Donor Stem Cell Transplantation for Congenital Immunodeficiencies

NCT00426517 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: 07007507-I-0075
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

This study uses transplantation to treat patients with problems in their immune system. The immune system cells come from the bone marrow where they grow from special cells called stem cells. Giving patients stem cells from someone else may help to cure many patients with certain immune diseases. This is called 'bone marrow transplantation'. This procedure can have side effects that are life-threatening. To try to make transplantation safer we are using lower doses of the medications used in preparing the patient for the transplant. 'Conditioning' treatments are given to patients to create space in their bone marrow. This lets the cells of the donor go into the bone marrow and produce normal immune cells. This study will use lower doses of a drug called busulfan and lower doses of radiation than what are currently being used in other kinds of bone marrow transplantation for other diseases. Another problem that can occur with bone marrow transplantation is 'graft-versus-host disease'. This happens when the cells of the donor attacks different parts of the patient s body. This study will use a medicine called sirolimus instead of the usual medicine, cyclosporine, to prevent graft-versus-host disease. To go onto this study, you must have:

• To create space in the bone marrow, patients are given two drugs, Campath-1H and busulfan. To prevent the body from getting rid of the donated cells, patients are given sirolimus. On the day before the BMT, patients in the matched unrelated donor group also receive a low-dose of whole-body radiation. This will further improve the chances that the patients body will accept the donor cells.
• Patients will get the donor stem cells through an intravenous (IV) line that goes into a vein in their body. The cells make their way to the bone marrow space and slowly refill the marrow over the next several weeks. Patients will usually stay in the hospital for 30 days after the transplant.
• For the first 3 months after the transplant, patients are watched closely. The patients will have frequent visits to the clinic. During these visits the patient will have a physical examination and blood tests. The doctor and nurse will also check any symptoms the patient may have. At day 100 after the transplant a sample of bone marrow is taken.
• Patients will continue to be followed periodically for at least 5 years after the transplant.

Conditions

Inherited Immune Deficiencies

Keywords

MUD Transplant; Transplant; AlloPBSC; HLA Matched Transplant; BMT; Congenital Immunodeficiency; Bone Marrow Transplant

Outcome Measures

Primary Outcomes (1)

• Stem Cell Transplant Engraftment

  Engraftment of allogeneic or matched unrelated (including cord blood) hematopoietic progenitor cells using moderate-dose busulfan and Campath-1H with or without whole body irradiation so as to attain phenotypic correction of congenital immunodeficiencies.

  1 year

Secondary Outcomes (7)

• Engraftment Without Development of GVHD

  1 year

• Participants With Established Stable Mixed Chimerism

  1 year

• Days to CD3 Count Greater Than 100 u/L

  1 year

• Days to Absolute Neutrophil Recovery (ANC)

  1 year

• Number of RBC Transfusions Per Subject

  1 year

Study Arms (4)

Matched related donor stem cell transplant

EXPERIMENTAL

Conditioning with Campath 1 mg/kg total dose given intravenously over 5 days, Busulfan 10 mg/kg total dose given intravenously over 2 days

Drug: Campath 1H; Drug: Busulfan; Drug: Sirolimus or equivalent based on response

Matched unrelated donor stem cell transplant

EXPERIMENTAL

Conditioning with Campath 1 mg/kg total dose given intravenously over 5 days, Busulfan 5 mg/kg total dose given intravenously over 2 days, and Total Body Irradiation (TBI) 200 cGy in two fractions on the same day

Drug: Campath 1H; Drug: Busulfan; Drug: Total Body Irradiation (TBI); Drug: Sirolimus or equivalent based on response

Matched unrelated donor stem cell transplant (MUD-non CGD)

EXPERIMENTAL

Conditioning with ATG 40 mg/kg total dose over 4 days IV, Busulfan 5 mg/kg total dose over 2 days IV, and TBI 300 cGy in two fractions at day -2

Drug: Busulfan; Drug: Horse Anti-human Thymocyte Globulin (h-ATG); Drug: Total Body Irradiation (TBI); Drug: Sirolimus or equivalent based on response

Matched unrelated donor transplant (MUD-CGD) cord blood

EXPERIMENTAL

Conditioning with Campath 1 mg/kg total dose given intravenously over 5 days, Busulfan 5 mg/kg total dose given intravenously over 2 days, and Total Body Irradiation (TBI) 200 cGy in two fractions on the same day

Drug: Campath 1H; Drug: Busulfan; Drug: Total Body Irradiation (TBI); Drug: Sirolimus or equivalent based on response

Interventions

Campath 1H DRUG

Conditioning with Campath 1 mg/kg total dose given intravenously over 5 days

Also known as: alemtuzumab

Matched related donor stem cell transplant; Matched unrelated donor stem cell transplant; Matched unrelated donor transplant (MUD-CGD) cord blood

Busulfan DRUG

Busulfan 5-10 mg/kg total dose given intravenously over 2 days based on patient underlining immune deficiency disorder

Also known as: Busulfex® (IV formulation)

Matched related donor stem cell transplant; Matched unrelated donor stem cell transplant; Matched unrelated donor stem cell transplant (MUD-non CGD); Matched unrelated donor transplant (MUD-CGD) cord blood

Horse Anti-human Thymocyte Globulin (h-ATG) DRUG

Conditioning with h-ATG 40 mg/kg total dose over 4 days given intravenously

Also known as: ATG

Matched unrelated donor stem cell transplant (MUD-non CGD)

