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Fludarabine

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Fludarabine 40 mg/m2 intravenous (IV) over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV over 3 hours every 24 hours. Both delivered for 4 consecutive days (days -6 to -3). Stem cell transplant Day 0.

Fludarabine 10 mg/m2 over 1 hour. Clofarabine 40 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, infused over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV over 3 hours every 24 hours, immediately after Clofarabine. All delivered on 4 consecutive days (days -6 through -3). Stem cell transplant Day 0.

Flu + Bu Group: 40 mg/m2 by vein on Days -6 through -3.

Flu +Clo + Bu Group: 10 mg/m2 by vein on Days -6 through -3.

30 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, and infused on Days -6 through -3.

Busulfan systemic exposure dose of 6000 µMol-min in normal saline over three (3) hours by vein every twenty-four (24) hours for four (4) consecutive days (days -6 to -3), starting immediately after the completion of Clofarabine. The dose on day -6 to -3 based on pharmacokinetic analysis of target AUC of 4,000 µMol-min ± 5% for 61-70 years of age (without Pharmacokinetics alternate dose 130 mg/m2).

Both groups who receive a graft from an unrelated donor:

0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.0 mg/kg on day -1. On day -3, administered after the chemotherapy is complete.

Cryopreserved bone marrow or peripheral blood progenitor cells infused on day 0.

Stem Cell Infusion

Starting dose: 0.015 mg/kg (ideal body weight) as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml. Changed to oral dosing when tolerated and can be tapered off after day +90 if no graft versus host disease (GVHD) present.

5 mg/m2 by vein on Days 1, 3, 6 and 11 post transplant.

Richard E. Champlin, BS,MD

The goal of this clinical research study is to learn if combining busulfan with clofarabine and fludarabine can help control the disease better than the previous standard method (using busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination therapy will also be studied.

Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells), which may cause cancer cells to die. Busulfan is commonly used in stem cell transplantation.

Clofarabine is designed to interfere with the growth and development of cancer cells.

Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer cells to die.

Study Groups:

You will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups.

* Group 1 will receive busulfan, fludarabine, and clofarabine.
* Group 2 will receive busulfan and fludarabine.

Both groups will have a stem cell transplant. The stem cells will be given by vein. The cells will travel to your bone marrow where they are designed to make healthy, new blood cells after several weeks.

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:

Both 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 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 fludarabine by vein over 1 hour, then clofarabine (if you are in Group 1) by vein over 1 hour, then busulfan by vein over 3 hours.

After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive (lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host disease (GvHD), a reaction of the donor's immune cells against the recipient's body.

If you are going to be receiving a transplant from an HLA-nonidentical or 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 of the transplant.

You will receive filgrastim as an injection under the skin 1 time a day, starting 1 week after the transplant, until your blood cell levels return to normal. Filgrastim is designed to help with the growth of white blood cells.

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.

As part of standard care, you will remain in the hospital for about 3-4 weeks after 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:

* You will be asked about how you are feeling and about any side effects you may be having.
* 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.

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, including measurement of your vital signs (blood pressure, heart rate, temperature, and breathing rate).
* You will be asked about how you are feeling and about any side effects you may be having.
* 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. 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 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, 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, 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. Busulfan and fludarabine are both FDA approved and commercially available for the treatment of AML and MDS. Clofarabine is FDA approved for treating other types of cancer, but is being used in AML and MDS for research only. The use of these study drugs together at the dose level used in this study is investigational.

Up to 250 patients will take part in this study. All will be enrolled at MD Anderson.

Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

A Randomized Study of Once Daily Fludarabine-Clofarabine Versus Fludarabine Alone Combined With Intervenous Busulfan Followed by Allogeneic Hemopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Number of events with progression free survival. (Progression is defined as more than 5% blast in the peripheral blood or bone marrow biopsy.) or expired from treatment related mortality post transplant.

Number of participants in the study who are alive and disease free at 1, 3 and 5 years post transplant.

Number of participants in the study who are with no Grade 3 or 4 acute graft-versus-host disease at any time during the first 100 days post transplant.

Number of participants expired from complications other than relapsed disease at 100 day Post Transplant.

