Fludarabine/Clofarabine/Busulfan Combined With SAHA in Acute Leukemia

Condition(s) targeted: Leukemia

Intervention: Fludarabine (Drug); Clofarabine (Drug); Busulfan (Drug); SAHA (Drug); Stem Cell Infusion (SCT) (Procedure); Thymoglobulin (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

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

Overall contact:
Partow Kebriaei, MD, Phone: 713-745-0663

The goal of this clinical research study is to evaluate the safety of combining vorinostat (also called SAHA) with fludarabine, clofarabine, and busulfan.

Official title: Fludarabine/Clofarabine/Busulfan Combined With SAHA in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Maximum Tolerated dose (MTD) of SAHA in Combination with Fludarabine, Clofarabine, and Busulfan

Detailed description: Study Groups: All participants will receive the same dose levels of fludarabine, clofarabine, and busulfan. You will be assigned to a dose level of vorinostat based on when you joined this study. Up to 6 dose levels of vorinostat may be tested. Up to 3 participants may be enrolled at each dose level. The first group of participants will receive the first dose level of vorinostat. Each new group will receive a higher dose than the group before it, if no intolerable side effects are seen. When the highest tolerated dose level is found, more participants may be enrolled at that level. 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 Drug Administration and Procedures: All groups will receive a "test" dose of busulfan by vein over about 45 minutes to 1 hour. This low-level test dose of busulfan is to check how fast busulfan is processed by your body and cleared from your blood. This information will determine the amount of busulfan you will receive. You may receive the busulfan test dose as an outpatient during the week before you are admitted to the hospital or as an inpatient 8 days before your stem cell transplant. About 11 samples of blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the body at different time points and will also help determine your dose of busulfan. These blood samples will be drawn at various times before you receive the test dose of busulfan and over the next 11 hours. These blood draws will be repeated again on the first day of high-dose busulfan

treatment (Day - 6, which is 6 days before the transplant).

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 or scheduling reasons, you will receive the standard fixed dose of busulfan.

On Days - 6 through -3, you will receive vorinostat as a tablet by mouth once a day, then

fludarabine by vein over 1 hour, then clofarabine by vein over 1 hour, and then busulfan by vein over 3 hours. If you are going to be receiving a transplant from an HLA-matched unrelated donor, you will also receive antithymocyte globulin (ATG) by vein over 4 hours on the 3 days before the transplant. This drug is designed to further weaken your immune system to reduce the risk of rejecting the transplant. You will be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks. While you are in the hospital, you will be checked for any side effects as part of your standard of care. Blood (about 2 teaspoons) will be drawn every day to check for side effects, for routine tests, to check your blood counts, kidney and liver function, and to check for infections. Tests may be repeated, if your doctor thinks it is needed. As part of standard care, you will remain in the hospital for about 3-4 weeks after the transplant. After you are released from the hospital, you must remain in the Houston area to be monitored 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. The following tests and procedures will be performed:

- Blood (about 2 teaspoons) will be drawn for routine tests.

Around 14-30 days after the transplant (when the transplant "engrafts", or "takes"), you will have a bone marrow aspirate to check the status of the disease. To collect a bone marrow aspirate, 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. Around Day 30, if you have ALL, you will have a lumbar puncture to check the status of the disease. To perform a lumbar puncture (also called a spinal tap), a special needle is inserted into the lower back through the space between the bones. The needle is used to draw a sample of the fluid that surrounds the spinal cord. Around Day 30, and about 3, 6, and 12 months after the transplant, the following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn to see how well the transplant has taken.

- You will have a bone marrow aspiration to check the status of the disease.

After the first year from transplant through the end of your participation in the study, the study staff may also call you and your local doctor to ask about your health. This call may take about 10 minutes. Length of Study: You will be taken off study 5 years after the end of treatment. You may be taken off study early if the disease gets worse, if you have any intolerable side effects, if the stem cell transplant does not "take", if the disease relapses (returns), or 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, you still may need to return for routine post-transplant follow-up visits, if your transplant doctor decides it is needed. 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. Fludarabine, clofarabine, and vorinostat are FDA approved and commercially available for the treatment of cancer. Busulfan is also FDA approved for use with stem cell transplants. The use of these drugs together with a stem cell transplant is investigational. The study doctor can explain how the study drugs are designed to work. Up to 72 patients will take part in this study. All will be enrolled at MD Anderson.

Minimum age: N/A. Maximum age: 60 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Patients with biopsy-proven acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome in remission or relapse. 2. Estimated creatinine clearance at least 50 ml/min. 3. Bilirubin equal or less than 1. 5 (unless Gilbert's Syndrome), SGPT <3 X upper limit of normal and alkaline phosphatase <2 X upper limit of normal. 4. Pulmonary function with FEV1, FVC and DLCO at least 45% of expected corrected for hemoglobin. Children unable to perform pulmonary functions must have an oxygen saturation greater than 92% at room air. 5. Adequate cardiac function with left ventricular ejection fraction at least 45% on appropriate medical therapy. No uncontrolled arrhythmias or symptomatic cardiac disease. 6. Zubrod performance status 0-1 or Lansky/Karnofsky PS equal or greater to 80%. 7. Patients must have a related, genotypically HLA identical donor, or they must have a unrelated donor who is 8/8 HLA match by high resolution typing. 8. Patient or patient's legal representative, parent(s) or guardian should provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years. 9. Negative Beta HCG test in a woman with child bearing potential defined as not post-menopausal for 12 months and no previous surgical sterilization. Exclusion Criteria: 1. Patients with active CNS disease. 2. Evidence of acute or chronic active hepatitis or cirrhosis. 3. Uncontrolled infection, including HIV, HTLV-1, hepatitis B or hepatitis C viremia. 4. Patients greater than 60 years-old. 5. Prior allogeneic SCT. 6. Prior autologous SCT in last 12 months. 7. Patients with AML in first remission after one course of induction and with favorable cytogenetics [t(8;21, inv 16, or t(15;17)] and/or molecular profile (NPM1). 8. Patients with ALL in first complete remission after one course of induction without minimal residual disease. 9. Prior radiation to liver in form of total body or involved field.

Partow Kebriaei, MD, Phone: 713-745-0663

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

University of Texas MD Anderson Cancer Center Website

Starting date: March 2014
Last updated: August 7, 2015