Study of Treatment of Inflammation before Stem Cell Transplant in People with a Primary Immune Regulatory Disorder (PIRD) and/or an Autoinflammatory Condition, BRIDGE Study
This phase II trial tests how well treatment of inflammation with emapalumab or fludarabine and dexamethasone before stem cell transplant work in treating patients with primary immune regulatory disorder. Emapalumab is an antibody, like the proteins made by the immune system to protect the body from harm. Emapalumab blocks the protein interferon gamma (INF-gamma), which activates the immune system and increases inflammation. By blocking INF-gamma, emapalumab may decrease inflammation. Fludarabine is a chemotherapy drug that binds to proteins (such as deoxyribonucleic acid [DNA] polymerase) that are responsible for making DNA in dividing cells. By binding to these proteins, fludarabine works to kill cancer cells. Dexamethasone is a corticosteroid that binds to receptors (molecules inside cells) that play a role in cell growth. This binding action has been shown to reduce inflammation and lower the body’s immune response. This study may help determine if emapalumab or fludarabine and dexamethasone can help prepare people to receive a stem cell transplant.
Inclusion Criteria
- Patients receiving first allo-HCT for the following immunologic conditions: * Primary immune regulatory disorder with or without a genetic lesion as defined by the Primary Immune Deficiency Treatment Consortium (PIDTC) * Patients with autoinflammatory disorders evidenced by cytokine or inflammation assays with at least 1.5 x upper limit of normal (ULN) of measured cytokines and/or an elevated ferritin or erythrocyte sedimentation rate (ESR) > 2 ULN * For inclusion on the emapalumab group, the lesion must be isolated to the IFNγ pathway (or mediators thereof) with an elevated CXCL9 > 1.5 ULN OR sIL2R > 1.5 ULN (or already controlled on immune modulation, provided that CXCL9 or sIL2R levels were elevated prior to initiation of immune modulation). Inclusion on the fludarabine/dexamethasone group requires inflammation (as defined above) other than an isolated IFNγ pathway
- Able to tolerate cytoreduction (based on adequate organ function as described below)
- Patients of any age can enroll so long as they meet other inclusion criteria
- Serum bilirubin =< 2 mg/dL, unless benign congenital hyperbilirubinemia. Patients with hyperbilirubinemia related to paroxysmal nocturnal hemoglobinuria or other hemolytic disorders related to their primary immune regulatory disorder (PIRD) diagnosis are eligible
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase < 2.5 times the upper limit of normal unless thought to be disease-related. Investigator will need to perform clinically indicated evaluations to assess if disease related or intrinsic liver disease. Additional testing may be done if clinically indicated, after the pre-transplant immune prophase and prior to start of conditioning as this will provide additional data to confirm disease related versus intrinsic liver dysfunction
- Serum creatinine < 1.5x normal for age. If serum creatinine is outside the normal range, then creatinine clearance (CrCl) > 50 mL/min/1.73 m^2 (calculated or estimated) or glomerular filtration rate (GFR) (mL/min/1.72 m^2) > 30% of predicted normal for age * Age: 1 week; MeanGFR +/- standard deviation (SD) (mL/min/1.73 m^2): 40.6 + / - 14.8 * Age: 2 – 8 weeks; MeanGFR +/- standard deviation (SD) (mL/min/1.73 m^2): 65.8 + / - 24.8 * Age: > 8 weeks; MeanGFR +/- standard deviation (SD) (mL/min/1.73 m^2): 95.7 +/- 21.7 * Age: 2 – 12 years; MeanGFR +/- standard deviation (SD) (mL/min/1.73 m^2): 133 +/- 27 * Age: 13 – 21 years (males); MeanGFR +/- standard deviation (SD) (mL/min/1.73 m^2): 140 +/- 30 * Age: 13 – 21 years (females); MeanGFR +/- standard deviation (SD) (mL/min/1.73 m^2): 126.0 + / - 22.0
- Left ventricular ejection fraction (LVEF) >= 50% by multigated acquisition scan (MUGA) or resting echocardiogram
- Pulmonary function testing (forced expiratory volume in 1 second [FEV1] and corrected diffusion capacity of the lung for carbon monoxide [DLCO]) >= 50% predicted (pediatric patients unable to complete pulmonary function testing (PFTs) will need oxygen saturation as recorded by pulse oximetry of >= 92% on room air)
- Age >= 16 years: Eastern Cooperative Oncology Group (ECOG) =< 1 or Karnofsky 70%
- Age < 16 years: Lansky 70%
- Each patient must be willing to participate as a research subject and must sign an informed consent form or legal guardian with assent as appropriate
- DONOR: Related Donors: * 8/8 or 7/8 human leukocyte antigen (HLA) matched at A, B, C, and DRB1 loci, as tested by DNA analysis * Haploidentical donors at A, B, C and DRB1 loci, as tested by DNA analysis
- DONOR: Unrelated Donors: * 8/8 or 7/8 matched at A, B, C, and DRB1 loci, as tested by DNA analysis
- DONOR: Able to provide informed consent for the donation process per institutional standards
- DONOR: Meet standard criteria for donor collection (e.g. National Marrow Donor Program Guidelines or collecting center guidelines as approved by treating physician)
Exclusion Criteria
- Uncontrolled infection at the time of enrollment
- Patients who have undergone previous allo-HCT
- Patient seropositivity for human immunodeficiency virus (HIV) I/II and/or HTLV I/II
- Females who are pregnant or breastfeeding
- Patients unwilling to use contraception during the study period
- Patient or parent or guardian unable to give informed consent or unable to comply with the treatment protocol including research tests
Additional locations may be listed on ClinicalTrials.gov for NCT05787574.