Total Body Irradiation (TBI) DRUG

TBI 200 - 300 centigray (cGy) in two fractions at day -2 or same day depending on patient underlining immune deficiency disorder

Also known as: TBI

Matched unrelated donor stem cell transplant; Matched unrelated donor stem cell transplant (MUD-non CGD); Matched unrelated donor transplant (MUD-CGD) cord blood

Sirolimus or equivalent based on response DRUG

post Transplantation immunosuppressants

Also known as: Rapamune®/rapamycin

Matched related donor stem cell transplant; Matched unrelated donor stem cell transplant; Matched unrelated donor stem cell transplant (MUD-non CGD); Matched unrelated donor transplant (MUD-CGD) cord blood

Eligibility Criteria

• Age: 2 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• PATIENTS (RECIPIENT)
• Must have confirmed genetic diagnosis of XSCID (common gamma chain disorder) by identification of a mutation in the IL2RG gene or by demonstrating failure to detect gamma c protein in patient immune blood cells.
• Must have sufficient complications from underlying disease to warrant undergoing transplantation as defined as follows:.
• Clinical Criteria: (greater than or equal to 1 must be present)
• i. Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii and viii below): 3 significant new or chronic active infections during the 2 years preceding evaluation for enrollment, with each infection accounting for one criteria.
• Infections are defined as an objective sign of infection (fever \>38.30C \[1010F\] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging evidence or typical lesion or histology or new severe diarrhea or cough with sputum production). In addition to one or more of these signs/symptoms of possible infection, there also must be at least 1 of the following criteria as evidence of the attending physician's intent to treat a significant infection (a. and b.) or objective evidence for a specific pathogen causing the infection (c.)
• Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics . 14 days OR
• Hospitalization of any duration for infection OR
• Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood, nasal washing, bronchoscopy, cerebrospinal fluid or stool likely to be an etiologic agent of infection
• ii. Chronic pulmonary disease as defined by:
• Bronchiectasis by x-ray computerized tomography OR
• Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is . 60% of Predicted for Age OR
• Pulse oximetry . 94% in room air (if patient is too young to comply with performance of PFTs).
• iii. Gastrointestinal enteropathy:
• Diarrhea-watery stools . 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion # i. above) OR

You may not qualify if:

• PATIENT (RECIPIENT)
• Eastern Cooperative Oncology Group (ECOG) or equivalent performance status of 3 or more (See Supportive Care guidelines, available at http://intranettst2.cc.nih.gov/bmt/clinicalcare).
• Left ventricular ejection fraction less than 40%.
• Transaminases greater than 5 times upper limit of normal based on the patient s clinical situation and at the discretion of the investigator.
• Liver alkaline phosphatase \>10x upper limit of normal based on the patient's clinical situation and at the discretion of the investigator
• Psychiatric disorder or mental deficiency severe enough as to make compliance with the BMT treatment unlikely, and/or making informed consent impossible.
• Major anticipated illness or organ failure incompatible with survival from AlloPBSC, MUD or unrelated cord blood transplant
• Pregnant or lactating.
• HIV positive.
• Uncontrolled seizure disorder.

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (6)

• Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo LD, Roifman CM. Bone marrow transplantation for severe combined immune deficiency. JAMA. 2006 Feb 1;295(5):508-18. doi: 10.1001/jama.295.5.508.

  PMID: 16449616 BACKGROUND

• Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000 May;79(3):155-69. doi: 10.1097/00005792-200005000-00003.

  PMID: 10844935 BACKGROUND

• Johnston RB Jr. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001 Jan;8(1):17-22. doi: 10.1097/00062752-200101000-00004.

  PMID: 11138621 BACKGROUND

• Roesler J, Brenner S, Bukovsky AA, Whiting-Theobald N, Dull T, Kelly M, Civin CI, Malech HL. Third-generation, self-inactivating gp91(phox) lentivector corrects the oxidase defect in NOD/SCID mouse-repopulating peripheral blood-mobilized CD34+ cells from patients with X-linked chronic granulomatous disease. Blood. 2002 Dec 15;100(13):4381-90. doi: 10.1182/blood-2001-12-0165. Epub 2002 Aug 1.

  PMID: 12393624 BACKGROUND

• Kang EM, de Witte M, Malech H, Morgan RA, Phang S, Carter C, Leitman SF, Childs R, Barrett AJ, Little R, Tisdale JF. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with acquired immunodeficiency syndrome. Blood. 2002 Jan 15;99(2):698-701. doi: 10.1182/blood.v99.2.698.

  PMID: 11781257 BACKGROUND

• 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.

  PMID: 11259721 BACKGROUND

MeSH Terms

Interventions

Alemtuzumab; Busulfan; Dosage Forms; Whole-Body Irradiation; Sirolimus

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Pharmaceutical Preparations; Technology, Pharmaceutical; Investigative Techniques; Radiotherapy; Therapeutics; Macrolides; Lactones

Limitations and Caveats

No limitations. Treatment of a rare disease.

Results Point of Contact

• Title: Kang, Elizabeth
• Organization: National Institute of Allergy and Infectious Diseases

ekang@niaid.nih.gov

+1 301 402 7567

Study Officials

• Elizabeth M Kang, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2007
• First Posted: January 24, 2007
• Study Start: January 19, 2007
• Primary Completion: November 1, 2019
• Study Completion: November 1, 2019
• Last Updated: May 11, 2021
• Results First Posted: May 11, 2021

Record last verified: 2019-11-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)