Gemcitabine/Clofarabine/Busulfan and Allogeneic Transplantation for Aggressive Lymphomas

The goal of this clinical research study is to find the highest tolerable dose of gemcitabine (out of 6 possible doses) that can be given in combination with busulfan and clofarabine before an allogeneic stem cell transplant. Researchers also want to learn if this combination can help to control lymphoma. The safety of this treatment will also be studied.

Busulfan is designed to bind to DNA (the genetic material of cells), which may cause cancer cells to die. It is commonly used in stem cell transplants.

Clofarabine and gemcitabine are designed to block the growth of cancer cells, which may cause the cancer cells to die.

Study Drug Administration and Pharmacokinetic (PK) Testing:

The days before you receive your stem cells are called minus days, such as Day -2, Day -1. The day you receive the stem cells is called Day 0. The days after you receive the stem cells are called plus days, such as Day +1, Day +2.

Between Days -15 and -8, you will receive a low-level "test" dose of busulfan by vein over about 45 minutes to 1 hour. Test doses are used to study how your body breaks down busulfan and decide the dose of busulfan that you will receive. You may receive the test dose before Day -8 as an outpatient in the clinic, or on Day -8 as an inpatient in the hospital.

Blood (about 1 teaspoon each time) will then be drawn for PK testing up to 11 times over the 11 hours after the busulfan test dose. PK testing measures the amount of study drug in the body at different time points. The study staff will tell you more about the PK testing schedule.

A heparin lock line will be placed in your vein before the PK testing to lower the number of needle sticks needed for these draws. If for any reason it is not possible for the PK tests to be performed, you will receive the standard dose of busulfan.

On Day -9 or Day -7, you will be admitted to the hospital and given fluids by vein to hydrate you.

On Days -6 and -4, you will receive gemcitabine by vein over 40-180 minutes. The dose you receive will be based on when you join the study. The length of time it takes to infuse the gemcitabine will be based on when you join this study and the dose amount you are assigned. Up to 6 dose levels of gemcitabine will be tested. Up to 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of gemcitabine is found. After the highest dose is found, additional participants will be enrolled at that dose. The number of patients in the group that receives the highest tolerable dose will depend on how many have been enrolled in the other groups.

On Days -6 through -3, you will receive clofarabine by vein over 1 hour, followed by your dose of busulfan by vein over 3 hours. If for any reason you could not have the PK tests performed, you will receive the standard busulfan dose on these days.

On Days -3 through -1, if your stem cell donor is not related to you, you will receive antithymocyte globulin (ATG) by vein over 4 hours each day. ATG is designed to weaken your immune system in order to lower the risk that your body will reject the transplant. If your stem cell donor is related to you, you will not receive this drug.

Beginning on Day -2, you will receive tacrolimus by vein over 24 hours every day until you are able to take it by mouth. Tacrolimus is designed to weaken the immune system and lower the risk of graft-versus-host-disease (GVHD - a reaction of the donor's immune cells against your body). After you are able to take tacrolimus by mouth, you will take it every day for about 6 months, or until the doctor thinks it is safe to stop.

On Day 0, you will receive the donor's stem cells by vein. The infusion will last anywhere from about 30 minutes to several hours.

On Days +1, + 3, +6, and +11, you will receive methotrexate by vein over about 15 minutes. Methotrexate is also designed to weaken the immune system and lower the risk of GVHD.

Starting 1 week after the transplant (Day +7), you will receive filgrastim (G-CSF) as an injection under the skin 1 time each day until your blood cell levels return to normal. Filgrastim is designed to make white blood cells grow, which may help to fight infections.

You may be given other standard drugs to help lower the risk of side effects. You may ask the study staff for more information about how the drugs are given and their risks.

Study Visits:

Within 30 days of receiving the stem cells, you will have a positron emission tomography (PET) scan to check the status of the disease.

About 4 weeks after the stem cell transplant:

• You will have a physical exam, including measurement of your height, weight, and 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.
• You will be checked for possible reactions to the study treatment, including GVHD.
• Blood (about 4 tablespoons) will be drawn for routine tests, to see how the transplant has taken, and to check the status of the disease.

Follow-Up Visits:

About 3, 6, and 12 months after the transplant, and then every 6 months for 4 more years:

• You will have a physical exam, including measurement of your vital signs.
• You will be asked about how you are feeling and about any side effects you may be having.
• You will be checked for possible reactions to your treatment, including GVHD.
• Blood (about 4 tablespoons) will be drawn for routine tests, to see how well the transplant has taken, and to check the status of the disease.
• At any point that your doctor thinks they are needed, you will have a bone marrow aspiration and computed tomography (CT) and/or PET scans 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.

The study staff will also stay in contact with your local doctor to find out if the disease comes back and to check how you are doing.

