Autoimmune Lymphoproliferative, Immune System Diseases, Primary Immune Regulatory Disorder
Conditions
Keywords
Stem Cell Transplant, Emapalumab, Fludarabine, Dexamethasone
Brief summary
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"
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.
Interventions
DRUGEmapalumab
Emapalumab on Days -22 (22 days before the day of the stem cell transplant), -15, -8, and -1.
DRUGFludarabine and Dexamethasone
Fludarabine and dexamethasone for 5 days in a row on Days -22 through -18.
PROCEDUREAllogeneic hematopoietic stem cell transplant (allo-HCT)
Participants in both groups will receive their standard-of-care stem cell transplant on Day 0.
Sponsors
Joseph Oved
Sobi, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a two-stage phase 2 study.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment | Day 100 post-alloHCT | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 1 year | Overall Survival (OS) is defined as the duration of time between allo-HCT and death due to any cause. |
| Event Free Survival (EFS) | Up to 2 years post-alloHCT | 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). |
| Non-Relapse Mortality (TRM) | 1 year | 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. |
| GVHD free/relapse free survival (GRFS) | 1 year | Duration of time between transplantation and development of grade III-IV GVHD, chronic GVHD requiring systemic therapy, disease relapse, or death, whichever occurs first. |
| Chronic graft vs host disease/relapse free survival (CRFS) | 1 year | Duration of time between transplantation and development of moderate or severe chronic GVHD (NIH consensus criteria), or death, whichever occurs first. |
| All-cause mortality at 1 & 2 years | 1 year and 2 years post-alloHCT | — |
| Incidence of viral reactivations | 1 year | 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. |
| 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 | 100 days | Neutrophil engraftment is defined as the first of 3 consecutive days of absolute neutrophil count (ANC) ≥ 500 K/µL. |
| Time to platelet engraftment | 100 days | Platelet engraftment is defined as the first of 7 consecutive days with a platelet count exceeding 20,000/µL without transfusion support. |
| Incidence of primary engraftment failure | Day 30 post-alloHCT | Primary engraftment failure is defined as failure to achieve neutrophil engraftment by Day 30 after transplantation. |
| Incidence of secondary engraftment failure | 1 year post-alloHCT | 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. |
| Donor Chimerism | Day 30, 100, 180, and 1 year post-alloHCT | 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). |
| Incidence of grade ≥ 3 non-hematologic adverse events | Day 100, 180, and 1 year post-alloHCT | 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. |
| Lymphocyte Reconstitution | Day 30, 60, 100, 180, and 1 year and 2 years post-alloHCT | 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. |
| Quality of Life (PROMIS score) | up to 3 years post-alloHCT | 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. |
| Percentage of patients who are eligible to proceed to transplant after receiving an immune suppression prophase | 30 days | — |
Countries
United States
Contacts
CONTACTJoseph Oved, MD
PRINCIPAL_INVESTIGATORJoseph Oved, MD
Columbia University
Outcome results
None listed