Sanofi

M.D. Anderson Cancer Center

Fludarabine 40 mg/m2 intravenous (IV) over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV for 60 years and younger or 4000 uMol-min IV for 61 years and older over 3 hours every 24 hours. Both delivered for 4 consecutive days (days -6 to -3). Stem cell transplant Day 0.

Arm A (Flu+Bu)

Fludarabine 10 mg/m2 over 1 hour. Clofarabine 40 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, infused over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV for 60 years and younger or 4000 uMol-min IV for 61 years and older over 3 hours every 24 hours, immediately after Clofarabine. All delivered on 4 consecutive days (days -6 through -3). Stem cell transplant Day 0.

Arm B (Flu+Clo+Bu)

FlFludarabine 10 mg/m2 over 1 hour. Clofarabine 40 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, infused over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV for 60 years and younger or 4000 uMol-min IV for 61 years and older over 3 hours every 24 hours, immediately after Clofarabine. All delivered on 4 consecutive days (days -6 through -3). Stem cell transplant Day 0.

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Saudi Arabia

Qatar

Region of Enrollment

Richard Champlin, MD / Stem Cell Transplantation

Progression-Free Survival (PFS)

1 Year Post Transplant

3 Year Post Transplant

5 Year Post Transplant

Overall Survival (OS) Post Transplant at 1, 3 and 5 Years

Fludarabine 40 mg/m2 intravenous (IV) over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV for 60 years and younger or 4000 uMol-min IV for 61 years and older over 3 hours every 24 hours. Both delivered for 4 consecutive days (days -6 to -3). Stem cell transplant Day 0..

Number of Participants in the Study Who Are With no Grade 3 or 4 Acute Graft-versus-host Disease at Any Time During the First 100 Days Post Transplant.

Number of Participants With Non Relapse Mortality at 100 Day Post Transplant

Overall Study

Lymphoma

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Lymphoma, T-Cell, Cutaneous

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Peripheral T-cell Lymphoma

Cutaneous T-cell Lymphoma

Melphalan

Fludarabine 25 mg/m\^2 intravenous (IV) daily for 5 Days prior to Allogeneic Transplant, Melphalan 70 mg/m\^2 IV daily for 2 Days prior to IV Allogeneic Transplant following Fludarabine \& Melphalan. Thymoglobulin 2 mg/kg/day IV on days -3, -2 \& -1 for patients receiving matched unrelated marrow/stem cells or mismatched related marrow.

25 mg/m\^2 Given By Vein Daily for 5 Days Prior to Allogeneic Transplant.

70 mg/m\^2 Given By Vein Daily for 2 Days Prior to Allogeneic Transplant.

Allogeneic transplant given by vein after completion of Fludarabine and Melphalan.

Allogeneic Transplant

2 mg/kg/day by vein on days -3, -2 and -1 for patients receiving matched unrelated marrow/stem cells or mismatched related marrow.

Chitra M. Hosing, MD

The goal of this clinical research study is to see if receiving a transplant of blood stem cells (cells that can produce blood) or bone marrow from either a related donor (brother, sister or other relative) or an unrelated voluntary donor will help patients with advanced cutaneous T-cell lymphoma. The length of time that patients who receive the treatment remain free of disease will also be studied.

You will receive the chemotherapy drug fludarabine for 5 days (Days 1 to 5). The drug melphalan will be given on Days 4 and 5. You may also receive the drug anti-thymocyte globulin (ATG) on Days 4, 5, 6. This will be followed by infusion of blood stem cells or bone marrow from a donor on Day 7. A separate consent will be provided to the donor. The donor can be a brother, sister or another family member or a compatible unrelated donor. The drugs and the stem cells will be given through a catheter (a small tube) placed under the collarbone. You may receive your treatment on an inpatient or outpatient basis. If treated on an inpatient basis, you will stay in the hospital during treatment and recovery, which can take 4 to 5 weeks even if there are no complications.

The chemotherapy and the ATG are given to help the body accept the transplanted stem cells or bone marrow. You will receive antibiotics to fight infection and a medicine called G-CSF (Neupogen®) to help blood counts rise back to healthier levels. G-CSF is given as an injection under the skin. You will also need blood and platelet transfusions.

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.

