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Allogeneic Stem Cell Transplantation, Severe Homzygous 0/+Thalassemia or Sever Variants of Beta 0/+ Thalassemia, THALLO (THALLO)

Primary Purpose

Thalassemia

Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Busulfan
Fludarabine
Campath 1H
Cyclophosphamide
MESNA
Sponsored by
Baylor College of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thalassemia focused on measuring transfusion-dependent, homozygous b0/+-thalassemia, severe variants of b0/+-thalassemia, transfusion, iron chelating agents, severe, transfusion-dependent homozygous

Eligibility Criteria

undefined - 64 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with documented diagnosis of severe (transfusion-dependent) homozygous b0/+-thalassemia or severe variants of b0/+-thalassemia requiring chronic transfusion therapy and iron chelating agents, who fulfill the following conditions:

  1. Patient does not have an HLA genotype-identical donor available and has a 5/6 or 6/6 matched unrelated donor, or a 5/6 matched related donor available.
  2. Must be between 1 and 16 yrs of age (all Pesaro risk groups).
  3. Patients older than 17 yrs of age must be in Pesaro Risk Class 2 or lower (see Appendix B).
  4. Women of childbearing potential must have a negative pregnancy test.
  5. Documentation of compliance with iron chelation, absence or presence of hepatomegaly, and presence or absence of hepatic fibrosis prior to transplant (criteria for the Pesaro Risk Classification). This information will be obtained by history, physical exam and interpretation of liver biopsy results.
  6. Documentation of awareness of alternative treatment options.

Exclusion Criteria:

  1. Biopsy-proven chronic active hepatitis or fibrosis with portal bridging.
  2. Has previous history of malignancies.
  3. Creatinine clearance < 35 mL/min/1.73 M2.
  4. Severe cardiac dysfunction defined as shortening fraction < 25%.
  5. HIV infection.
  6. Inadequate intellectual capacity to give informed consent (in the case of minors, this criteria must be fulfilled by the legal guardian).
  7. Be pregnant, lactating or unwilling to use appropriate birth control.

Sites / Locations

  • Texas Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bone Marrow or Stem Cell Infusion

Arm Description

Mesna, Cyclophosphamide, Busulfan, Fludarabine, Campath 1H Bone Marrow or Stem Cell infusion with pre-meds to take place on Day 0. Bone marrow dose/stem cell dose: To ensure the probability for bone marrow engraftment, 4 x 10e8 nucleated cells/kg patient weight or 5 x 10e6/kg of CD34+ cells/kg patient weight if the product is mobilized peripheral blood, will be the target to be obtained from the unrelated donor.

Outcomes

Primary Outcome Measures

Engraftment Rate After Transplant
Engraftment is defined as an absolute neutrophil count (ANC) >500/microL x 3 days.
Number of Participants With Stable Mixed Hematopoietic Chimerism (HC)
Stable hematopoietic chimerism is defined as having 50-99 percent of donor cells.
Number of Participants With Transient Mixed Hematopoietic Chimerism (HC)
Transient mixed hematopoietic chimerism is defined as any mixed chimerism return to 100 percent donor.
Number of Participants With Infectious Complications
All AEs and SAEs (including infections) will be collected for evaluation of infectious complications.
Hematopoietic Reconstitution
Hematopoietic: defined as transfusion independence.
Immune Reconstitution
Immune reconstitution: defined as absolute lymphocyte count (ALC) >1000x10e3/microL
Number of Participants With ACUTE GVHD
Acute GVHD is graded by the method of Przepiorka D. et al, which evaluates skin involvement, lower and upper GI, and liver function (bilirubin), each being graded in stages from 0 to 4, where 0 means no acute GVHD, and 4 is the highest stage of acute GVHD
Number of Participants With CHRONIC GVHD
Chronic GVHD is graded by NIH guidelines for chronic GVHD, which evaluates skin, joints, oral, ocular, hepatic, esophagus, GI, respiratory, platelet, and musculoskeletal involvement, in stages from 0 to 3 where 0 means no chronic GVHD, and 3 is the highest stage of chronic GVHD.
Event-free Survival
Event-free survival is calculated from the date of transplant to the date of graft failure, disease recurrence or death from any cause.

