Siplizumab for Sickle Cell Disease Transplant

Registration Number
NCT06078696
Lead Sponsor
Markus Mapara
Brief Summary

The purpose of this study is to find out whether siplizumab is safe and effective for patients with SCD undergoing an allogeneic transplant and to prevent development of Graft versus Host Disease (GVHD) and graft failure. The main goals of this study are :
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Detailed Description

Phase I/II label single arm safety assessment study of Siplizumab-based conditioning. It is designed to determine the safety and feasibility of hematopoietic stem cell transplantation for patients with advanced sickle cell disease using in vivo T cell depletion with Siplizumab.
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Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
18
Inclusion Criteria

  1. Patients with sickle cell anemia (Hb SS, Sβ0 thalassemia or severe SC) who are 18 - 50 years of age inclusive AND who have 1 or more of the following:

    1. Clinically significant neurologic event (stroke) or any neurological deficit lasting at least 24 hours. Stroke will be defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI or cerebral arteriopathy requiring chronic transfusion therapy.
    2. History of two or more episodes of ACS in the 2-year period preceding enrollment despite supportive care measures (i.e. asthma therapy and/or hydroxyurea).
    3. History of three or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea).
    4. Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for 1 year or more to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and ACS)
    5. An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity > or equal to 2.7 m/sec or pulmonary hypertension diagnosed by right heart catheterization.
    6. Chronic kidney disease including patients on hemo-dialysis
    7. Recurrent tricorporal priapism defined as at least 2 episodes of an erection last ≥4 hours involving the corpus cavernosa and corpus spongiosa.
    8. Recipient cannot be pregnant or lactating.

  2. Adequate organ functions as defined as:

    1. Eastern Cooperative Group (ECOG) performance status of 2 or better
    2. Cardiac function: left ventricular ejection fraction (LVEF) of 40% or greater
    3. Pulmonary Function: Pulse oximetry with a baseline oxygen saturation of 85% or greater and corrected diffusing capacity of the Lungs for carbon monoxide (DLCO) of 35% or greater
    4. Hepatic Function: Serum conjugated (direct) bilirubin less than 3x upper limit of normal for age as per local laboratory, alanine aminotransferase (ALT) and aspartate transaminase (AST) less than 5 x upper limit of normal as per local laboratory. Patients whose hyperbilirubinemia is the result of hyperhaemolysis, or a sever drop in hemoglobin post blood transfusion are not excluded.
    5. Absence of liver cirrhosis, bridging fibrosis and active hepatitis as documented by liver biopsy for patients with evidence of iron overload by serum ferritin or MRI. The histological grading and scale described by Ishak and colleagues (1995) will be used.

  3. Patient must have a matched-or mismatched unrelated donor or mismatched related family donor.

    1. For HLA-matching we will assess 12 HLA-antigens (HLA-A, B, C, DRB1, DQB1 and DPB1).
    2. Fully matched unrelated transplanted are defined as matched at 12/12 HLA-alleles. We will include up to 7/8 (HLA-A, B, C, and DRB1) matched unrelated donors.
    3. One haplotype-mismatched related donors will be included.

Recipient

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Exclusion Criteria
  1. Pulmonary dysfunction defined as DLCO (corrected for hemoglobin and alveolar volume) < 35% of predicted OR baseline oxygen saturation of <85% or oxygen pressure in arterial blood (PaO2) <70.
  2. Severe cardiac dysfunction defined as ejection fraction <45% or subjects who have been receiving chronic transfusion therapy for > 1 year and have evidence of iron overload (serum ferritin levels >1000 ng/mL), a cardiac MRI is required. Cardiac T2* <10 ms results in exclusion.
  3. Liver iron content (LIC) ≥15 mg Fe/g dry weight on R2 MRI of liver, unless liver biopsy within 3 months prior to or at screening shows no evidence of bridging fibrosis or cirrhosis. Presence of bridging (portal to portal) fibrosis or cirrhosis in liver biopsy OR transaminases >5x normal upper limit (ULN) for age or direct bilirubin >3x normal upper limit (ULN).
  4. Clinical stroke within 6 months of anticipated transplant
  5. Karnofsky performance score < 50%
  6. HIV infection
  7. Uncontrolled viral, bacterial, fungal, or protozoal infection at the time of study enrollment.
  8. Patient with unspecified chronic toxicity serious enough to detrimentally affect the patient's capacity to tolerate HSCT in the opinion of the investigator.
  9. Patient unable to understand the nature and risks inherent in the HSCT process.
  10. History of non-compliance severe enough in the estimation of the treating team to preclude the patient from undergoing unrelated donor transplantation.
  11. Patient is pregnant or lactating.
  12. Inability to provide adequate transfusion support or increased risk immunohematological complications due presence of anti-RBC antibody against stem cell donor.
  13. Presence of donor-specific HLA antibodies

