- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01998633
Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204) (RICHI)
Reduced-Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (RICHI) (BMT CTN #1204)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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British Columbia
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Vancouver, British Columbia, Canada, V5Z 4E3
- British Columbia Children's Hosp-Vancouver
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Quebec
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Montreal, Quebec, Canada, H3T1C5
- Hopital Sainte-Justine
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Montreal, Quebec, Canada, H4A 3J1
- McGill University - Montreal
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Alabama
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Birmingham, Alabama, United States, 35294
- University of Alabama at Birmingham
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District of Columbia
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Washington, District of Columbia, United States, 20010
- Children's National Medical Center
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Georgia
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Atlanta, Georgia, United States, 30322
- Children's Healthcare of Atlanta
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Illinois
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Chicago, Illinois, United States, 60614-3363
- Ann and Robert H. Lurie Children's Hospital of Chicago
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Maryland
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Baltimore, Maryland, United States, 21231
- Johns Hopkins
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Dana Farber Cancer Institute/Children's Hospital of Boston
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Michigan
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Ann Arbor, Michigan, United States, 48105-2967
- University of Michigan Medical Center
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Missouri
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Saint Louis, Missouri, United States, 63110
- Washington University/St. Louis Children's Hospital
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New York
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New York, New York, United States, 10065
- Memorial Sloan-Kettering Cancer Center
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Rochester, New York, United States, 14642
- University of Rochester Medical Center
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North Carolina
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Chapel Hill, North Carolina, United States, 27599-7305
- University of North Carolina at Chapel Hill
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Durham, North Carolina, United States, 27705
- Duke University Medical Center
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Ohio
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Cincinnati, Ohio, United States, 45229-3039
- Cincinnati Children's Hospital Medical Center
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Oregon
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Portland, Oregon, United States, 97239-3098
- Oregon Health and Science University
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Texas
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Dallas, Texas, United States, 75235
- Children's Medical Center of Dallas
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Fort Worth, Texas, United States, 76104
- Cook Children's Medical Center
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Houston, Texas, United States, 77030
- Baylor College of Medicine
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Washington
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Seattle, Washington, United States, 98109-1024
- Fred Hutchinson Cancer Research Center
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Wisconsin
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Milwaukee, Wisconsin, United States, 53211
- Midwest Children's Cancer
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria
- Patient is ≥ 3 months and ≤ 45 years of age at time of enrollment.
- Meets criteria for one of the following immune disorders (2A-2F) requiring HCT:
2A. HLH or related disorder with indication for HCT [a. Inherited gene mutation associated with HLH: PRF1, UNC13D (MUNC13-2), STXBP2 (MUNC18-2), STX11, RAB27A (Griscelli syndrome, type 2), SH2D1A (XLP1), XIAP (XLP2), LYST (Chediak-Higashi syndrome) - OR - b. Meets clinical criteria for HLH, refractory to therapy according to HLH-94 or HLH-2004 (dexamethasone/etoposide), or recurrent episodes of hyper-inflammation - OR - c. Meets clinical criteria for HLH, without identified gene defects, with affected sibling - OR - decreased or absent NK cell function at the last evaluation, - OR - a history of CNS inflammation as evidenced by pleocytosis in CSF or MRI evidence of hyper-inflammation in the CNS]
2B. CAEBV: Patients with chronic EBV infection (CAEBV) with or without associated lymphoma (in complete remission) or active HLH. Note that this diagnosis is distinct from post-transplant lymphoproliferative disorder/ EBV-associated lymphoproliferative disease (PTLD/LPD). [Patients must meet all of the following: a. Severe progressive illness, usually with fever, lymphadenopathy and splenomegaly that either began as primary EBV infection or was associated with markedly elevated antibody titers to EBV viral capsid antibody (≥ 1:5120) or early antigen (≥ 1:640), or markedly elevated EBV DNA in the blood; - AND - b. Infiltration of tissues (e.g., lymph nodes, liver, lungs, CNS, bone marrow, eye, skin) with lymphocytes; - AND - c. Elevated EBV DNA, RNA or proteins in affected tissues; - AND - d. The absence of HIV or post-transplant lymphoproliferative disorder]
2C. Chronic granulomatous disease with indication for HCT [a. Oxidative burst < 10% normal with dihydrorhodamine (DHR) assay - AND - b. Documented CGD mutation(s) in gp91phox, p47phox, p67phox, p22phox or p40phox - AND - c. Severe disease as evidenced by one or more of the following: history of one or more potentially life-threatening infections; inflammatory bowel disease; failure to thrive with height <10% for age (unless parent(s) height <10%); or autoimmune complication felt to be linked to CGD]
2D. X-linked Hyper IgM Syndrome (HIGM1) [a. Decreased serum IgG (more than 2 standard deviations below normal for age) - AND - b. Mutation in CD40LG - OR - family history of maternally related males with HIGM1]
2E. IPEX Syndrome [a. Absent FOXP3+ CD4+ T cells - OR - abnormal function of FOXP3+CD4+ T cells - AND - b. Disease-associated mutation in FoxP3 (bi-allelic in females) - OR - family history of maternally related males with clinical diagnosis of IPEX]
2F. Severe Leukocyte Adhesion Deficiency, type I (LAD-I) [a. Decreased CD18 expression on neutrophils (<5% normal for age) - AND - b. Mutation of ITGB2 - OR - absence of ITGB2 mRNA in leukocytes]
