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Addition of JSP191 (C-kit Antibody) to Nonmyeloablative Hematopoietic Cell Transplantation for Sickle Cell Disease and Beta-Thalassemia

Primary Purpose

Sickle Cell Anemia, Beta Thalassemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
TBI
Hydroxyurea
briquilimab
Filgrastim (G-CSF)
Sirolimus
Alemtuzumab
Plerixafor
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Anemia focused on measuring Myeloid Chimerism, Lymphoid Cells, Myeloid Cells, Donor Leukocyte Engraftment, Non-Myeloablative Conditioning

Eligibility Criteria

4 Years - 100 Years (Child, Adult, Older Adult)All SexesAccepts Healthy Volunteers
  • INCLUSION CRITERIA:

Recipient: patients must fulfill one disease category under inclusion criteria 1 and all of criteria 2

1. Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having an end-organ damage (A, B, C, D, or E) or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F):

A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (>=200 m/s); OR

B. Sickle cell related renal insufficiency defined by a creatinine level >=1.5 times the upper limit of normal (see table below) and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance <60mL/min/1.73m2 for patients <16 years of age or <50mL/min for patients >16 years of age OR requiring peritoneal or hemodialysis. OR

Age (Years) Upper limit of normal serum creatinine (mg/dl)

<= 5 0.8

5 < age <= 10 1.0

10 < age <= 15 1.2

> 15 1.3

C. Tricuspid regurgitant jet velocity (TRV) of >=2.5 m/s in patients >=18 years of age at least 3 weeks after a vaso-occlusive crisis; OR

D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting >=4 hours involving the corpora cavernosa and corpus spongiosa; OR

E. Sickle hepatopathy defined as EITHER ferritin >1000mcg/L OR direct bilirubin >0.4 mg/dL at baseline in patients >18 years of age; OR

F. Any one of the below complications:

Complication - Eligible for HSCT

  • Vaso-occlusive crises- More than 1 hospital admission per year while on a therapeutic dose of sickle cell treatment /medication
  • Acute chest syndrome (ACS)- Any ACS while on sickle cell treatment /medication
  • Osteonecrosis of 2 or more joints- And on sickle cell treatment /medication where total hemoglobin increase less than 1 g/dL or fetal hemoglobin increases <2.5 times the baseline level
  • Red cell alloimmunization- Total hemoglobin increase <1 g/dL while on therapeutic doses of sickle cell treatment /medication

Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following:

  • portal fibrosis by liver biopsy
  • inadequate chelation history (defined as failure to maintain adequate compliance with chelation with deferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week)
  • hepatomegaly of greater than 2 cm below the costochondral margin or by other imaging scans

    2. Non disease specific

    • Ages >=4 years (>=18 years for phase 1 portion of the study)
    • 6/6 HLA matched family donor available
    • Ability to comprehend and willing to sign an informed consent, assent obtained from minors
    • Negative serum or urine -HCG, when applicable
    • Agree to use birth control throughout the study and 12 months after drug product infusion.
  • Female subjects must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from start of screening through 12 months after drug product infusion.
  • Male subjects must agree to use effective contraception (including condoms) from start of screening through 12 months after drug product infusion.

    3. Patients and Capacity to Consent

    • Subject provides informed consent prior to initiation of any study procedures.
    • Subject understands and agrees to comply with planned study procedures.

      4. Donor

Fully matched human leukocyte antigen (HLA) donors at A, B, C, and DR loci (8 of 8 or 10 of 10) are intended for this study. Donors age 4 or older and >=20 kg, eligible to donate hematopoietic stem cells, who are additionally willing to donate blood for research are eligible for this study. Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all eligible donors, but is Abbreviated Title: CD117 Antibody in MRD HCT for beta globin disorders not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study.

EXCLUSION CRITERIA:

Recipient exclusion criteria

  • ECOG performance status of 3 or more, or Lanksy performance status of <40 (See Appendix A).
  • Diffusion capacity of carbon monoxide (DLCO) <35% predicted (corrected for hemoglobin and alveolar volume).
  • Baseline oxygen saturation of <85% or PaO2 <70
  • Left ventricular ejection fraction: <35% estimated by ECHO
  • Transaminases >5x upper limit of normal for age
  • Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen
  • Major anticipated illness or organ failure incompatible with survival from PBSC transplant.
  • Pregnant or breastfeeding

Donor exclusion criteria

  • Pregnant or breastfeeding
  • Cognitively impaired subjects

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

briquilimab in stem cell transplant recipients for SCD

Stem cell Donors of Recipients undergoing stem cell transplant

Arm Description

Affected SCD and beta-thal subjects will receive briquilimab

Participants donate stem cells for recipient to undergo stem cell transplant

Outcomes

Primary Outcome Measures

percent myeloid (CD14/15) chimerism
The primary objective is to determine if addition of CD117 antibody (JSP191) would increase proportion of patients with donor myeloid chimerism =98% at 1 year post transplant.

Secondary Outcome Measures

Transplant related mortality
Transplant related mortality
Rates of graft failure
Rates of graft failure
Rate of viral infection and/or reactivation
Rate of viral infection and/or reactivation
Alemtuzumab levels
To measure alemtuzumab clearance at 1 and 2 years post transplant
Rate of chronic GVHD
Rate of chronic graft vs host disease (GvHD)
Days to neutrophil engraftment
Day of neutrophil engraftment
JSP antibody PK levels
To measure JSP191 and alemtuzumab clearance at 1 and 2 years post transplant
Proportion of patients with donor myeloid chimerism at or above 75%
Estimate the proportion of patients with donor myeloid chimerism at or above 75%
Non-transplant related mortality
Non-transplant related mortality
Rate of bacterial infection
Rate of bacterial infection
Rates of acute GVHD
Rate of acute graft vs host disease (GvHD)

Full Information

First Posted
April 30, 2022
Last Updated
October 20, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT05357482
Brief Title
Addition of JSP191 (C-kit Antibody) to Nonmyeloablative Hematopoietic Cell Transplantation for Sickle Cell Disease and Beta-Thalassemia
Official Title
Addition of JSP191 (C-kit Antibody) to Non-myeloablative Hematopoietic Cell Transplantation For Sickle Cell Disease and Beta-Thalassemia
Study Type
Interventional

2. Study Status

Record Verification Date
October 19, 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 12, 2022 (Actual)
Primary Completion Date
November 1, 2032 (Anticipated)
Study Completion Date
November 1, 2033 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Background: Sickle cell disease (SCD) is an inherited disorder of the blood. It can damage a person s organs and cause serious illness and death. A blood stem cell transplant is the only potential cure for SCD. Treatments that improve survival rates are needed. Objective: To find out if a new antibody drug (briquilimab, JSP191) improves the success of a blood stem cell transplant Eligibility: People aged 13 or older who are eligible for a blood stem cell transplant to treat SCD. Healthy family members over age 13 who are matched to transplant recipients are also needed to donate blood. Design: Participants receiving transplants will undergo screening. They will have blood drawn. They will have tests of their breathing and heart function. They may have chest x-rays. A sample of marrow will be collected from a pelvic bone. Participants will remain in the hospital about 30 days for the transplant and recovery. They will have a large intravenous line inserted into the upper arm or chest. The line will remain in place for the entire transplant and recovery period. The line will be used to draw blood as needed. It will also be used to administer the transplant stem cells as well as various drugs and blood transfusions. Participants will also receive some drugs by mouth. Participants must remain within 1 hour of the NIH for 3 months after transplant. During that time, they will visit the clinic up to 2 times a week. Follow-up visits will include tests to evaluate participants mental functions. They will have MRI scans of their brain and heart.
Detailed Description
Study Description: We propose to add briquilimab, an antibody targeting CD117 (c-Kit), to the 03-H-0170 regimen to improve myeloid chimerism, in patients considered at high risk for complications from or ineligible from standard myeloablative HSCT. Given the preclinical and clinical data, the addition of briquilimab has the potential to further deplete host lymphoid and myeloid cells to achieve a higher percentage of donor leukocyte engraftment without increased toxicity. Our prior non-myeloablative conditioning (NMA) regimen includes 1 mg/kg of alemtuzumab divided over 5 days, 300 cGy total body irradiation (TBI), and sirolimus for immune suppression. This regimen demonstrated a disease-free survival (DFS) and overall survival (OS) of 87% and 94% respectively, a 13% graft failure rate, no treatment related mortality (TRM), and no acute or chronic GVHD. A large proportion of patients achieves robust (>=98%) donor myeloid chimerism early, but this proportion decreases to 57% at 1, 54% at 2, and 49% at 3, and 50% at 4 years post transplant.Monoclonal antibodies (mAb) targeting human stem cells (HSCs) is one strategy to improve DFS and may have synergy when combined with TBI as part of transplant conditioning regimen. Objectives: Primary Objective: -To determine if addition of CD117 antibody (briquilimab) would increase proportion of patients with donor myeloid chimerism >=98% at 1 year post transplant Secondary Objectives: To measure briquilimab and alemtuzumab clearance at 1 and 2 years post transplant: To compare CD14/15 and CD3 chimerism to protocol 03-H-0170 Estimate the proportion of patients with donor myeloid chimerism at or above 75% To assess the usual transplant related parameters, such as count recovery, transfusion support, rates of GVHD, viral/bacterial infections, and rates of transplant related and overall mortality, and compare to those results in 03-H-0170 Endpoints: Primary Endpoint: -Percent myeloid (CD14/15) chimerism Secondary Endpoints: Briquilimab antibody PK levels Alemtuzumab levels Percent T cell (CD3) chimerism Day of neutrophil engraftment Day of platelet engraftment Rates of viral infection and/or reactivation Rates of bacterial infection Rates of acute and chronic GVHD Transplant related mortality Non-transplant related mortality Rates of graft failure Quality of life and neuropsychologic function

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Anemia, Beta Thalassemia
Keywords
Myeloid Chimerism, Lymphoid Cells, Myeloid Cells, Donor Leukocyte Engraftment, Non-Myeloablative Conditioning

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
briquilimab in stem cell transplant recipients for SCD
Arm Type
Experimental
Arm Description
Affected SCD and beta-thal subjects will receive briquilimab
Arm Title
Stem cell Donors of Recipients undergoing stem cell transplant
Arm Type
No Intervention
Arm Description
Participants donate stem cells for recipient to undergo stem cell transplant
Intervention Type
Radiation
Intervention Name(s)
TBI
Intervention Description
300 cGy total body irradiation (TBI, day -2)
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Intervention Description
Optimized 4-12 weeks prior to planned transplant date
Intervention Type
Biological
Intervention Name(s)
briquilimab
Intervention Description
briquilimab, anti-CD117 monoclonal antibody at 0.6mg/kg at day -11 prior to infusion of allogeneic HSCs
Intervention Type
Drug
Intervention Name(s)
Filgrastim (G-CSF)
Intervention Description
May be used to minimize the days of neutropenia, and may be administered beginning near day 10 post stem cell infusion at 5 mcg/kg (rounding to the nearest vial) at the discretion of investigator.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Intervention Description
For immune suppression (day -1)
Intervention Type
Biological
Intervention Name(s)
Alemtuzumab
Intervention Description
Alemtuzumab 1 mg/kg of alemtuzumab divided over 5 days (-7 through -3),
Intervention Type
Drug
Intervention Name(s)
Plerixafor
Intervention Description
For autologous HSC collection; dose of plerixafor at 240 mcg/kg (capped at 20mg)
Primary Outcome Measure Information:
Title
percent myeloid (CD14/15) chimerism
Description
The primary objective is to determine if addition of CD117 antibody (JSP191) would increase proportion of patients with donor myeloid chimerism =98% at 1 year post transplant.
Time Frame
1 year post transplant
Secondary Outcome Measure Information:
Title
Transplant related mortality
Description
Transplant related mortality
Time Frame
1 and 2 years post transplant
Title
Rates of graft failure
Description
Rates of graft failure
Time Frame
1 and 2 years post transplant
Title
Rate of viral infection and/or reactivation
Description
Rate of viral infection and/or reactivation
Time Frame
day 100
Title
Alemtuzumab levels
Description
To measure alemtuzumab clearance at 1 and 2 years post transplant
Time Frame
day 100
Title
Rate of chronic GVHD
Description
Rate of chronic graft vs host disease (GvHD)
Time Frame
1 and 2 years post transplant
Title
Days to neutrophil engraftment
Description
Day of neutrophil engraftment
Time Frame
day 100
Title
JSP antibody PK levels
Description
To measure JSP191 and alemtuzumab clearance at 1 and 2 years post transplant
Time Frame
day 100
Title
Proportion of patients with donor myeloid chimerism at or above 75%
Description
Estimate the proportion of patients with donor myeloid chimerism at or above 75%
Time Frame
1 and 2 years post transplant
Title
Non-transplant related mortality
Description
Non-transplant related mortality
Time Frame
1 and 2 years post transplant
Title
Rate of bacterial infection
Description
Rate of bacterial infection
Time Frame
1 and 2 years post transplant
Title
Rates of acute GVHD
Description
Rate of acute graft vs host disease (GvHD)
Time Frame
1 and 2 years post transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
INCLUSION CRITERIA: Recipient: patients must fulfill one disease category under inclusion criteria 1 and all of criteria 2 1. Patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having an end-organ damage (A, B, C, D, or E) or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F): A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (>=200 m/s); OR B. Sickle cell related renal insufficiency defined by a creatinine level >=1.5 times the upper limit of normal (see table below) and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome OR creatinine clearance <60mL/min/1.73m2 for patients <16 years of age or <50mL/min for patients >16 years of age OR requiring peritoneal or hemodialysis. OR Age (Years) Upper limit of normal serum creatinine (mg/dl) <= 5 0.8 5 < age <= 10 1.0 10 < age <= 15 1.2 > 15 1.3 C. Tricuspid regurgitant jet velocity (TRV) of >=2.5 m/s in patients >=18 years of age at least 3 weeks after a vaso-occlusive crisis; OR D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting >=4 hours involving the corpora cavernosa and corpus spongiosa; OR E. Sickle hepatopathy defined as EITHER ferritin >1000mcg/L OR direct bilirubin >0.4 mg/dL at baseline in patients >18 years of age; OR F. Any one of the below complications: Complication - Eligible for HSCT Vaso-occlusive crises- More than 1 hospital admission per year while on a therapeutic dose of sickle cell treatment /medication Acute chest syndrome (ACS)- Any ACS while on sickle cell treatment /medication Osteonecrosis of 2 or more joints- And on sickle cell treatment /medication where total hemoglobin increase less than 1 g/dL or fetal hemoglobin increases <2.5 times the baseline level Red cell alloimmunization- Total hemoglobin increase <1 g/dL while on therapeutic doses of sickle cell treatment /medication Patients with beta-thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following: portal fibrosis by liver biopsy inadequate chelation history (defined as failure to maintain adequate compliance with chelation with deferoxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week) hepatomegaly of greater than 2 cm below the costochondral margin or by other imaging scans 2. Non disease specific Ages >=4 years (>=18 years for phase 1 portion of the study) 6/6 HLA matched family donor available Ability to comprehend and willing to sign an informed consent, assent obtained from minors Negative serum or urine -HCG, when applicable Agree to use birth control throughout the study and 12 months after drug product infusion. Female subjects must agree to use a medically acceptable method of birth control such as oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from start of screening through 12 months after drug product infusion. Male subjects must agree to use effective contraception (including condoms) from start of screening through 12 months after drug product infusion. 3. Patients and Capacity to Consent Subject provides informed consent prior to initiation of any study procedures. Subject understands and agrees to comply with planned study procedures. 4. Donor Fully matched human leukocyte antigen (HLA) donors at A, B, C, and DR loci (8 of 8 or 10 of 10) are intended for this study. Donors age 4 or older and >=20 kg, eligible to donate hematopoietic stem cells, who are additionally willing to donate blood for research are eligible for this study. Donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all eligible donors, but is Abbreviated Title: CD117 Antibody in MRD HCT for beta globin disorders not required for a donor to make a stem cell donation, so it is possible that not all donors will enroll onto this study. EXCLUSION CRITERIA: Recipient exclusion criteria ECOG performance status of 3 or more, or Lanksy performance status of <40 (See Appendix A). Diffusion capacity of carbon monoxide (DLCO) <35% predicted (corrected for hemoglobin and alveolar volume). Baseline oxygen saturation of <85% or PaO2 <70 Left ventricular ejection fraction: <35% estimated by ECHO Transaminases >5x upper limit of normal for age Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen Major anticipated illness or organ failure incompatible with survival from PBSC transplant. Pregnant or breastfeeding Donor exclusion criteria Pregnant or breastfeeding Cognitively impaired subjects
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Priscilla S Pollack, R.N.
Phone
(301) 496-1781
Email
priscilla.pollack@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
John F Tisdale, M.D.
Phone
(301) 402-6497
Email
johntis@mail.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John F Tisdale, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY dial 711
Email
ccopr@nih.gov

12. IPD Sharing Statement

Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_000539-H.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Addition of JSP191 (C-kit Antibody) to Nonmyeloablative Hematopoietic Cell Transplantation for Sickle Cell Disease and Beta-Thalassemia

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