Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation in Aplastic Anemia

Aplastic Anemia Clinical Trial

Official title:

Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation From HLA-Compatible Unrelated Donors in Severe Aplastic Anemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00474747
• Other study ID #: 2005-0513
• Secondary ID: NCI-2010-00908
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: May 16, 2007
• Last updated: November 10, 2017
• Start date: February 7, 2006
• Est. completion date: November 9, 2017

Study information

• Verified date: November 2017
• Source: M.D. Anderson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical research study is to find out the best dose of cyclophosphamide that can be given with fludarabine, antithymocyte globulin (ATG), and low-dose total body irradiation (TBI) to patients before a bone marrow transplant to decrease the risks related to the transplant while not decreasing the effectiveness of the transplant from an unrelated donor.

Description:

Your bone marrow normally produces white cells, red cells, and platelets. Once ready, these cells are released into the bloodstream. Aplastic anemia is a blood disorder where the bone marrow has stopped working and produces very few or no cells to be released into the bloodstream. If not successfully treated, this condition will almost always lead to death, primarily because of infection or bleeding. A bone marrow transplant is an option for you because your doctors believe it may cure your aplastic anemia. As you do not have a matched, sibling donor, a matched, unrelated donor (i.e. not a blood relative) has been selected for you. Before you receive a matched, unrelated donor marrow transplant, you will receive medications and low dose total body irradiation (TBI) to kill immune cells in your body that might reject the cells from your donor. This will allow your body to accept the donor marrow. This is called engraftment.

Cyclophosphamide is a medication that will be used in this study to lower your immune system in order to allow your body to accept the donor marrow cells.

If you are found eligible to take part in this study, you will be given medications and TBI before your bone marrow transplant to allow your body to accept your donor's stem cells. This is called the conditioning regimen. Before your transplant, a catheter (i.e. a soft plastic tube) will be inserted into a vein under the collarbone to allow for medications and fluids to be given.

The conditioning regimen includes a combination of drugs used to kill the cells in your body that may reject the donor cells. The drugs to be used in this study are fludarabine, cyclophosphamide, and ATG, as well as low-dose to TBI. All participants in this study will receive the same amount of fludarabine, ATG and low-dose TBI. You will receive fludarabine on the fifth, fourth, third and second days before your transplant by intravenous infusion through your catheter over about 30 minutes.

You will receive ATG on the fourth, third, and second days before your transplant. This will be given intravenously through your catheter over 4 to 6 hours. ATG is an animal product, and your study doctor may decide to use a horse or a rabbit product. Both products have similar side effects and efficacy. You will receive TBI on the day before your transplant.

Different groups of patients will get different amounts of cyclophosphamide. You will receive cyclophosphamide for a total of either 1 or 2 days before your transplant. The number of days depends on your group. You will be placed in the group that is being tested at that time. Your doctor will tell you which group you are in. Neither you nor your doctor can choose the group. Sometimes there may be a short waiting period for a new patient to be entered in the study, and you should discuss with your doctor how this waiting period may affect you.

The main purpose of this study is to find the best dose of cyclophosphamide. This means that small groups of patients are treated with a given dose of cyclophosphamide and followed closely until it can be shown that the new marrow has been accepted by the body and the treatment has not caused any unacceptable harm. In the early part of the study, participants were receiving cyclophosphamide for either 3, 2, 1 or 0 days. The doctors who are conducting the study have by now gained some experience with this conditioning schedule, and this has helped them to narrow down the number of possible doses of cyclophosphamide that you, as a new participant, may receive. You should be aware that some participants who received 3 days of cyclophosphamide (the highest dose) suffered severe side effects (including death), and therefore, new patients are no longer being placed in this group. You should also be aware that participants who received zero days of cyclophosphamide (the lowest dose) experienced graft rejection (meaning, their body did not accept the new marrow, and the new cells failed to grow). Therefore, new participants are no longer being assigned to this group. Participants who now come to transplantation will be treated with either 1 or 2 days of cyclophosphamide.

After the conditioning regimen, the donor marrow cells will be given to you through your catheter. The cells will travel into the bloodstream to reach your bone marrow where they are expected to make healthy, new blood cells. This step is necessary to replace your diseased marrow and because the high dosages of drugs given to you during the conditioning regimen may also damage or destroy healthy cells in your bone marrow. Until the new cells begin producing healthy blood cells, you will be at an increased risk of bleeding or developing an infection.

Following the transplant (at least every week until roughly 100 days after transplant, then every 3-6 months for 2 years after that), you will have a complete medical history and physical exam, including measurement of height and weight. Blood (about 2-4 tablespoons) and urine may be collected for routine tests. You will also have a bone marrow aspiration and biopsy at 30 and 100 days after transplant and then every 4-6 months for 2 years after that.

