Haploidentical Transplant for People With Chronic Granulomatous Disease Using Post Transplant Cyclophosphamide

Haploidentical Transplant for Patients With Chronic Granulomatous Disease (CGD) Using Post-Transplant Cyclophosphamide

Background:

- Chronic Granulomatous Disease (CGD) causes immune system problems. Treatment is usually a bone marrow transplant from a fully matched donor. Researchers want to try using partially matched donors for patients who do not have a fully matched donor available. The researchers will also use the drug cyclophosphamide to try to improve the outcomes when using a partially matched donor.

Objective:

- To learn the effectiveness of using cyclophosphamide with a transplant from a partially matched donor in treating CGD.

Eligibility:

- Recipients: age 2-65 with CGD with an ongoing infection that has not been cured by standard treatment and no fully matched donor available in an appropriate timeframe.

Design:

• Recipients will:

  • be admitted to the hospital 2 weeks before transplant.
  • be screened with blood and urine tests, breathing and heart health tests, X-rays, and/or magnetic resonance imaging. They may have a bone marrow aspiration and biopsy.
• meet with a social worker and dentist.
• get chemotherapy, radiation, and other medicines.
• get an intravenous (IV) catheter in their chest.
• have the transplant.
• get more medicines and standard supportive care.
• have blood drawn frequently.
• have to stay in the Washington, D.C. area for 3 months post-transplant.
• be followed closely for the first 6 months, and then less frequently for at least 5 years.

Study Overview

• Status: Terminated
• Conditions: Chronic Granulomatous Disease
• Intervention / Treatment: Drug: Sirolimus; Biological: Donor peripheral blood stem cells.; Drug: Cyclophosphamide post transplant; Radiation: Total body 200cGy; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Busulfan

Detailed Description

Allogeneic transplant using HLA matched donors, both related and unrelated, has proven curative for patients with various immunodeficiencies, including those with ongoing infections. However donor availability remains a limiting factor in the application of this treatment modality. The use of haploidentical donors has in the past been fraught with a greater rate of complications related to both higher rates of GvHD and delayed immunorecovery. Newer transplant regimens appear to have diminished these risks and improved outcomes. We propose using a subablative conditioning regimen followed by post-transplant cyclophosphamide for patients with CGD who do not have an HLA matched donor but whose circumstances necessitate the use of a potentially curative, albeit high-risk treatment modality.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:
• Must have sufficient complications from underlying disease to warrant undergoing transplantation
• Ages 2 years - 65 years
• No appropriate HLA matched donor (available donor has greater than 1 mismatch or the single mismatch is not at DQ for unrelated donors (including cord blood products), or no available 6 out of 6 HLA matched related donor), or patients who may have an unrelated donor, but whose clinical status is such that the time required to obtain an unrelated donor would be life threatening.
• HLA haploidentical family donor graft available.
• Ability to comprehend and willingness to sign the informed consent or have a parent/guardian consent if the donor is a minor; assent being obtained from minors as appropriate
• Must be HIV negative
• Must not be pregnant (confirmed by a negative serum beta-human chorionic gonadotropin (Beta-hCG) for women of child-bearing potential) or breastfeeding
• 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 Form-200 NIH Durable Power of Attorney for Health Care Decision Making.
• Where appropriate, subjects must agree to use contraception for 3 months post-transplant

EXCLUSION CRITERIA:

• Major anticipated illness or organ failure incompatible with survival from Allo-transplant
• Inadequate collection from prospective donors.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CGD Recipient; CGD patients that will undergo haplo transplantation with post-transplant cyclophosphamide as described

Drug: Sirolimus; For pediatric patients: Begin sirolimus 1 mg/m2 PO q4h for 3 doses, then 1 mg/m2 once a day (QD). For adult patients, begin sirolimus 5 mg PO q4h for 3 doses, then 5 mg once a day (QD). Doses may be adjusted to maintain trough levels between 8-14 ng/ml. Recipients will take sirolimus from Day +5 to at least Day 100 (minimum).; Other Names: Rapamycin; Biological: Donor peripheral blood stem cells.; Infuse donor graft.; Drug: Cyclophosphamide post transplant; 50 mg/kg/d IV infused over 90 minutes. Day +3 and +4; Other Names: Cytoxan post transplant; Radiation: Total body 200cGy; Day -1; Drug: Cyclophosphamide; 14.5 mg/kg IV over one hour Day -6 and -5; Other Names: Cytoxan; Drug: Fludarabine; 30 mg/m2 over 30 minutes Day -6 through Day -2; Other Names: Fludara; Drug: Busulfan; Busulfan 3.2 mg/kg IV once daily over 2-3 hours Day -4,-3,-2; Other Names: Busulfex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Determine the Efficacy of This Allogeneic Transplant Approach in Reconstituting Normal Hematopoiesis and Reversing the Clinical Phenotype of CGD	Patient will have donor chimerism of greater than 20% and resolution of infection or autoimmunity at end of follow up	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Determine the Safety of This Allogeneic HSCT Approach in Patients With CGD Including Transplant Related Toxicity, the Incidence of Acute and Chronic Graft-versus-host Disease, Immune Reconstitution, Overalland Disease-free Survival.	1. Stable chimerism as indicated by 30-50% myeloid engraftment and 50% lymphoid engraftment as assessed by 1 year post transplant. 2. Immune reconstitution levels with DHR as a marker of normal neutrophil function by 1 year post transplant. 3. GvHD grades of less than 3.	1 year post transplant

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.
• Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: current status and future perspectives. Blood. 2011 Dec 1;118(23):6006-17. doi: 10.1182/blood-2011-07-338822. Epub 2011 Sep 14.
• Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL, Jones RJ, Fuchs EJ. Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-transplantation cyclophosphamide. Pediatr Rep. 2011 Jun 22;3 Suppl 2(Suppl 2):e15. doi: 10.4081/pr.2011.s2.e15.

Study record dates

Study Major Dates

• Study Start: October 23, 2014
• Primary Completion (Actual): April 10, 2019
• Study Completion (Actual): December 10, 2019

Study Registration Dates

• First Submitted: November 4, 2014
• First Submitted That Met QC Criteria: November 4, 2014
• First Posted (Estimate): November 5, 2014

Study Record Updates

• Last Update Posted (Actual): May 12, 2020
• Last Update Submitted That Met QC Criteria: April 30, 2020
• Last Verified: December 10, 2019

More Information

Terms related to this study

• Keywords: Transplant; Chronic Granulomatous Disease; Halo-Identical Protocol
• Additional Relevant MeSH Terms: Pathologic Processes; Immunologic Deficiency Syndromes; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Leukocyte Disorders; Phagocyte Bactericidal Dysfunction; Granuloma; Granulomatous Disease, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cyclophosphamide; Fludarabine; Sirolimus; Busulfan
• Other Study ID Numbers: 150007; 15-I-0007 (Other Identifier: NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No