Allogeneic Transplantation Using Timed Sequential Busulfan, Cladribine, and Fludarabine Conditioning in Patients With Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Condition(s) targeted: Acute Myeloid Leukemia; Myelodysplastic Syndrome

Intervention: Busulfan (Drug); Fludarabine (Drug); Cladribine (Drug); Stem Cell Transplant (Procedure); G-CSF (Drug); Methotrexate (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Uday Popat, MD, Principal Investigator, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Uday Popat, MD, Phone: 713-792-8750

The goal of this clinical research study is to compare how well two different schedules of giving busulfan with fludarabine and cladribine before a stem cell transplant in patients with AML or MDS may help to control the disease. The safety of this drug combination will also be studied.

Official title: Allogeneic Transplantation Using Timed Sequential Busulfan, Cladribine, and Fludarabine Conditioning in Patients With Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Progression-Free Survival (PFS)

Detailed description: Central Venous Catheter: If you choose to take part in this study, the chemotherapy, some of the other drugs in this study, and the stem cell transplant will be given by vein through a central venous catheter (CVC). A CVC is a sterile flexible tube and needle that will be placed into a large vein while you are under local anesthesia. Blood samples will also be drawn through your CVC. The CVC will remain in your body during treatment. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form. For a stem cell transplant, the days before you receive your stem cells are called minus days. The day you receive the stem cells is called Day 0. The days after you receive the stem cells are called plus days. Study Groups: You will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups:

- Group 1 will receive busulfan on Days -13 and -12, and busulfan, fludarabine, and

cladribine on Days - 6 through -3.

- Group 2 will receive will receive busulfan on Days -20 and -13, and busulfan,

fludarabine, and cladribine on Days - 6 through -3.

You will have a 50/50 chance of being assigned to either group. Both groups will then have a stem cell transplant. Study Drug Administration:

If you are in Group 1, you will receive busulfan by vein over about 3 hours on Day - 13 and

Day - 12. You will receive this as either an outpatient in the clinic or as an inpatient in

the hospital. If you are in Group 2, you will receive a dose of busulfan by vein over about 3 hours on Day

- 20 and Day -13. You will receive this as either an outpatient in the clinic or as an

inpatient in the hospital. For both arms, about 11 samples of blood (about 1-2 teaspoons each time) will be drawn for pharmacokinetic (PK) testing at time points before and after you receive your first dose of

busulfan. For Group 1, this will be on Day - 13. For Group 2, this will be on Days -20 and

- 13. The study staff will tell you the blood testing schedule. PK testing measures the

amount of study drug in the body at different time points and will help the doctor decide

your dose of busulfan for Days - 6 through -3. If the doctor thinks it is needed, PK blood

testing may also be done on Day - 6 during your dose of busulfan.

A heparin lock line will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for the PK tests to be performed for technical reasons, you will be taken off study and receive the standard fixed dose of busulfan.

On Days - 11 through -8, you will not receive anything.

On Day - 7, you will be admitted to the hospital and will receive fluids by vein.

On Days - 6 through -3, you will receive busulfan by vein over 3 hours, fludarabine by vein

over 1 hour, then cladribine by vein over 2 hours each day.

Starting on Day - 2, you will receive tacrolimus nonstop by vein until you are able to take

it by mouth to help lower the risk of graft-versus-host disease (GVHD). You will then take tacrolimus by mouth 2 times a day for about 3 months. After that, your tacrolimus dose may be lowered if you do not have GVHD. Your doctor will discuss this with you. On Day 0, you will receive the stem cell transplant by vein. On Days 1, 3, and 6, if the stem cells are from a related or matched unrelated donor, you will receive methotrexate over 30 minutes each day by vein to help lower the risk of GVHD. Participants receiving a matched unrelated donor will also receive methotrexate on Day 11. Starting 1 week after the transplant, you will receive filgrastim as an injection under the skin 1 time a day until your blood cell levels return to normal. Filgrastim is designed to help with the growth of white blood cells. Study Testing: While you are in the hospital, you will be checked for any side effects as part of standard care. Blood (about 2 teaspoons) will be drawn every day to check for side effects, for routine tests, to check your blood counts, to check your kidney and liver function, and to check for infections. As part of standard care, you will remain in the hospital for about 3-4 weeks after the transplant. After you are sent home from the hospital, you must remain in the Houston area to be checked for infections and other transplant side effects until about 3 months after transplant. During this time, you will return to the clinic at least 1 time each week. At each visit, blood (about 2 teaspoons) will be drawn for routine tests. About 1, 3, 6, and 12 months after the transplant:

- You will have a physical exam.

- Blood (about 5 teaspoons) will be drawn to see how the body has reacted to the

transplant.

- If your doctor thinks it is needed, you will have a bone marrow aspiration to check the

status of the disease. To collect a bone marrow aspiration, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. Length of Study: You will be on study for up to 1 year after the transplant. You may be taken off study early if the disease gets worse, if you have any intolerable side effects, of if you are unable to follow study directions. You should talk to the study doctor if you want to leave the study early. If you are taken off study early, or if you are unable to receive the NK cells, you still may need to return for routine follow-up visits after the transplant, if your doctor thinks it is needed. You should talk to the study doctor if you want to leave the study early. It may be life-threatening to leave the study after you have begun to receive the study drugs but before you receive the stem cells. This is an investigational study. Busulfan, fludarabine, and cladribine are FDA approved and commercially available. It is investigational to give cladribine in combination with busulfan and fludarabine with a stem cell transplant. Up to 116 patients will take part in this study. All will be enrolled at MD Anderson.

Minimum age: 2 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Patients with acute myeloid leukemia or myelodysplastic syndrome not in complete remission (patients with disease detectable only by flow cytometry, cytogenetics, or molecular studies are eligible). 2. HLA-identical sibling or 8/8 matched unrelated donor transplant. 3. Patients age 18 to 70 years old. Eligibility for pediatric patients will be determined in conjunction with an MDACC pediatrician. Patients age 2-17 years old may be enrolled after at least 10 adults (ages 18-70 years old) have been assessed for safety at Day 30, as defined in the Statistical Considerations section. 4. Direct Bilirubin < 1 mg/dl and ALT < 3 times upper limit of normal. 5. Creatinine clearance > 50 ml/min (calculated creatinine clearance is permitted). 6. Adequate pulmonary function with FEV1, FVC and DLCO >/=50% of expected corrected for hemoglobin and/or volume. Children unable to perform pulmonary function tests (e. g., less than 7 years old) pulse oximetry of >/= 92% on room air. 7. LVEF >/= 40%. 8. Patient, LAR, or parent able to sign informed consent. Able to give assent for patients age 7-17. 9. Negative Beta HCG test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization. Women of child bearing potential must be willing to use an effective contraceptive measure while on study. 10. Performance score of >/= 70 by Karnofsky/Lansky or PS 0 to 1 (ECOG

Locations and Contacts

Uday Popat, MD, Phone: 713-792-8750

University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting

Additional Information

University of Texas MD Anderson Cancer Center Website

Starting date: October 2014
Last updated: August 14, 2015