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

• ClinicalTrials.gov Identifier: NCT02629120
• Recruitment Status: Active, not recruiting
• First Posted: December 14, 2015
• Last Update Posted: January 25, 2023
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information

• First Submitted Date: December 10, 2015
• First Posted Date: December 14, 2015
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: December 17, 2015
• Estimated Primary Completion Date: November 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 25, 2022)

To determine engraftment rates with the use of high cell doses, without increasing the risk of GvHD by using post-transplant cyclophosphamide and sirolimus in conjunction with a busulfan- based conditioning regimen. We will compare the incidence... [ Time Frame: 5 years ]

This study is still recruiting patients.

• Original Primary Outcome Measures (submitted: December 10, 2015): Reduced incidence of graft failure or rejection (Engraftment as defined by & gt; 20% engraftment by oxidase positive neutrophils in at least 95% of participants by Day 100) [ Time Frame: Day 100 s/p BMT ]

Current Secondary Outcome Measures (submitted: December 15, 2020)

• To measure the engraftment rate and the engraftment kinetics using such a regimen [ Time Frame: 5 years ]
  This study is still recruiting patients
• To assess the level and kinetics of immune reconstitution (via chimerism) when using post- transplant cyclophosphamide [ Time Frame: 5 years ]
  This study is still recruiting patients
• To further elucidate the factors involved in the development of GvHD and graft rejection/failure [ Time Frame: 5 years ]
  This study is still recruiting patients

Original Secondary Outcome Measures (submitted: December 10, 2015)

• Same or reduced rate of Graft versus Host Disease of & lt; 10% [ Time Frame: 5 years s/p BMT ]
• Establish stable mixed chimerism. [ Time Frame: 5 years s/p BMT ]
• Improve rapidity of immune reconstitution. [ Time Frame: 5 years s/p BMT ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: High Dose Peripheral Blood Stem Cell Transplantation With Post Transplant Cyclophosphamide for Patients With Chronic Granulomatous Disease
• Official Title: High Dose Peripheral Blood Stem Cell Transplantation With Post Transplant Cyclophosphamide for Patients With Chronic Granulomatous Disease
• 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.

Detailed Description

Study Description:

Alemtuzumab, targeted busulfan, and TBI, with a 10/10 related or MUD donor graft or a 9/10 single HLA mismatch graft followed by post-transplant cyclophosphamide.

Primary Objectives:

To determine engraftment rates with the use of high cell doses, without increasing the risk of GvHD by using post-transplant cyclophosphamide and sirolimus in conjunction with a busulfan based conditioning regimen. We will compare the incidence of graft rejection/failure and GvHD to the incidence obtained from Protocol 07-I-0075.

Secondary Objectives:

To measure the engraftment rate and the engraftment kinetics using such a regimen.

To assess the level and kinetics of immune reconstitution (via chimerism) when using post- transplant cyclophosphamide.

To further elucidate the factors involved in the development of GvHD and graft rejection/failure.

To evaluate the risk of viral infections in the setting of Alemtuzumab (Campath-1H) and post-transplant cyclophosphamide.

Primary Endpoint:

Reduced incidence of graft failure or rejection (as defined by >20% engraftment by oxidase- positive neutrophils in at least 95% of participants by Day 100, 6 months, and 1 year post BMT) will be assessed as event-free survival (EFS). Graft failure will result in disease recurrence. This will be assessed in a composite form along with GvHD (see Biostatistical Considerations section 17).

Secondary Endpoints:

Same or reduced rate of grade 3-4 aGvHD of <20% .

Establish stable mixed chimerism.

Improve rapidity of immune reconstitution.

Overall survival.

Tertiary Endpoints:

Evaluation of inflammatory markers as risk factors for

engraftment syndrome

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Granulomatous Disease Transplant

Intervention

• Drug: Alemtuzumab
  Transplant Conditioning Drug: Monoclonal antibody that targets recipient and donor T-cells to prevent graft verses host disease. Not an IND. This is a well studied drug, and is not under an IND.
• Drug: Busulfan
  Transplant Conditioning Drug: Chemotherapy to create space in the patient's bone marrow so that the donor peripheral blood stem cells can repopulate in the patient's bone marrow. This is a well studied drug, and is not under an IND.
• Drug: Sirolimus
  Immunosuppressant to prevent donor peripheral blood stem cell rejection and graft versus host disease. This is a well studied drug, and is not under an IND.
• Drug: Cyclophosphamide
  Post transplant cyclophosphamide given to prevent graft verses host disease. This is a well studied drug, and is not under an IND.
• Radiation: Total Body Irradiation
  Transplant Conditioning Total Body Radiation (300cGy in 2 fractionated doses), given only to patient receiving matched unrelated donor cells, to create space in the patient's bone marrow so that the donor peripheral blood stem cells can repopulate in the patient's bone marrow.
• Biological: Peripheral blood stem cells
  Donor Peripheral blood stem cells, either matched unrelated donor or matched related relative to replace the patient's immune cells with functional immune cells. The peripheral blood stem cells are not regulated by the FDA.