3. Lansky or Karnofsky performance status ≥ 50%.
4. The patient's donor must be willing and able to give bone marrow stem cells and be:
a. An unaffected sibling donor who is a 6/6 match at HLA-A and -B (intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) OR b. An unaffected related donor (other than sibling) who is a 7/8 or 8/8 match for HLA-A, -B, -C (at intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing) OR c. An unrelated donor who is a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at high resolution using DNA-based typing).
5. Patient must have adequate organ function as measured by:
- Cardiac: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction (LVSF) > 26% by echocardiogram.
- Renal: Calculated or radioisotope Glomerular Filtration Rate (GFR) > 50 mL/min/1.73m^2
- Hepatic: Adequate liver function: serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local laboratory (with the exceptions of isolated hyperbilirubinemia due to Gilbert's syndrome, or hyperbilirubinemia as the result of liver inflammation in the setting of persistent, active HLH); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 10x upper limit of normal as per local laboratory (with the exception of elevated transaminase levels as the result of liver inflammation in the setting of persistent, active HLH).
Pulmonary: Patient may not be on mechanical ventilation support or have progressive pulmonary infection at the time of transplant; Pulmonary Function Testing (PFT) with forced expiratory volume in one second (FEV1) > 50% of normal and Diffusing capacity of the lung for carbon monoxide (DLCO) corrected for Hgb > 50% of normal. Patients unable to undergo PFTs should have stable respiratory status with SaO2 > 90% on a maximum of 2L/min supplemental oxygen.
6. Signed informed consent.
Exclusion Criteria:
- Hematopoietic stem cell transplant within 6 months of enrollment.
- Uncontrolled bacterial, viral or fungal infection (currently receiving appropriate antimicrobials and experiencing progression or no clinical improvement) at time of enrollment. We recognize that patients with CAEBV may have ongoing EBV viremia at the time of initiating transplant therapy, but other patients should have no uncontrolled bacterial, viral or fungal infections at the time of enrollment (or prior to initiating the preparative regimen).
- Pregnant or breastfeeding.
- Seropositive for human immunodeficiency virus (HIV).
- Alemtuzumab within 2 weeks of enrollment.
- History of prior or current malignancy, especially malignancies with a likelihood of relapse and progression, with the exception of (1) EBV-associated lymphomas related to immune deficiency or lymphomas associated with X-linked LPD in a good remission, as they are unlikely to relapse after treatment; (2) Resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Hematopoietic Stem Cell Transplant
Participants will undergo a non-myeloablative allogeneic hematopoietic stem cell transplant.
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NOTE: The - sign is the number of days before the transplant and the + sign is the number of days after the transplant.
The GVHD prophylaxis will consist of the following:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of Participants With Overall Survival (OS)
Time Frame: 1 year and 18 months post-transplant
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Overall survival is defined as survival of death from any cause.
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1 year and 18 months post-transplant
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of Participants With Overall Survival (OS) by Disease Type
Time Frame: 1 year and 18 months post-transplant
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Overall survival is defined as survival of death from any cause.
