Transplantation Using Reduced Intensity Approach for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow (TRANSFORM)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02757885|
Recruitment Status : Recruiting
First Posted : May 2, 2016
Last Update Posted : June 14, 2019
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Disease||Procedure: Bone Marrow Transplant (BMT) Procedure: Bone Marrow Harvest (Donation) Drug: Hydroxyurea Drug: Thiotepa Drug: Fludarabine monophosphate Drug: Cyclophosphamide Other: Rabbit Anti-thymocyte Globulin Radiation: Total Body Irradiation||Phase 2|
The purpose of this study is to learn if it is possible and safe to treat persons with severe sickle cell disease (SCD) by bone marrow transplant (BMT) from human leukocyte antigen (HLA) half-matched related donors. Preparation before transplant includes the chemotherapy drugs hydroxyurea, fludarabine, thiotepa, anti-thymocyte globulin, and cyclophosphamide. It also includes radiation.
Investigators also seek to understand the side effects of BMT in adolescents and young adults with SCD and measure how often serious side effects occur including those that are expected and unexpected. After transplant, investigators will measure the health of the body organs that ordinarily would have been damaged by having SCD in addition to testing the lungs, brain, and kidneys.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||15 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Transplantation Using Reduced Intensity Approach for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow|
|Study Start Date :||April 2016|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2020|
Bone Marrow Donor
Participants who are related marrow donors and are 2-4 (out of 8) human leukocyte antigen (HLA) antigen mismatched and towards whom the recipient does not have donor specific antibodies.
Procedure: Bone Marrow Harvest (Donation)
The donation of bone marrow is a surgical procedure in which bone marrow is removed from the back of both of the hip bones through a large, hollow needle. At least two small cuts (less than ¼ inch) will be made in the skin to put the needle into the bone. Many small samples are collected through the needle into syringes. The total amount of marrow take will be up to ¼ ounce of marrow per pound. Bone marrow harvest is done under general anesthesia. Participants will be in the hospital for 8 to 10 hours.
Experimental: Bone Marrow Recipient
Participants with sickle cell disease (SCD) will receive bone marrow from a human leukocyte antigen (HLA) matched donor.
Procedure: Bone Marrow Transplant (BMT)
Participants will receive a bone marrow infusion from a human leukocyte antigen (HLA) matched donor through a central venous catheter.
Hydroxyurea is part of the bone marrow transplant preparative regimen. Hydroxyurea will be administered at a dose of 30 mg/kg orally as a single daily dose for 90 days (from day -100 to day-10). Hydroxyurea dosing will be based on adjusted body weight in participants weighing >125% ideal body weight.
Thiotepa is part of the bone marrow transplant preparative regimen. Thiotepa will be administered at a dose of 10mg/kg intravenously (IV) over 2 hours or per institutional guidelines on day -7. Thiotepa dosing will be based on adjusted body weight in patients weighing >125% ideal body weight.
Drug: Fludarabine monophosphate
Fludarabine is part of the bone marrow transplant preparative regimen. Fludarabine 30 mg/m2/day will be administered from day -7 to day -3 (for a total of 150 mg/m2 over 5 consecutive days) and administered intravenously (IV) over a minimum of 30 minutes. In participants weighing > 125% ideal body weight, fludarabine will be dose based upon adjusted body weight.
Cyclophosphamide is part of the bone marrow transplant preparative regimen. Cyclophosphamide will be administered on days -6 and -5 prior to bone marrow infusion at a dose of 14.5 mg/kg intravenously (IV) infused over 1-2 hours.
Post bone marrow infusion cyclophosphamide will be infused on days +3 (between 60 and 72 hours post marrow infusion) and +4 (approximately 24 hours after day +3 dose) at a dose of 50 mg/kg IV infused over 1-2 hours.
For participants weighing more than 125% of their ideal body weight, dosing will be based on adjusted ideal body weight.
Other: Rabbit Anti-thymocyte Globulin
Rabbit anti-thymocyte globulin (ATG) is part of the bone marrow transplant preparative regimen. It is an infusion of rabbit-derived antibodies against human T cells used for prevention of acute rejection in organ transplantation. Rabbit ATG will be administered on day -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (for a total dose 4.5 mg/kg).