Study Arms

Active Comparator: 1

There is only one treatment arm for this study

Interventions:

• Drug: Alemtuzumab
• Drug: Busulfan
• Drug: Sirolimus
• Drug: Cyclophosphamide
• Radiation: Total Body Irradiation
• Biological: Peripheral blood stem cells

Publications *

• Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, Peggs K, Verfuerth S, Pettengell R, Marsh JC, Schey S, Mahendra P, Morgan GJ, Hale G, Waldmann H, de Elvira MC, Williams CD, Devereux S, Linch DC, Goldstone AH, Mackinnon S. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood. 2000 Oct 1;96(7):2419-25.
• Kang EM, Hsieh MM, Metzger M, Krouse A, Donahue RE, Sadelain M, Tisdale JF. Busulfan pharmacokinetics, toxicity, and low-dose conditioning for autologous transplantation of genetically modified hematopoietic stem cells in the rhesus macaque model. Exp Hematol. 2006 Feb;34(2):132-9. doi: 10.1016/j.exphem.2005.10.010.
• Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001 Mar 22;344(12):881-8. doi: 10.1056/NEJM200103223441203.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 7, 2022): 44
• Original Estimated Enrollment (submitted: December 10, 2015): 40
• Estimated Study Completion Date: November 30, 2026
• Estimated Primary Completion Date: November 30, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:
• Must have confirmed Chronic Granulomatous Disease.
• Must have sufficient complications from underlying disease to warrant undergoing transplantation (either a history of or ongoing inflammation/CGD related autoimmunity OR a CGD related infection while on prophylaxis) OR 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 peripheral blood stem cell (PBSC) graft (10/10 or 9/10 mismatch) available
• Must be HIV negative
• When discharged from the hospital 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
• Individuals 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.

• Individuals 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.

  --NOTE: Alemtuzumab (Campath-1H) (intravenous [IV] formulation) is no longer distributed commercially. In order to receive product, the physician must contact the program for the patient. If the patient is not willing to consent to submit their info (demographics, contact information, and rationale for use) to the program such that we can obtain the drug, then we cannot proceed with conditioning; therefore no transplant will occur on this protocol.

• Patients with a CRP greater than 100 mg/L within 30 days of anticipated transplant.

  • If the underlying inflammation is controlled for one month with repeat CRP testing showing a level of less than 100 on at least two separate testings, the patient will be reconsidered for transplant. If during this time period a CRP of greater than 100 is measured, then the patient would no longer be eligible for transplant.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02629120
• Other Study ID Numbers: 160032; 16-I-0032
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: .The following data will be shared: @@@@@@All the individual participant data collected during the trial, after deidentification.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Analytic Code
• Time Frame: Data availability and the duration of the data availability are as follows:@@@@@@Transplant data shared with CIBMTR, BTRIS, and the NML will be shared at the onset of signing the protocol and will be maintained in shared databases with no end date. @@@@@@Transplant data submitted for publication will be immediately available following publication with no end date.
• Access Criteria: IIndividual deidentified data will be shared with: @@@The Center for International Blood and Transplant Research (CIBMTR), as required by the Stem Cell Therapeutic and Research Act of 2005 https://www.congress.gov/bill/109th-congress/house-bill/2520 @@@An NIH-funded or approved public repository. @@@Publications@@@Public presentations. @@@Individual identified participant data will be shared with: @@@Approved outside collaborators under appropriate agreements, such as the Neutrophil Monitoring Lab (NML) in Frederick, Md.@@@Biomedical Translational Research Information System (BTRIS).@@@The following related documents will be available:@@@Study Protocol @@@Statistical analysis plan @@@Analytic code@@@CIBMTR, BTRIS, and the NML data will be shared at the onset of signing the protocol and will be maintained in shared databases with no end date. @@@Data submitted for publication will be immediately available following publication with no end date.@@@

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Elizabeth M Kang, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: January 5, 2023