A Study of Treatment of Inflammation Before Stem Cell Transplant in People With a Primary Immune Regulatory Disorder (PIRD) and/or an Autoinflammatory Condition

Phase 2 Study Bridging Pre-Transplant Inflammatory Dampening for Primary Immune Regulatory Disorders (BRIDGE Trial)

The researchers are doing this study to find out whether emapalumab or a combination of fludarabine and dexamethasone are effective in preparing people with a primary immune regulatory disorder (PIRD) and/or an autoinflammatory condition to receive a stem cell transplant. The researchers will look at how well the study treatments reduce inflammation and aid in the engraftment process (the process of donated stem cells traveling to the bone marrow, where they begin to make new immune cells.

"Funding Source - FDA OOPD"

Study Overview

• Status: Recruiting
• Conditions: Immune System Diseases; Autoimmune Lymphoproliferative; Primary Immune Regulatory Disorder
• Intervention / Treatment: Drug: Emapalumab; Drug: Fludarabine and Dexamethasone; Procedure: Allogeneic hematopoietic stem cell transplant (allo-HCT)

Detailed Description

Defects in the immune cells can hinder the immune system's ability to fight infection. A stem cell transplant can replace non-working immune system cells with a donor's fully functioning immune cells, but if inflammation is present, the immune cells from the donor may not graft successfully. The proposed trial tests whether emapalumab or fludarabine and dexamethasone can help prepare the body to receive a stem cell transplant by reducing inflammation, so that the immune system will be able to produce fully functioning immune cells. Participants will receive emapalumab or a combination of fludarabine and dexamethasone over the course of four days in the hospital prior to a planned transplant procedure.

This study has two study groups:

1. Participants in Group A have a high CXCL9, a specific cytokine, level and will receive emapalumab on Days -22, -15, -8, and -1.
2. Participants in Group B have a generalized inflammation and will receive fludarabine and dexamethasone from Days -22 to -18 (5 days).

All study participants are eligible to receive one additional emapalumab 3mg/kg in the first 30 days post-transplant if they begin to have CXCL9 levels that are trending up. Participants will receive personalized rATG dosing. Participants will remain in the hospital according to the usual standard of care guidelines for stem cell transplant. Subject status and follow-up examination/data collection will occur on days 0, 7, 14, 21,30, 45, 60, 7, 100, 180, 270, and 365, then quarterly until 3 years post-transplant.

• Study Type: Interventional
• Enrollment (Estimated): 39
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Joseph Oved, MD; Phone Number: 212 305 9770; Email: jho2001@cumc.columbia.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California, San Francisco
      • Contact: Christopher Dvorak, MD; Phone Number: 415-476-2188
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Children's Healthcare of Atlanta
      • Contact: Shanmuganathan Chandrakasan, MD; Phone Number: 404-785-1200
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Active, not recruiting
      • Memorial Sloan Kettering Basking Ridge
    • Middletown, New Jersey, United States, 07748
      • Active, not recruiting
      • Memorial Sloan Kettering Monmouth
    • Montvale, New Jersey, United States, 07645
      • Active, not recruiting
      • Memorial Sloan Kettering Bergen
  • New York
    • Commack, New York, United States, 11725
      • Active, not recruiting
      • Memorial Sloan Kettering Suffolk - Commack
    • Harrison, New York, United States, 10604
      • Active, not recruiting
      • Memorial Sloan Kettering Westchester
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10065
      • Active, not recruiting
      • Memorial Sloan Kettering Cancer Center
    • Rockville Centre, New York, United States, 11553
      • Active, not recruiting
      • Memorial Sloan Kettering Nassau
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Children's Hospital of Philadelphia
      • Contact: Susan McClory, MD, PhD; Phone Number: 267-426-0762
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Contact: Caridad Martinez, MD; Phone Number: 832-822-4242
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Children's Hospital of Wisconsin
      • Contact: Larisa Broglie, MD; Phone Number: 414-266-2420