Locations matching your search criteria
United States
California
San Francisco
Georgia
Atlanta
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Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
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Pennsylvania
Philadelphia
Texas
Houston
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PRIMARY OBJECTIVE:
I. To assess the effects of a targeted inflammatory cool-down prophase prior to myeloablative allogeneic bone marrow transplant (BMT) on achieving and maintaining trilineage engraftment at day+100 in patients with primary immune regulatory disorders (PIRDs) and/or autoinflammatory conditions.
SECONDARY OBJECTIVES:
I. Determine overall survival (OS), event free survival (EFS), non-relapse mortality (TRM), steroid refractory acute or chronic graft versus (vs) host disease/relapse free survival (GRFS/CRFS) and all causes of mortality at 1 & 2 years.
II. Determine the incidence of viral reactivations: cytomegalovirus (CMV), adenovirus, Epstein-Barr virus (EBV), human herpes-6 (HHV6), BK-virus defined as viral reactivations necessitating use of anti-viral treatment.
III. Determine use of viral specific T cells (VST) at Day +100, +180, and 1-year follow-up.
IV. Estimate incidence of Acute graft versus host disease (GVHD) at day +100, +180, and 1-year follow-up.
V. Estimate incidence of Chronic GVHD at +180, and 1-year follow-up.
VI. Determine the time to neutrophil engraftment defined as the first of 3 consecutive days of absolute neutrophil count (ANC) >= 500 K/uL.
VII. Determine the time to platelet engraftment defined as the first of 7 consecutive days with a platelet count exceeding 20,000/uL without transfusion support.
VIII. Determine incidence of primary engraftment failure (failure to achieve neutrophil engraftment by day 30 after transplantation).
IX. Determine incidence of secondary engraftment failure (defined as < 500/uL circulating neutrophils at any time after primary engraftment that is not attributed to disease recurrence or drug therapy).
X. Determine kinetics of donor chimerism in bone marrow (short tandem repeat [STR] analysis) and peripheral blood (lineage specific donor chimerism).
XI. Evaluate the incidence of grade >= 3 non-hematologic adverse events by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 by day +100, +180, and 1 year post allogeneic hematopoietic cell transplantation (allo-HCT).
XII. To determine lymphocyte subset reconstitution by evaluation of lymphocyte subsets (immune function).
XIII. Describe the feasibility of obtaining and results of Patient Reported Outcome (PRO)(Global Health, Mental Health, Physical Health, Social Health Measures) using Patient- Reported Outcomes Measurement Information System (PROMIS)2 in patients >= 5 years of age.
XIV. Determine what percentage of patients are eligible to proceed to transplant after receiving an immune suppression prophase.
EXPLORATORY OBJECTIVES:
I. Determine pharmacokinetics (PK) model for emapalumab in HCT.
II. Evaluate effect of emapalumab on global endothelial injury post-HCT.
OUTLINE: Patients are assigned to 1 of 2 groups.
GROUP A: Patients with CXCL9 or sIL2R > 1.5 x upper limit of normal or with any elevation of CXCL9 or sIL2R while on medically indicated immune modulation receive emapalumab intravenously (IV) on days -22, -15, -8 and -1. Patients who do not have low enough inflammation biomarker levels (decreased inflammation) receive the same study treatment course again (a second regimen). Patients then undergo standard-of-care stem cell transplant on day 0. Patients also undergo echocardiography (ECHO) at screening, and undergo lumbar puncture, bone marrow aspiration, bone marrow biopsy, and collection of blood samples throughout the trial.
GROUP B: Patients with generalized inflammation evidenced by elevations of more than one cytokine or inflammatory marker receive fludarabine IV and dexamethasone IV on days -22 to - 18 (5 days). Patients who do not have low enough inflammation biomarker levels (decreased inflammation) receive the same study treatment course again (a second regimen). Patients then undergo standard-of-care stem cell transplant on day 0. Patients also undergo ECHO at screening, and undergo lumbar puncture, bone marrow aspiration, bone marrow biopsy, and collection of blood samples throughout the trial.
After completion of study treatment, patients follow up on day 7, 14, 21, 30, 45, 60, 75, 100, 120, 150, 180, 270 and 365.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorAndromachi Scaradavou
- Primary ID23-040
- Secondary IDsNCI-2023-02808
- ClinicalTrials.gov IDNCT05787574