TRANSFORM: Transplantation Using Reduced Intensity Approach for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow

Sponsor

Emory University (Other)

Overall Status

Recruiting

CT.gov ID

NCT02757885

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

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

Detailed Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Transplantation Using Reduced Intensity Approach for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow

Study Start Date :

Apr 1, 2016

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Other: 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. Drug: Hydroxyurea 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. Drug: Thiotepa 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. Drug: Cyclophosphamide 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.

Arm

Intervention/Treatment

Other: 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.

Drug: Hydroxyurea

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.

Drug: Thiotepa

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.

Drug: Cyclophosphamide

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.

Outcome Measures

Primary Outcome Measures

Event-free Survival (EFS) Rate [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 [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 [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 [Up to One Year]
Disease recurrence is defined as the return of sickle erythropoiesis (HbS level > 70%) and the absence of donor cell representation.

Secondary Outcome Measures

Overall Survival Rate [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 [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 [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) [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 [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 [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 [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 [Up to One Year]
An overt stroke is defined as a focal neurologic event and neurologic deficit lasting > 24 hours with neuroimaging changes.

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Disease severity: Participants with SCD who have 1 or more of the following (i-v).

Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours;
History of two or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea);
History of three or more severe 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);
Administration of regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for ≥ 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and ACS). Patients on chronic transfusion who have to discontinue transfusion because of allo-sensitization will be eligible.
An echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity ≥ 2.7 m/sec. Patients under the age of 18 years must have cardiac catheterization proven pulmonary arterial hypertension to qualify on this eligibility criterion.

Age: Patients must be 15 - 40 years of age inclusive OR if younger than 15 years must be pubertal
Adequate physical function as measured by:

Karnofsky/Lansky performance score ≥ 60
Cardiac function: Left ventricular ejection fraction (LVEF) > 40% or LV shortening fraction > 26% by cardiac echocardiogram or by MUGA scan.
Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥ 85% and DLCO > 40% (corrected for hemoglobin).
Renal function: Serum creatinine ≤ 1.5 x the upper limit of normal for age as per local laboratory and 24 hour urine creatinine clearance > 70 mL/min/1.73 m2 or GFR > 70 mL/min/1.73 m2 by radionuclide GFR.
Hepatic function: Serum conjugated (direct) bilirubin < 2 x upper limit of normal for age as per local laboratory and ALT and AST < 5 x upper limit of normal as per local laboratory. Patients with hyperbilirubinemia as a consequence of hyperhemolysis, or who experience a sudden, profound change in the serum hemoglobin after a RBC transfusion, are not excluded.
For participants with a suitable donor who meet eligibility criteria and are willing to proceed to HCT, if they have received chronic transfusion therapy for ≥ 1 year and have clinical evidence of iron overload by serum ferritin or MRI, an evaluation by liver biopsy is required. Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis, and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale

Suitable Donor: To undergo transplantation on this study, participants must have an adult first degree relative who shares at least 1 human leukocyte antigen (HLA) haplotype with the participant, does not have SCD or other hemoglobinopathy, and is in good health; if these criteria are met, they will be allowed to serve as donors. Relatives with sickle cell trait are not excluded as donors. When more than 1 donor is available, the donor with the fewest HLA allele mismatches will be chosen, unless the patient had donor anti-HLA antibodies or there was a medical reason to exclude the donor. If donor anti-HLA antibodies are detected, the next best related match will be chosen. Umbilical cord blood or peripheral blood stem cell donors will not be accepted.

Exclusion Criteria:

Availability of HLA matched sibling or 8 of 8 HLA-A, B, C and DRB1 matched unrelated donor
Presence of donor specific antibodies in the patient
Histological examination of the liver must document the absence of cirrhosis, bridging fibrosis and active hepatitis. The absence of bridging fibrosis will be determined using the histological grading and staging scale as described by Ishak and colleagues (1995). The presence of bridging fibrosis will be an exclusion criterion.
Uncontrolled bacterial, viral or fungal infection in the 6 weeks before enrollment
Seropositivity for HIV
Previous hematopoietic cell transplantation (HCT)
Participation in a clinical trial in which the patient received an investigational drug or device or off-label use of a drug or device within 3 months of enrollment
Demonstrated lack of compliance with prior medical care
Unwilling to use approved contraception for at least 6 months after transplant
A history of substance abuse in the last 5 years that interferes with care
Pregnant or breast feeding females at the time of consideration for HCT

Donor Selection Criteria:

Preference will be given to related marrow donors who are 2-4 (out of 8) HLA antigen mismatched and towards whom the recipient does not have donor specific antibodies. Donors will sign an informed consent disclosing that the marrow donation will be used by a patient participating in this study. The donor must be matched with the recipient for at least 4 of 8 HLA alleles (HLA -A, -B, -C and -DRB1 by allele-level DNA methodology). The target total nucleated cell count (TNC) is 3.5-8.0 x 108/kg of recipient weight. Marrow will be collected without mobilization. Mobilized peripheral blood stem cell (HPC-A) collections will not be permitted. Donors must undergo hemoglobinopathy screening by electrophoresis; donors who have a hemoglobinopathy will be excluded but trait condition is acceptable.