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. 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)12 - Patients with autoinflammatory disorders evidenced by cytokine or inflammation assays with at least 1.5x ULN of measured cytokines (defined in section 4) and/or an elevated ferritin or ESR > 2 ULN
   • For inclusion on the emapalumab group, the lesion must be related 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 IFNy pathway defect
2. Able to tolerate cytoreduction (based on adequate organ function as described below)
3. Patients of any age can enroll so long as they meet all other eligibility criteria

4. Adequate organ function is required, defined as follows:

   • Hepatic: Serum bilirubin ≤ 2 mg/dL, unless benign congenital hyperbilirubinemia. Patients with hyperbilirubinemia related to paroxysmal nocturnal hemoglobinuria or other hemolytic disorders related to their PIRD diagnosis are eligible.
   • Hepatic: AST, 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.
   • Renal: serum creatinine <1.5x normal for age. If serum creatinine is outside the normal range, then CrCl > 50 mL/min/1.73m^2 (calculated or estimated) or GFR (mL/min/1.72m^2) >30% of predicted normal for age.
   • Cardiac: LVEF ≥ 50% by MUGA or resting echocardiogram.
   • Pulmonary: Pulmonary function testing (FEV1 and corrected DLCO) ≥ 50% predicted (pediatric patients unable to complete PFTs will need oxygen saturation as recorded by pulse oximetry of ≥92% on room air).

5. Adequate performance status:

   • Age ≥ 16 years: ECOG ≤ 1 or Karnofsky ≥ 70%
   • Age < 16 years: Lansky 70%
6. 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 Inclusion Criteria:

1. Related Donors:

   • 8/8 or 7/8 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

2. Unrelated Donors:

   • 8/8 or 7/8 matched at A, B, C, and DRB1 loci, as tested by DNA analysis.
3. Able to provide informed consent for the donation process per institutional standards.
4. Meet standard criteria for donor collection (e.g. National Marrow Donor Program Guidelines or collecting center guidelines as approved by treating physician).

Exclusion Criteria:

1. Uncontrolled infection at the time of enrollment.
2. Patients who have undergone previous allo-HCT.
3. Patient seropositivity for HIV I/II and/or HTLV I/II.
4. Females who are pregnant or breastfeeding.
5. Patients unwilling to use contraception during the study period.
6. Patient or parent or guardian unable to give informed consent or unable to comply with the treatment protocol including research tests.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Emapalumab (for isolated Interferongamma mediated disease); Participants in this group will receive emapalumab on Days -22 (22 days before the day of the stem cell transplant), -15, -8, and -1.	Drug: Emapalumab; Emapalumab on Days -22 (22 days before the day of the stem cell transplant), -15, -8, and -1.; Other Names: Gamifant; Procedure: Allogeneic hematopoietic stem cell transplant (allo-HCT); Participants in both groups will receive their standard-of-care stem cell transplant on Day 0.; Other Names: stem cell transplant
Experimental: Group B: Fludarabine and Dexamethasone (for generalized autoinflammation); Participants in this group will receive fludarabine and dexamethasone for 5 days in a row on Days -22 through -18.	Drug: Fludarabine and Dexamethasone; Fludarabine and dexamethasone for 5 days in a row on Days -22 through -18.; Procedure: Allogeneic hematopoietic stem cell transplant (allo-HCT); Participants in both groups will receive their standard-of-care stem cell transplant on Day 0.; Other Names: stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment	Engraftment is defined as the first of three days of absolute neutrophil count >500,000/µL and the first of seven days of platelets >20,000/µL in the absence of transfusional support.	Day 100 post-alloHCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall Survival (OS) is defined as the duration of time between allo-HCT and death due to any cause.	1 year
Event Free Survival (EFS)	Event-Free Survival (EFS) is the length of time from the start of a treatment or study until a patient experiences a defined negative "event" (such as disease recurrence, progression, or death).	Up to 2 years post-alloHCT
Non-Relapse Mortality (TRM)	Participants who die for any reason after disease recurrence are considered to have experienced disease related mortality, and will be counted as competing events. Patients alive will be censored at the day of last follow up.	1 year
GVHD free/relapse free survival (GRFS)	Duration of time between transplantation and development of grade III-IV GVHD, chronic GVHD requiring systemic therapy, disease relapse, or death, whichever occurs first.	1 year
Chronic graft vs host disease/relapse free survival (CRFS)	Duration of time between transplantation and development of moderate or severe chronic GVHD (NIH consensus criteria), or death, whichever occurs first.	1 year
All-cause mortality at 1 & 2 years		1 year and 2 years post-alloHCT
Incidence of viral reactivations	Incidence of viral reactivations including: Cytomegalovirus (CMV), Adenovirus, Epstein-Barr Virus (EBV), Human Herpes-6 (HHV6), BK-virus defined as viral reactivations necessitating use of anti-viral treatment.	1 year
Incidence of Acute graft versus host disease (GVHD) at Day 100, 180, and 1-year follow-up		Day 100, 180, and 1 year post-alloHCT
Incidence of Chronic GVHD at Day 180 and 1-year follow-up		Day 180 and 1 year post-alloHCT
Time to neutrophil engraftment	Neutrophil engraftment is defined as the first of 3 consecutive days of absolute neutrophil count (ANC) ≥ 500 K/µL.	100 days
Time to platelet engraftment	Platelet engraftment is defined as the first of 7 consecutive days with a platelet count exceeding 20,000/µL without transfusion support.	100 days
Incidence of primary engraftment failure	Primary engraftment failure is defined as failure to achieve neutrophil engraftment by Day 30 after transplantation.	Day 30 post-alloHCT
Incidence of secondary engraftment failure	Secondary engraftment failure is defined as <500/µL circulating neutrophils at any time after primary engraftment that is not attributed to disease recurrence or drug therapy.	1 year post-alloHCT
Donor Chimerism	The percentage of donor contribution to hematopoiesis (chimerism) will be determined using short tandem repeat (STR) based analysis of the peripheral blood (Chimerism - all lineages on Day 30, 100, 180, and 365) and bone marrow (all samples obtained post-alloHCT).	Day 30, 100, 180, and 1 year post-alloHCT
Incidence of grade ≥ 3 non-hematologic adverse events	Incidence of grade ≥ 3 non-hematologic adverse events as defined by CTCAE version 5.0 at Day 100, 180, and 1 year post allo-HCT.	Day 100, 180, and 1 year post-alloHCT
Lymphocyte Reconstitution	CD4+ Immune Reconstitution (CD4+IR) is defined at CD4+ > 50u/L at two consecutive measures within 100 days post-alloHCT. Lymphocyte subsets (includes CD3, CD4, CD8, CD19, CD56+16, CD45RA, CD45) will be documented by flow cytometry.	Day 30, 60, 100, 180, and 1 year and 2 years post-alloHCT
Quality of Life (PROMIS score)	Patient-reported outcomes will be self-reported using the PROMIS Profile Measure Scores. Scores are reported as standardized T-scores based on a U.S. general population average of 50 and a standard deviation of 10.	up to 3 years post-alloHCT
Percentage of patients who are eligible to proceed to transplant after receiving an immune suppression prophase		30 days

Collaborators and Investigators

• Sponsor: Joseph Oved
• Collaborators: Sobi, Inc.
• Investigators: Principal Investigator: Joseph Oved, MD, Columbia University

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2023
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: March 15, 2023
• First Submitted That Met QC Criteria: March 15, 2023
• First Posted (Actual): March 28, 2023

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Dexamethasone; Fludarabine; Stem Cell Transplant; Emapalumab
• Additional Relevant MeSH Terms: Immune System Diseases; Therapeutics; Surgical Procedures, Operative; Polycyclic Compounds; Transplantation; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Pregnadienetriols; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Dexamethasone; fludarabine; Stem Cell Transplantation; Emapalumab
• Other Study ID Numbers: AAAV8620; R01FD007829 (U.S. FDA Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No