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1 year and 18 months post-transplant
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Percentage of HLH Participants With HLH Reactivation Post-Transplant
Time Frame: 1 year post-transplant
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Systemic HLH Reactivation: Post-transplant HLH reactivation is defined by clinical and lab evidence of pathologic inflammation (persistent fever, progressive cytopenias, rising ferritin and soluble IL2Rα, decreasing fibrinogen, hepatosplenomegaly, end-organ damage) not attributable to other causes. Central nervous system (CNS) HLH Reactivation: Reactivation of CNS inflammation in patients with HLH may present with or without altered mental status and is defined by pleocytosis in Cerebrospinal fluid (CSF) or an MRI consistent with CNS inflammation not attributable to other causes. |
1 year post-transplant
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Percentage of Participants With Neutrophil Engraftment
Time Frame: Day 42 post-transplant
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Time to absolute neutrophil count (ANC) engraftment is defined as the first of three measurements on different days that the patient has an absolute neutrophil count of ≥ 500x10^6/liter following conditioning regimen induced nadir.
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Day 42 post-transplant
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Percentage of Participants With Platelet Engraftment
Time Frame: Day 100 post-transplant
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Platelet engraftment is defined as the first day of a minimum of three measurements on different days that the patient has achieved a platelet count > 20,000 / microliter AND the patient is platelet transfusion independent for a minimum of seven days following conditioning regimen induced nadir.
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Day 100 post-transplant
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Percentage of Participants Alive With Sustained Engraftment
Time Frame: 1 year post-transplant
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Sustained engraftment is defined as the occurrence of whole blood donor chimerism > 5% by Day 42 accompanied by the absence of any primary or secondary graft failure.
Primary graft failure is defined as < 5% donor chimerism by Day +42, second stem cell infusion, DLI (except in the case of donor CTLs given for infection control), or second HCT following original HCT.
Secondary graft failure is defined as < 5% donor chimerism following initial engraftment.
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1 year post-transplant
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Percentage of Participants Alive With Sustained Engraftment by Disease Type
Time Frame: 1 year post-transplant
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Sustained engraftment is defined as the occurrence of whole blood donor chimerism > 5% by Day 42 accompanied by the absence of any primary or secondary graft failure.
Primary graft failure is defined as < 5% donor chimerism by Day +42, second stem cell infusion, DLI (except in the case of donor CTLs given for infection control), or second HCT following original HCT.
Secondary graft failure is defined as < 5% donor chimerism following initial engraftment.
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1 year post-transplant
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Number of Participants With Acute Graft-Versus-Host Disease (GVHD)
Time Frame: 1 year post-transplant
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Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash
Liver stage (based on bilirubin level)*: 0: <2 mg/dL
GI stage*: 0: No diarrhea or diarrhea <500 mL/day
GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
1 year post-transplant
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Percentage of Participants With Grade II-IV and Grade III-IV Acute GVHD
Time Frame: Day 100 and 6 months post-transplant
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Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash
Liver stage (based on bilirubin level)*: 0: <2 mg/dL
GI stage*: 0: No diarrhea or diarrhea <500 mL/day
GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
Day 100 and 6 months post-transplant
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Number of Participants With Chronic GVHD
Time Frame: 1 year post-transplant
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Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
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1 year post-transplant
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Percentage of Participants With Chronic GVHD
Time Frame: 1 year post-transplant
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Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.
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1 year post-transplant
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Collaborators and Investigators
Publications and helpful links
General Publications
- Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
- Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Virus Diseases
- Infections
- Immune System Diseases
- Lymphatic Diseases
- Hematologic Diseases
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- DNA Virus Infections
- Fibrosis
- Tumor Virus Infections
- Leukocyte Disorders
- Herpesviridae Infections
- Cicatrix
- Phagocyte Bactericidal Dysfunction
- Histiocytosis, Non-Langerhans-Cell
- Histiocytosis
- Immunologic Deficiency Syndromes
- Primary Immunodeficiency Diseases
- Tissue Adhesions
- Granulomatous Disease, Chronic
- Epstein-Barr Virus Infections
- Lymphohistiocytosis, Hemophagocytic
Other Study ID Numbers
- BMTCTN1204
- 5U24CA076518 (U.S. NIH Grant/Contract)
- 2U10HL069294-11 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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