Secondary Outcome Measures

Full Information

First Posted
December 19, 2007
Last Updated
April 30, 2020
Sponsor
Baylor College of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT00578292
Brief Title
Allogeneic Stem Cell Transplantation, Severe Homzygous 0/+Thalassemia or Sever Variants of Beta 0/+ Thalassemia, THALLO
Acronym
THALLO
Official Title
Pilot Study of Allogeneic Stem Cell Transplantation From Unrelated Donors for Patients With Severe Homozygous Beta 0/+ Thalassemia or Severe Variants of Beta 0/+ Thalassemia
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Terminated
Why Stopped
Stem cell transplant was determined SOC for this disease (study is not relevant)
Study Start Date
February 2004 (undefined)
Primary Completion Date
May 2016 (Actual)
Study Completion Date
May 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Baylor College of Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Patients have severe beta-thalassemia or one of the thalassemia variants. Thalassemia is a hereditary disease in which the bone marrow produces abnormal red blood cells that have a shorter life span than normal red blood cells. Because of that, the patient has chronically low red blood cell numbers (anemia) and need regular blood transfusions to help the patient feel better and to help prevent damage to important organs such as the heart. The following treatments are currently available to patients: lifelong blood transfusions and drugs that help remove iron from the body, and long-term antibiotics to prevent infections. These treatments are difficult for patients to take, and do not stop the effects of the disease. Currently, the only treatment that may cure thalassemia is bone marrow or blood stem cell transplantation. Special blood or bone marrow cells from a healthy person might allow the bone marrow to create healthy cells, which will replace the abnormal red blood cells of thalassemia. There is a lot of experience using special blood or bone marrow cells from a healthy brother or sister who is the same HLA (immune) type. For patients who do not have such a donor in the family, an unrelated volunteer donor can be used. It is important for the patient to realize that this kind of transplant can have more problems than a transplant from a brother or sister. Because we do not know the long-term effects of this treatment and because this type of transplant has not been used often for people with thalassemia, this is a research study. We hope, but cannot promise, that the transplanted marrow/stem cells will produce healthy cells and the patient will no longer have severe thalassemia.
Detailed Description
To be treated on this study, we will test the blood to check for viruses, including HIV (the virus that causes AIDS). If the HIV test is positive, a transplant cannot be done because it would be too dangerous for the patient. Secondly, we will do a liver biopsy to determine if the liver has been damaged (which can happen from iron overload that develops after many transfusions). Too much liver damage could mean that the patient will have a higher risk to develop problems with the transplant. To participate in this study, the patients also need to have a central line (a thin plastic catheter or tube that is placed during surgery into one of the large veins in the neck or chest). Central lines are used to give intravenous medications (go directly into the vein) or to take blood samples without the patient having to endure frequent needle sticks. Before the treatment starts, we will remove a small amount of the bone marrow (back-up bone marrow) and store it. The reason for this is that if the donors bone marrow or blood stem cells do not grow properly after the transplant and the patients blood counts stay low, we can put the patients own bone marrow cells back into their body. This will help the blood counts to recover, but this means that the patient will also have thalassemia again. To prepare the body for the transplant, the patients own blood forming system has to be destroyed and their immune system has to be weakened. To do this, they will be given high dose chemotherapy and medications that weaken their immune system (also called a conditioning treatment) for 9 days before the transplant. The main chemotherapy drugs used in the conditioning treatment are: cyclophosphamide, fludarabine and busulfan. The chemotherapy treatment will last 9 days. The patient will be admitted 10 days before the transplant to start a medicine to prevent seizures before they receive the first dose of busulfan since one of the side effects of busulfan is risk of seizures. First the patient will be given a drug called busulfan through the central line every 6 hours starting 9 days before transplant (called Day -9) until 6 days before transplant (called Day -6). Starting one day after receiving the last busulfan dose (Day -5), they will receive cyclophosphamide, fludarabine and Campath IH, which will all be given through the central line once a day for the next four days. Campath IH is a special type of protein called an antibody that works against certain types of blood cells. Also on Day -5, we will add a drug called MESNA. MESNA is used to decrease the side-effects caused by cyclophosphamide. One day after the chemotherapy treatment is finished (Say -1) the patient will have a day to rest. On Say 0, the patient will receive the bone marrow/stem cells from the donor. Once in the bloodstream, the cells will go to the bone marrow and should begin to grow. To help prevent a problem call graft-versus-host disease (GVHD), the patient will receive a small dose of methotrexate on four different days after transplant. Another drug to help prevent GVHD, tacrolimus, will be started 2 days (Day -2) before the transplant and continued for approximately one year after the transplant. To tell whether the transplant has "taken" or "engrafted", we will take samples of blood two to three weeks after the transplant. The patient will need to be in the hospital for at least 4 weeks after the transplant to make sure the transplant has engrafted. To find out how much the treatment has helped them and how much it might help other patients, we will do several routine lung, kidney, and liver tests, including liver biopsies, after the bone marrow/stem cell transplant. Additionally, we will be looking at the immune function. To do this, we will take 30 mL (2 tablespoonfuls) of blood every three months for the first year after transplant and then every 6 months during the second year after transplant. When possible, the blood that is taken will be taken through an existing IV line. However, at times drawing the blood will require another stick with a needle. The total amount of blood to be taken will not exceed 12 tablespoonfuls. Because bone marrow/stem cell transplant from an unrelated volunteer donor is a new therapy for severe thalassemia and because problems may happen months afterward, the patient will need to have exams and blood tests done every few months during the first and second year following transplantation. The patient may still need to use iron removing agents for some time after transplant or undergo blood-letting to get rid of the excess iron in the body. During that time, we will monitor the amount of iron in the body. Looking at the iron stored in the liver can most accurately tell us how much excess iron the patient has in the body. We will do liver biopsies once or twice per year if the patient is receiving iron chelation treatment after the transplant.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Thalassemia
Keywords
transfusion-dependent, homozygous b0/+-thalassemia, severe variants of b0/+-thalassemia, transfusion, iron chelating agents, severe, transfusion-dependent homozygous