You will be expected to take medications such as cyclosporine (or tacrolimus) by mouth for no less than 6-9 months to prevent graft-versus-host disease. You will also be expected to stay at the transplant center for at least 3 months after your transplant. You will be asked to return to the transplant center for regular follow-up care. The standard tests will be done at that time.

You will be in the study for up to 2 years. Follow-up for transplant will last as long as you require care. However, researchers would like to keep track of your medical condition for the rest of your life by contacting you and the doctor providing your regular medical care by phone or mail once a year. Keeping in touch with you and checking on your condition every year helps researchers to look at the long-term effects of the study and transplantation in general. It is not necessary for you to agree to follow-up for longer than 2 years to participate in this study. After 2 years, you will continue to be followed by your transplant doctor, but no longer as part of the study.

You can be taken off the study (with or without your consent) for several reasons. You may be taken off study if you no longer meet the study requirements. Ask you doctor if you would like more information about this. You can be taken off study if you need a medical treatment not allowed in this study, or the study chair decides that it would be in your best interest to leave the study. You may be taken off study if intolerable side effects occur. You will be taken off study if your transplant fails to take. In this case, your doctor will decide what the best treatment for you will be. You may be taken off study if you are unable to follow study instructions or keep study appointments. You may also be taken off study if the study is stopped by the Food and Drug Administration (FDA) or the National Institutes of Health (NIH).

This is an investigational study. All of the drugs and medications used in this study are FDA-approved and commercially available.

Up to 94 participants will be enrolled in this multicenter study. Up to 9 will be enrolled at MD Anderson.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: November 9, 2017
• Est. primary completion date: November 9, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 65 Years

Eligibility

Inclusion Criteria:

1. Patients up to 65 years of age at time of registration with a diagnosis of severe aplastic anemia (SAA). SAA is defined as follows: - Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30% residual hematopoietic cells. Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L. SAA diagnostic criteria may be applied to assessment at initial diagnosis or to the follow-up assessments.

2. Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C and DRB1 antigen. Typing is by DNA techniques: intermediate resolution for A, B and C, and high resolution for DRB1. HLA-DQ typing is recommended but will not count in the match

3. Patient and/or legal guardian able to provide signed informed consent.

4. Matched unrelated donor must consent to provide marrow allograft.

5. Patients with adequate organ function as measured by: a) cardiac: left ventricular ejection fraction at rest must be > 40% or shortening fraction > 20% b) hepatic: serum total bilirubin < 2x upper limit of normal for age as per local laboratory; ALT and AST < 4x upper limit of normal for age as per local laboratory; c) renal: serum creatinine < 2x upper limit of normal for age (as per local laboratory). d) pulmonary forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLCO) (corrected for Hb) > 50% predicted. For pts where pulse oxymetry is performed, O2 saturation > 92%

6. The diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane (DEB) testing on peripheral blood or comparable testing or marrow.

Exclusion Criteria:

1. Clonal cytogenetic abnormalities associated with myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) on marrow examination.

2. Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital megakaryocytosis.

3. Symptomatic or uncontrolled cardiac failure or coronary artery disease.

4. Karnofsky performance status < 60% or Lansky < 40% for patients < 16 years of old.

5. Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms). Patients with fevers despite broad-spectrum antimicrobials but no clinical or hemodynamic evidence of sepsis will be allowed.

6. Seropositive for the human immunodeficiency virus (HIV).

7. Pregnancy (positive ß-HCG) or breastfeeding.

8. Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for graft-versus-host disease (GVHD) prophylaxis.

9. Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/tacrolimus.

10. Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis.

11. Concomitant enrollment in a Phase I study.

12. Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants (test recommended but not mandatory). The definition of match is in Section 2.2.1.

13. Prior allogeneic marrow or stem cell transplantation.

14. Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair. Cancer treated with curative intent > 5 years previously will be allowed.

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Aplastic Anemia

Intervention

Drug:
• Antithymocyte Globulin
3 mg/kg IV over no less than four (and preferably six) hours daily x 3 days
• Cyclophosphamide
Starting maximum dose 50 mg/kg IV x 3 days (de-escalating doses follow).
• Fludarabine
30 mg/m^2 IV over no less than 30 minutes daily x 4 days

Radiation:
• Total Body Irradiation (TBI)
TBI: 200 cGy from a linear accelerator at 20 cGy/min on Day -1 (single dose)

Procedure:
• Bone Marrow Transplant
Infusion of matched unrelated donor marrow on Day 0.

Locations

Country	Name	City	State
United States	University of Texas MD Anderson Cancer Center	Houston	Texas

Sponsors (3)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center	National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Optimal dose level of cyclophosphamide based on assessments of graft failure, toxicity and early death		During 100 days of follow-up post-transplant
Secondary	Two-year post-transplant survival		2 Years post transplant

External Links

•   University of Texas MD Anderson Cancer Center Website