Donor Eligibility and Selection Criteria

Please note, donor selection will follow our institutional standard operating procedure (SOP). Key criteria are summarized below for convenience:

  1. Donor should be evaluated for eligibility to donate by an independent physician not directly caring for the patient on study protocol
  2. Donor is willing to sign informed consent allowing the use of the peripheral blood stem cell (PBSC) product for the hematopoietic stem cell transplant (HSCT) of the recipient
  3. Donor must meet HLA match criteria outlined in the inclusion criteria above
  4. Donor cannot be pregnant or lactating and must agree to contraception until after the donation procedure is complete
  5. Testing negative for HIV and viral hepatitis
  6. Free of Hb S (defined as Hb S less than 50%) and other hemoglobinopathies that are symptomatic or of clinical significance
  7. Targeted minimum stem cell dose of 5.0 x 10e6 CD34 cells/Kg (a marker of human hematopoietic stem cells) of recipient weight 8. Fulfills standard criteria for eligibility as a donor for hematopoietic stem cell transplant (HSCT)
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
SiplizumabExchange TransfusionParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabTotal Body IrradiationParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabStem Cell InfusionParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabCyclophosphamide 50mgParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabSirolimus Oral TabletParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabRituximab or BiosimilarParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabSiplizumabParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
SiplizumabMesnaParticipants will receive 5 infusions of siplizumab. The first dose is given 14 days prior to the infusion of stem cells; the second dose is given 6 days before infusion; and doses 3, 4, and 5 are given on the day before, day of, and day after stem cell infusion.
Primary Outcome Measures
NameTimeMethod
Failure Rate12 Months Post Stem Cell Transplant

Failure rate is a safety endpoint. Failure rate is defined as: graft failure (Primary Graft Rejection: Primary graft rejection is defined as the absence of donor cells (% donor cells \< 5%) assessed by bone marrow or peripheral blood chimerism assays by Day 42. Late Graft Rejection: The absence (\<5%) of donor hematopoietic cells in peripheral blood or bone ...

Secondary Outcome Measures
NameTimeMethod
Time to EngraftmentDay 100

Time to neutrophil engraftment is defined as the first of 3 measurements on consecutive days when the patient has an absolute neutrophil count of 500/μL after conditioning. Time to platelet engraftment will be defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count \> 50,000/μL AND did not rece...

Incidence of GVHD of Any Grade12 Months Post Stem Cell Transplant

Incidence of acute and chronic GVHD of any grade as evaluated according to the CIBMTR and NIH criteria respectively.

Incidence of other transplant related toxicities12 Months Post Stem Cell Transplant

Incidence of other transplant related toxicities, including Veno-occlusive disease (VOD), Idiopathic pneumonia syndrome (IPS), Central nervous system (CNS) toxicity, or Posterior reversible encephalopathy syndrome (PRES).

Incidence of Significant transplant-related infections12 Months Post Stem Cell Transplant

Significant infections will be recorded including but not limited to bacterial or fungal sepsis, cytomegalovirus (CMV) reactivation with/without clinical disease, adenovirus infection, epstein-barr virus (EBV) reactivation with or without post-transplant lymphoproliferative disorders (PTLD), other significant viral reactivations or community-acquired viral i...

Number of participants with donor chimerism >5%Day 30, Day 100, and 1 year

Chimerism is a measure of the engraftment of donor cells within the recipient and is expressed as the percentage ratio between the number of donor cells and recipient cells. Chimerism will be determined by Short Tandem Repeat analysis.

Percentage of Participants who Achieve Immune Reconstitution12 Months Post Stem Cell Transplant

Peripheral blood quantitative assessment of the main lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, and CD16+/56+). Lymphocytes will be assessed by flow cytometry. In addition, quantitative immunoglobulins will be measured for Immunoglobulin A (IgA), Immunoglobulin M (IgM) and Immunoglobulin (IgG). These will be performed at Day +60 (±10 days) as well a...

Trial Locations

Locations (1)

Columbia University Irving Medical Center

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New York, New York, United States

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