Radiation: Total Body Irradiation
Participants will receive 200 cGy of TBI in a single fraction.
- Event-free Survival (EFS) Rate [ Time Frame: Up to One Year ]Event-free Survival (EFS) is defined as the survival with stable donor erythropoiesis with no new clinical evidence of sickle cell disease (SCD). Primary or late graft rejection with disease recurrence or death will count as events for this endpoint.
- Primary Graft Rejection Rate [ Time Frame: Day 42 ]Primary graft rejection is defined as the absence of donor cells assessed by peripheral blood chimerism assays on day 42. Primary graft rejection can be accompanied by pancytopenia and marrow aplasia or by autologous hematopoietic reconstitution without aplasia.
- Late Graft Rejection Rate [ Time Frame: Post Day 42 ]The absence of donor hematopoietic cells in peripheral blood beyond day 42 in a patient who had initial evidence of hematopoietic recovery with > 20% donor cells will be considered a late graft rejection.
- Rate of Disease Recurrence [ Time Frame: Up to One Year ]Disease recurrence is defined as the return of sickle erythropoiesis (HbS level > 70%) and the absence of donor cell representation.
- Overall Survival Rate [ Time Frame: Up to One Year ]Overall survival is defined as survival with or without sickle cell disease (SCD) after hematopoietic cell transplantation (HCT).
- Cumulative Incidence of Neutrophil Engraftment and Platelet Engraftment [ Time Frame: Up to One Year ]
Total time to neutrophil engraftment and time to platelet engraftment. Time to neutrophil engraftment is defined as the first of 3 measurements on different 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 receive a platelet transfusion in the previous 7 days.
- Chimerism Rate following Hematopoietic Cell Transplantation for Sickle Cell Disease [ Time Frame: Up to One Year ]Genomic DNA extracted from peripheral blood will be analyzed for variable number of tandem repeats (VNTR) to detect donor engraftment in myeloid and lymphoid fractions.
- Frequency of Idiopathic Pneumonia Syndrome (IPS) [ Time Frame: Up to One Year ]
IPS is diagnosed by evidence of widespread alveolar injury:
- Radiographic evidence of bilateral, multi-lobar infiltrates (by chest x-ray or CT scan); AND
- Evidence of abnormal respiratory physiology based upon oxygen saturation (SpO2) < 93% on room air or the need for supplemental oxygen to maintain oxygen saturation ≥ 93%; AND
- Absence of active lower respiratory tract infection
- Veno-occlusive Disease (VOD) Rate [ Time Frame: Up to One Year ]
VOD is diagnosed by the presence of ≥ 2 of the following with no other identifiable cause for liver disease:
- Jaundice (direct bilirubin ≥ 2 mg/dL or > 34 μmol/L)
- Hepatomegaly with right upper quadrant pain
- Ascites and/or weight gain (> 5% over baseline)
- Rate of Central Nervous System (CNS) Toxicity [ Time Frame: Up to One Year ]CNS toxicity will be defined as seizures, CNS hemorrhage, or PRES. PRES is defined as an increased diffusion coefficient in areas of T2 hyperintensity on diffusion-weighted imaging in the context of clinical symptoms or physical findings including headache, seizures, visual disturbances, and altered level of consciousness.
- Infection Rate [ Time Frame: Up to One Year ]Significant infections will be recorded including but not limited to bacterial or fungal sepsis, CMV reactivation with/without clinical disease, adenovirus infection, EBV PTLD, other significant viral reactivations or community-acquired viral infections and invasive mold infections.
- Frequency of Stroke [ Time Frame: Up to One Year ]An overt stroke is defined as a focal neurologic event and neurologic deficit lasting > 24 hours with neuroimaging changes.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02757885
|Contact: Lakshmanan Krishnamurti, MDemail@example.com|
|Contact: Chanta Whitlowfirstname.lastname@example.org|
|United States, Georgia|
|Children's Healthcare of Atlanta||Recruiting|
|Atlanta, Georgia, United States, 30033|
|Contact: Lakshmanan Krishnamurti, MD 404-785-1441 email@example.com|
|Principal Investigator:||Lakshmanan Krishnamurti, MD||Emory University|