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bone Marrow or Stem Cell Infusion
Arm Type
Experimental
Arm Description
Mesna, Cyclophosphamide, Busulfan, Fludarabine, Campath 1H Bone Marrow or Stem Cell infusion with pre-meds to take place on Day 0. Bone marrow dose/stem cell dose: To ensure the probability for bone marrow engraftment, 4 x 10e8 nucleated cells/kg patient weight or 5 x 10e6/kg of CD34+ cells/kg patient weight if the product is mobilized peripheral blood, will be the target to be obtained from the unrelated donor.
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Myleran
Intervention Description
4.0 mg/kg/day divided into four doses daily for four days; total dose = 16 mg/kg Days -9 through -6
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
30mg/m2 Day -5 through Day -2
Intervention Type
Drug
Intervention Name(s)
Campath 1H
Other Intervention Name(s)
Alemtuzumab
Intervention Description
Per institutional guidelines Days -5 through -2
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
50 mg/kg Days -5 through -2
Intervention Type
Drug
Intervention Name(s)
MESNA
Other Intervention Name(s)
Mesnex
Intervention Description
10 mg/kg x 5 Days -5 through -2
Primary Outcome Measure Information:
Title
Engraftment Rate After Transplant
Description
Engraftment is defined as an absolute neutrophil count (ANC) >500/microL x 3 days.
Time Frame
up to 30 days
Title
Number of Participants With Stable Mixed Hematopoietic Chimerism (HC)
Description
Stable hematopoietic chimerism is defined as having 50-99 percent of donor cells.
Time Frame
1 year post-transplant
Title
Number of Participants With Transient Mixed Hematopoietic Chimerism (HC)
Description
Transient mixed hematopoietic chimerism is defined as any mixed chimerism return to 100 percent donor.
Time Frame
1 year post-transplant
Title
Number of Participants With Infectious Complications
Description
All AEs and SAEs (including infections) will be collected for evaluation of infectious complications.
Time Frame
up to day 100
Title
Hematopoietic Reconstitution
Description
Hematopoietic: defined as transfusion independence.
Time Frame
1 year post-transplant
Title
Immune Reconstitution
Description
Immune reconstitution: defined as absolute lymphocyte count (ALC) >1000x10e3/microL
Time Frame
1 year post-transplant
Title
Number of Participants With ACUTE GVHD
Description
Acute GVHD is graded by the method of Przepiorka D. et al, which evaluates skin involvement, lower and upper GI, and liver function (bilirubin), each being graded in stages from 0 to 4, where 0 means no acute GVHD, and 4 is the highest stage of acute GVHD
Time Frame
Assessed weekly from Day 0 to day 100
Title
Number of Participants With CHRONIC GVHD
Description
Chronic GVHD is graded by NIH guidelines for chronic GVHD, which evaluates skin, joints, oral, ocular, hepatic, esophagus, GI, respiratory, platelet, and musculoskeletal involvement, in stages from 0 to 3 where 0 means no chronic GVHD, and 3 is the highest stage of chronic GVHD.
Time Frame
Assessed monthly from month 3 to month 12
Title
Event-free Survival
Description
Event-free survival is calculated from the date of transplant to the date of graft failure, disease recurrence or death from any cause.
Time Frame
up to 2 years post transplant

10. Eligibility

Sex
All
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with documented diagnosis of severe (transfusion-dependent) homozygous b0/+-thalassemia or severe variants of b0/+-thalassemia requiring chronic transfusion therapy and iron chelating agents, who fulfill the following conditions: Patient does not have an HLA genotype-identical donor available and has a 5/6 or 6/6 matched unrelated donor, or a 5/6 matched related donor available. Must be between 1 and 16 yrs of age (all Pesaro risk groups). Patients older than 17 yrs of age must be in Pesaro Risk Class 2 or lower (see Appendix B). Women of childbearing potential must have a negative pregnancy test. Documentation of compliance with iron chelation, absence or presence of hepatomegaly, and presence or absence of hepatic fibrosis prior to transplant (criteria for the Pesaro Risk Classification). This information will be obtained by history, physical exam and interpretation of liver biopsy results. Documentation of awareness of alternative treatment options. Exclusion Criteria: Biopsy-proven chronic active hepatitis or fibrosis with portal bridging. Has previous history of malignancies. Creatinine clearance < 35 mL/min/1.73 M2. Severe cardiac dysfunction defined as shortening fraction < 25%. HIV infection. Inadequate intellectual capacity to give informed consent (in the case of minors, this criteria must be fulfilled by the legal guardian). Be pregnant, lactating or unwilling to use appropriate birth control.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tami John, MD
Organizational Affiliation
Baylor College of Medicine - Texas Children's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Tami John, MD
Organizational Affiliation
Baylor College of Medicine - Texas Children's Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Allogeneic Stem Cell Transplantation, Severe Homzygous 0/+Thalassemia or Sever Variants of Beta 0/+ Thalassemia, THALLO

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