant morbidity, such as renal failure and deafness.

Currently, the only available cure for these disorders is bone marrow transplantation, which most commonly uses a human leukocyte antigen (HLA)-matched related sibling as the donor (allogeneic stem sell transplantation). However, as only 30% of participants in the general population have an HLA- matched related sibling, allogeneic related transplantation is often not an option, resulting in the need for matched unrelated donor (MUD) transplantation. The National Marrow Donor Program (NMDP) serves as both a national registry of volunteers who are willing to donate progenitor cells to eligible recipients as well as a repository of cord blood products. Despite continued improvement in the use of transplantation schemas including the development of nonmyeloablative regimens there remain significant morbidity and mortality associated with transplantation, in particular, graft versus host disease (GvHD) and graft rejection.

GvHD is a result of the graft recognizing host antigens as foreign, typically in the presence of inflammation, and results in a type of iatrogenic autoimmune disease. For participants with non-malignant diseases, the aim of the transplant is solely to replace the defective or deficient cell population. Furthermore, as a graft versus tumor effect is not required, regimens designed to establish tolerance induction and/or stable mixed chimerism may be preferable for cure in this participant population; therefore, alternate transplant strategies can and should be used to further suppress the development of any GvHD effects.

In a prior protocol we observed low rates of GvHD, using a nonmyeloablative conditioning regimen but had significant rates of graft failure and/or loss. To improve upon our results we therefore propose to increase the target cell dose to be infused and use post transplant cyclophosphamide to mitigate the increased risk of GvHD.

For the patients with an HLA matched sibling donor (Group 1-Sibling Related) we propose using a busulfan-based, nonmyeloablative conditioning regimen combined with Alemtuzumab (Campath-1H, Campath ) an immunosuppressive monoclonal antibody currently approved by the U.S. Food and Drug Administration (FDA) as a single treatment for patients with B-cell chronic lymphocytic leukemia; however, for this protocol we are using it for its mechanism of action as an immunosuppressive agent. For GvHD prophylaxis we will use post-transplant cyclophosphamide (Cytoxan ) and sirolimus (Rapamune ).

For patients with only a MUD (Group 2-MUD) we will use a similar conditioning regimen, with a few modifications including the addition of total body irradiation (TBI) due to the increased risk of graft rejection with HLA-matched but unrelated cells, along with the posttransplant cyclophosphamide. We will compare the results obtained here to our previous clinical trial which did not use post transplant Cytoxan and where the cell dose infused was lower than the targeted dose of 12 million in this study, but did use the same conditioning regimen.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High Dose Peripheral Blood Stem Cell Transplantation With Post Transplant Cyclophosphamide for Patients With Chronic Granulomatous Disease
Study Start Date : December 10, 2015
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2030


Arm Intervention/treatment
MUD
Patient with Matched Unrelated Donor cells
Drug: Campath
a humanized monoclonal antibody directed against CD52 (which is abundantly expressed on all human lymphocytes), and causes T cell activation in vitro as well as complementmediated lysis and antibodydependent cellular toxicity. for this study, being used as part of the conditioning regimen. Given IV (dose escalation) over 5 days per package insert and and standard of practice

Drug: Busulfan
an alkylating chemotherapeutic agent determined to have broad myelosuppressive effects. On this study is being used as part of the conditioning regimen for its myelosuppressive properties. Given IV over 2 or 3 days depending on donor cells (sibling vs. unrelated donors) per package insert and standard of practice

Other: allogeneic peripheral blood allograft infusion
Prepared per the standard of operating procedure established in Department of Transfusion Medicaine and infuse

Drug: cyclophosphamide
Cyclophosphamide is an antineoplastic and for this study being used for its immunosuppresive mechanism of action. Patient will be given Cyclophosphamide 50 mg/kg/d IV per package insert and standand of care on Day +3 and 4 after receiving the cells

Allo
Patient with Sibling Donor Cells
Drug: Campath
a humanized monoclonal antibody directed against CD52 (which is abundantly expressed on all human lymphocytes), and causes T cell activation in vitro as well as complementmediated lysis and antibodydependent cellular toxicity. for this study, being used as part of the conditioning regimen. Given IV (dose escalation) over 5 days per package insert and and standard of practice

Drug: Busulfan
an alkylating chemotherapeutic agent determined to have broad myelosuppressive effects. On this study is being used as part of the conditioning regimen for its myelosuppressive properties. Given IV over 2 or 3 days depending on donor cells (sibling vs. unrelated donors) per package insert and standard of practice