If the cancer grows and graft-versus-host disease is not present, you may be eligible to receive donor blood cells (lymphocytes) infused through the catheter. This may cause graft-versus-host disease and may help shrink the cancer. If the cancer grows and graft-versus-host disease is already present, then donor lymphocytes are not given.

Sometimes, the body rejects the donor cells; this reaction is called "graft rejection". Sometimes the donor cells attack the body, a reaction called graft-versus-host disease (GvHD). The drugs tacrolimus and methotrexate will be given to help prevent these reactions from occurring. These drugs are given through a vein or by mouth before and/or after the transplant.

You must stay in the Houston area for at least 100 days after the transplant. After 100 days, you must return to Houston every 3 months for 2 years for tests and checkups, then once a year for at least 3 years. If there is no sign of lymphoma growth at the follow up visit(s), you will receive no further treatment.

This is an investigational study. The drugs used in this study are approved by the FDA and are commercially available. As many as 35 patients will take part in the study. All will be enrolled at MD Anderson.

Allogeneic Transplantation in Patients With Cutaneous T-Cell Lymphoma

Study of Allogeneic Transplantation in Patients With Cutaneous T-Cell Lymphoma (CTCL)

Response defined by Physician's Global Assessment of Clinical Condition (PGA) where Complete Response (CR) is No evidence of disease; 100% improvement; Partial Response (PR), one of following: 1) Very significant clearance ( \> 90% to \< 100%); only traces of disease remains; 2) Significant improvement ( \> 75% to \< 90%); some evidence of disease remain; 3) Intermediate between slight and marked improvement; ( \> 50% to \< 75%); 4) Some improvement ( \> 25% to \< 50%); however, significant evidence of disease remains; Stable Disease (SD): Disease has not changed from baseline condition (+\<25%); Progressive Disease (PD): Disease is worse than at baseline evaluation by \> 25% or more. Response confirmed by a second assessment at least 4 weeks following it. Assessments at baseline, pre and post transplant (100 days) then till disease progression or year one.

OS was defined as the time from transplantation to the date of death from any cause or last follow up, measured in days.

Fludarabine 25 mg/m\^2 intravenous (IV) daily for 5 days prior to allogeneic peripheral blood progenitor cell (PBPC) , Melphalan 70 mg/m\^2 IV daily for 2 days prior to IV Allogeneic Transplant following Fludarabine \& Melphalan. Thymoglobulin 2 mg/kg/day IV on days -3, -2 \& -1 for patients receiving matched unrelated marrow/stem cells or mismatched related marrow.

Fludarabine + Melphalan With PBPC

Age, Continuous

Chitra M. Hosing, Professor, Stem Cell Transplantation

Complete Response (CR) Converted Post Transplant

CR Prior to Transplant

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Participant's Response According to Physician's Global Assessment of Clinical Condition (PGA)

Baseline to disease progression, followed up to 5 years post transplant (assess at 100 days, every 3 months for 2 years, then once a year for at least 3 years)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)	NCT01471444	Disorder Relate... Leukemia Transplantation...	Fludarabine Clofarabine Busulfan Thymoglobulin Stem Cell Infus... Tacrolimus Methotrexate	3 Years - 70 Years	M.D. Anderson Cancer Center
Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)	NCT01471444	Disorder Relate... Leukemia Transplantation...	Fludarabine Clofarabine Busulfan Thymoglobulin Stem Cell Infus... Tacrolimus Methotrexate	3 Years - 70 Years	M.D. Anderson Cancer Center
Allogeneic Transplantation in Patients With Cutaneous T-Cell Lymphoma	NCT00506129	Lymphoma Disorder Relate...	Fludarabine Melphalan Allogeneic Tran... Thymoglobulin	- 70 Years	M.D. Anderson Cancer Center
Allogeneic Transplantation in Patients With Cutaneous T-Cell Lymphoma	NCT00506129	Lymphoma Disorder Relate...	Fludarabine Melphalan Allogeneic Tran... Thymoglobulin	- 70 Years	M.D. Anderson Cancer Center
Allogeneic Transplantation in Patients With Cutaneous T-Cell Lymphoma	NCT00506129	Lymphoma Disorder Relate...	Fludarabine Melphalan Allogeneic Tran... Thymoglobulin	- 70 Years	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for disorder related to bone marrow transplantation