Length of Treatment:

You will be on study for about 5 years. After 1 year, there is no study specific testing you will be required to complete. Your transplant doctor will perform routine standard of care follow-up that all patients receiving allogeneic stem cell transplantation receive.

You may be removed from the study early if the doctor thinks it is in your best interest, if the disease gets worse or comes back, if intolerable side effects occur, if you have graft failure (the transplanted cells do not grow), or if you are unable to follow study directions.

If for any reason you want to leave the study early, you must talk to the study doctor. It may be life-threatening to leave the study after you have started to receive the study drugs but before you receive the stem cell transplant because your blood cell counts will be dangerously low.

This is an investigational study. Gemcitabine and clofarabine are FDA approved and commercially available for the treatment of lymphoma. Busulfan is FDA approved and commercially available for use in stem cell transplantation. The combination of gemcitabine given in combination with busulfan and clofarabine before an allogeneic stem cell transplant is investigational.

Up to 30 patients will take part in this study. All will be enrolled at MD Anderson.

• Drug: Gemcitabine

  Phase I Starting dose of Gemcitabine: 75 mg/m2/ loading dose by vein targeting the desired steady state concentration of 20 µmolar on Day -6 and Day -4. This will be immediately followed by an infusion at a fixed rate of 10 mg/m2/min over varying lengths of time per study cohort.

  Phase II Starting dose of Gemcitabine: Maximum tolerated dose (MTD) from Phase I.

  Other Names:

  • Gemcitabine Hydrochloride
  • Gemzar
• Drug: Clofarabine
  Phase I and Phase II dose of Clofarabine: 40 mg/m2 by vein on Days -6 to -3.
  Other Names:

  • Clofarex
  • Clolar
• Drug: Busulfan

  Phase I and Phase II dose of Busulfan: Test dose of 32 mg/m2 by vein as an outpatient between Day -15 and Day -8, or on Day -8 as an inpatient.

  Busulfan 4000 µMol-min by vein four consecutive days (Days -6 to -3), starting immediately after the completion of clofarabine. If not feasible to perform pharmacokinetic monitoring, patients receive fixed dose of 100 mg/m2/day for 4 days, which is expected to yield a median daily AUC of 4,000 µMol.min-1.

  Other Names:

  • Busulfex
  • Myleran
• Procedure: Stem Cell Infusion
  Stem cell infusion on Day 0.
• Drug: Anti-Thymocyte Globulin
  0.5 mg/kg on Day -3, 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1 for patients receiving a graft from a matched unrelated donor.
  Other Names:

  • Thymoglobulin
  • ATG
• Drug: Rituximab
  375 mg/m2 by vein on Day -14 and Day -7 and then on Day +1 and Day +8 for patients with CD20+ disease.
  Other Name: Rituxan
• Drug: Filgrastim
  5 mcg/kg/day subcutaneously starting on Day +7 until blood cell levels return to normal.
  Other Names:

  • G-CSF
  • Neupogen
• Drug: Tacrolimus
  0.015 mg/kg by vein beginning on Day -2, as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml. Tacrolimus is changed to oral dosing when tolerated and can be tapered off after day +90 if no graft versus host disease (GVHD) is present.
  Other Name: Prograf
• Drug: Methotrexate
  5 mg/m2 by vein on Days +1, +3, +6 and +11.

Inclusion Criteria:

1. Age 12 to 65 years of age.
2. Patients with refractory B-cell or T-cell non-Hodgkin's lymphoma or Hodgkin's lymphoma who are eligible for allogeneic transplantation.
3. An 8/8 HLA matched (high resolution typing at A, B, C, DRB1) sibling or unrelated donor.
4. Left ventricular EF >/= 45%.
5. FEV1, FVC and corrected DLCO >/= 50%.
6. Adequate renal function, as defined by estimated serum creatinine clearance >/=50 ml/min (using the Cockroft-Gault formula: creatinine clearance = [(140-age)*kg/(72*serum creatinine)] * 0.85 if female) and/or serum creatinine </=1.6 mg/dL.
7. Serum bilirubin </= 2x upper limit of normal.
8. SGPT </= 2x upper limit of normal.
9. Voluntary signed IRB-approved informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
10. Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

1. Patient with active CNS disease.
2. Pregnancy (positive Beta HCG test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
3. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/=10,000 copies/mL, or >/= 2,000 IU/mL).
4. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
5. HIV infection.
6. Active uncontrolled bacterial, viral or fungal infections.
7. Exposure to other investigational drugs within 4 weeks before enrollment.
8. Grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to </= grade 1.
9. Radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment.
10. Prior whole brain irradiation.
11. Prior autologous SCT in the prior 12 months.