Other: allogeneic peripheral blood allograft infusion
Prepared per the standard of operating procedure established in Department of Transfusion Medicaine and infuse

Drug: cyclophosphamide
Cyclophosphamide is an antineoplastic and for this study being used for its immunosuppresive mechanism of action. Patient will be given Cyclophosphamide 50 mg/kg/d IV per package insert and standand of care on Day +3 and 4 after receiving the cells




Primary Outcome Measures :
  1. Reduced incidence of graft failure or rejection (Engraftment as defined by >20% engraftment by oxidase positive neutrophils in at least 95% of participants by Day 100) [ Time Frame: Day 100 s/p BMT ]

Secondary Outcome Measures :
  1. Same or reduced rate of acute Graft versus Host Disease of <20% in subjects who will be receiving a high stem cell dose in combination with post cyclophosphamide. [ Time Frame: 5 years s/p BMT ]
  2. Establish stable mixed chimerism. [ Time Frame: 5 years s/p BMT ]
  3. Improve rapidity of immune reconstitution. [ Time Frame: 5 years s/p BMT ]


Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Must have confirmed Chronic Granulomatous Disease.
  • Must have sufficient complications from underlying disease to warrant undergoing transplantation or have a Quartile 1 and/or 2 residual oxidase production level.
  • Ages 4 years 65 years
  • HLA-matched family donor graft or an HLA matched unrelated PBSC graft (10/10 or 9/10 mismatch) available
  • Must be HIV negative
  • Must be able to stay within one hour s travel of the NIH for the first 3 months after transplantation and have a family member or other designated companion to stay with during the post transplant period.
  • Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance to NIH -200 NIH Durable Power of Attorney for Health Care Decision Making .
  • If of child-bearing potential, must agree to consistently use contraception from one month prior to, and throughout, study participation, and for 3 months post-study. Acceptable forms of contraception are:

    • Contraceptive pills or patch, Norplant , Depo-Provera , or other FDA-approved contraceptive method
    • Male partner has previously undergone a vasectomy.
    • Male participants will be advised to consistently use contraception throughout study participation and for 3 months post-transplant.

EXCLUSION CRITERIA:

  • Eastern Cooperative Oncology Group (ECOG) or equivalent performance status greater than or equal to 3 (See Supportive Care guidelines, available at http://intranet.cc.nih.gov/bmt/clinicalcare)
  • Left ventricular ejection fraction < 40%
  • Transaminases > 5x upper limit of normal based on the participant s clinical situation and at the discretion of the investigator
  • Psychiatric disorder or mental deficiency severe enough as to make compliance with the HSCT treatment unlikely, and/or making regulatorily and legally effective informed consent impossible
  • Major anticipated illness or organ failure incompatible with survival from AlloPBSC transplant
  • Pregnant or lactating
  • HIV positive
  • Uncontrolled seizure disorder
  • Participants older than 65 are excluded. It is known from standard transplantation that these participants have a higher risk of morbidity and mortality related to transplantation. Given the investigational nature of this protocol, the risk benefit ratio is not warranted to include these participants at this time.
  • Any condition or circumstance which the PI feels would create difficulty in maintaining compliance with the requirements of this protocol.
  • Participants who are not willing to submit their information as part of the Alemtuzumab (Campath ) Distribution Program application or participants whom the Distribution Program committee has determined are not qualified to receive alemtuzumab

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): NCT02629120


Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Elizabeth M Kang, M.D. National Institute of Allergy and Infectious Diseases (NIAID)

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02629120     History of Changes
Other Study ID Numbers: 160032
16-I-0032
First Posted: December 14, 2015    Key Record Dates
Last Update Posted: September 27, 2018
Last Verified: September 24, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Chronic Granulomatous Disease
Allogeneic Stem Cell Transplantation
Graft Versus Host Disease
Matched Unrelated Donor BMT
Nonmyeloablative Conditioning Regimen

Additional relevant MeSH terms:
Granuloma
Granulomatous Disease, Chronic
Lymphoproliferative Disorders
Lymphatic Diseases
Pathologic Processes
Phagocyte Bactericidal Dysfunction
Leukocyte Disorders
Hematologic Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Immunologic Deficiency Syndromes
Immune System Diseases
Cyclophosphamide
Busulfan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists