Addition of JSP191 (C-kit Antibody) to Non-myeloablative Hematopoietic Cell Transplantation For Sickle Cell Disease and Beta-Thalassemia

• Status: Recruiting
• Trial end date: 2033-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Study Description:

We propose to add JSP191, 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 JSP191 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 (JSP191) would increase proportion of patients with donor myeloid chimerism >=98% at 1 year post transplant

Secondary Objectives:

• To measure JSP191 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:

• JSP 191 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

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Treatments: Alemtuzumab; Hydroxyurea; Plerixafor; Sirolimus

Criteria

• INCLUSION CRITERIA:

Recipient: patients must fulfill one disease category and all of

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 (37-39).

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 (40); OR

D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting >=4 hours involving the corpora cavernosa and corpus spongiosa (41); 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:

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

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.

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.

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