Graft Failure, Sickle Cell Disease, Hemoglobinopathies
Conditions
Brief summary
A single center, open label, interventional, phase II trial for donor transplant for high risk hemoglobinopathies and other red cell transfusion dependent disorders utilizing allogeneic hematopoietic stem cell transplantation (HSCT) regimens.
Interventions
DRUGThiotepa
Thiotepa will be administered at a dose 5 mg/kg IV every 12 hours on day - 7 over 2 hours. Patients will undergo thiotepa skin care per institutional guidelines
DRUGAlemtuzumab
Alemtuzumab (Campath) will be administered IV over 2 hours on day -8 to day -4.
RADIATIONTotal Body Irradiation
400 cGy in 2 split fractions will be administered per Department of RadiationOncology SOPs.
BIOLOGICALCell Infusion
On day 0 the cells will be infused per cell source specific institutional guidelines
DRUGThymoglobulin
ATG will be administered IV every 24 hours beginning on day -8 for all patients. Dosing will be model-based using Bayesian methodology13,14,15. Total doses and total number of doses (1-4 doses) will be determined based on absolute lymphocyte count and weight.
DRUGFludarabine
Fludarabine will be administered IV over 1 hour every 24 hours on day -5 to day - 2. The daily dose of fludarabine will be determined by model-based dosing utilizing Bayesian methodology with a cumulative area under the curve (cAUC) of 20 mg\*hr/L (range 18-22 mg\*hr/L).
DRUGBusulfan
Busulfan dosing and administration and therapeutic drug monitoring (TDM) per institutional guidelines. Initial busulfan dosing will be determined by model-based dosing utilizing Bayesian methods with a cumulative area under the curve (cAUC) of 75 mg\*hr/L.
DRUGCyclophosphamide
Cyclophosphamide will be administered at a dose of 14.5 mg/kg over 2 hours IV daily on days -6 and -5. Cyclophosphamide dosing is calculated based on actual body weight (ABW). For Arm D - Cyclophosphamide 50 mg/kg IV will be administered over 2 hours on days +3 and +4. Cyclophosphamide dosing for post-transplant is calculated based on ideal body weight (IBW) unless patient weighs less than IBW, in which case actual body weight (ABW) will be used.
DRUGSirolimus
Patients on Arm A and Arm D will receive sirolimus; beginning on day -3 and continuing until day +180 for patients on Arm A or beginning on day +5 and continuing until 1 year post transplant for patients on Arm D.
DRUGTacrolimus
Patients on Arm B and Arm C will receive tacrolimus, beginning on day -3 and continuing until day +180. Tacrolimus dosing and monitoring will be per institutional guidelines.
DRUGMycophenolate Mofetil
MMF will begin on day -3 (Arm A, B \& C) or day +5 (Arm D). Patients treated on adult service will receive 15 mg/kg (max 1500 mg/dose) given every 12 hours, rounded to nearest 250 mg. Patients on pediatric service will receive 15 mg/kg (max 1000 mg/dose) given every 8 hours. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. MMF will be stopped at day +30 (Arms A, B \& C) or day +35 (Arm D) or 7 days after engraftment, whichever day is later, if no acute GVHD.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Sickle Cell Disease (SCD) * SCD Patients with a fully matched sibling donor (MSD) irrespective of the frequency or severity of symptoms MSD transplant can be considered. Parents/patient must be counseled as to the risks and benefits and provide their voluntary informed consent * Transfusion Dependent Alpha- or Beta- Thalassemia * Diamond Blackfan Anemia * Other Non-Malignant Hematologic Disorders * Karnofsky ≥ 60%, Lansky play score ≥ 60. Patients with lower performance score can be considered based on study team's evaluation. * Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the transplant.
Exclusion criteria
* Pregnant, breastfeeding or intending to become pregnant during the study. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment * HIV Positive * Active, uncontrolled infection - infection that is stable or improving after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections) will be permitted * Known allergy to any of the study components * Psychiatric illness/social situations that, in the judgement of the enrolling Investigator, would limit compliance with study requirements * Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Graft versus Host Disease (GvHD) | 1 year |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 1 and 2 years | Overall survival post HCT |
| Grade 3-4 Acute GvHD | 2 years | Grade 3-4 acute Graft versus Host Disease (GvHD) at 2 years post HCT. |
| Chronic Graft versus Host Disease (GvHD) Free | 2 years | Chronic Graft versus Host Disease (GvHD) Free at 2 years post HCT. |
| Failure Free Survival | 2 years | Failure Free Survival 2 years post HCT. |
Countries
United States
Contacts
CONTACTAshish Gupta, MBBS, MPH
Outcome results
None listed