Trial Information

A Phase I Study of Targeted, Dose-Escalated Intravenous Busulfan and Bolus Etoposide as Preparative Therapy for Patients With Acute Myeloid Leukemia Undergoing Autologous Stem Cell Transplantation

TREATMENT: STEP 1 - CONSOLIDATION CHEMOTHERAPY

- Etoposide 10 mg/kg IV continuous infusion over 24 hrs for 4 days (total course dose 40
mg/kg). Dose should be based on corrected weight, calculated as follows: Ideal + 25%
of the difference between actual and ideal weight. If actual is less than ideal weight
use actual weight. Etoposide infusion should be mixed in normal saline at a
concentration of 0.4-0.5 mg/ml. The infusion volume will be approximately 1.39
ml/kg/hour and should be rounded to the nearest 500-1000 ml and infused through a
central venous catheter.

- Cytarabine (ara-C) 2,000 mg/m2 IV over 2 h q 12 h x 8 doses Days 1-4. Cytarabine
dosage should be based on corrected weight, calculated as follows: Ideal weight + 25%
of the difference between actual and ideal weight. If actual weight is less than ideal
weight, use actual weight.Begin concurrent with etoposide infusion. Cytarabine doses
should be mixed in 250 ml of D5W.

To prevent neurotoxicity from high-dose cytarabine (HDAC), cytarabine doses will be adjusted
according to renal function. The dose of cytarabine will be reduced to 1000 mg/m2/dose if
creatinine is 1.5-1.9 mg/dL or if there is an increase from baseline creatinine at start of
cytarabine of 0.6-1.1 mg/dL (example: baseline creatinine 0.8 mg/dL increase to 1.4 mg/dL
(difference of 0.6 mg/dL)), decrease cytarabine to 1000 mg/m2/dose.The dose of cytarabine
will be reduced to 100 mg/m2/dose if creatinine > 2.0 mg/dL or if there is an increase from
baseline > 1.2 mg/dL.Cytarabine will be discontinued immediately for any clinical evidence
of cerebellar neurotoxicity (dysarthria, dysmetria, gait disturbance).

Supportive Care Measures:

- G-CSF 5 mcg/kg (actual body weight) SQ daily beginning day 14. The dose will be
increased to 10 mcg/kg when WBC > 1000/uL is achieved. G-CSF 10 mcg/kg should then be
continued until the peripheral blood stem cell collection has been completed. All G-CSF
doses should be rounded up to a convenient dose based on vial sizes of 300 and 480mcg.

- Fluoromethalone 0.1% ophthalmic solution (or equivalent medication) 2 drops qid to each
eye Days 1-6.

- Voriconazole 200 mg PO Q12 hours beginning the day after completion of chemotherapy
(Day +6). Equivalent anti-fungal prophylaxis with itraconazole, posaconazole or
Liposomal-based amphotericin (1mg/kg) may be used.

- Patients should be hospitalized in private rooms when possible.

- Strict low bacteria diet should be used when ANC < 500 cells/uL.

- Recommended mouth care:

a. Salt and soda swish tid

- Transfusions: Institution standards should be followed for blood product support. In
lieu of standards, packed RBCes should be given to maintain the hemoglobin >8.5 gm/dl
or hematocrit >25%. Platelet should be transfused to keep the platelet count >10-20 x
109/l. Blood should be filtered and irradiated (3000 cGy). CMV seronegative patients
should receive CMV-seronegative blood products if available.

PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION

- Begin collections when the total white blood count exceeds 10,000/µl or when
appropriate based on peripheral CD34 cell counts (institutional standard)

- Aim for a total of 1-4 collections with a standard target CD34 cell dose of > 5 x 10 x
106/kg and an optimal target CD34 cell dose of > 10 x 106/kg. The minimum CD34 cell
dose is > 3 x 106/kg. Collections should continue until 10 x 106/kg CD34 (+) cell dose
is achieved unless not clinically feasible.

- Stem Cell Collection: Process 18-20 L of whole blood over 3-4 hours according to
institutional standards.

- PBSC Processing: The buffy coat is concentrated by centrifugation on Beckman
centrifuge. Cells are suspended in Normasol media with 5% autologous plasma and 10%
DMSO to a final cell concentration of 2.5 x 108/ml. Seventy ml aliquots are placed in
polyolefin bags and frozen in a controlled rate freezer. Bags are labeled then stored
in the liquid phase of a liquid nitrogen freezer. Institutional standard for PBSC
processing should be followed.

- Four 2 ml aliquots of PBSC will be frozen in liquid nitrogen for future analysis.

TREATMENT: STEP 2 - AUTOLOGOUS STEM CELL TRANSPLANT

- Mandatory Recovery Period: The patient may begin preparative therapy for stem cell
transplant following a minimum of four weeks "out-of-hospital" time since discharge
from consolidation/mobilization chemotherapy.

- Dose-Adjusted Busulfan

1. Busulfan dose should be calculated using the corrected weight which equals ideal
weight + 25% of the difference between actual and ideal weight. If the actual
weight is less than ideal weight use actual weight.

2. The initial dose of busulfan (Dose cohort #1 = 1 mg/kg, Dose cohort #2 = 1.2
mg/kg, Dose cohort # 3 = 1.4) will be given as a single intravenous dose on Day
-10 (in the morning, at 9:00AM). The dose will be administered by intravenous
injection over 2 hours in the Outpatient Ambulatory Care/Infusion Center.

1. The infusion tubing will be primed with busulfan diluted with saline to
ensure complete administration over 2 hours as detailed in Appendix 10.

2. The busulfan will be administered through a well functioning central venous
catheter. The busulfan infusion tubing should be connected directly to the
central venous catheter hub (i.e. directly to the catheter) to ensure
busulfan administration over two hours.

3. Busulfan levels will de drawn at 2, 3, 4 and 6 hours from the start of
Busulfan Dose #1. For Doses #4 and #12, levels will be drawn just prior to
infusion and at 2, 3, 4 and 6 hours, from a well functioning peripheral IV.
(SEE Appendix 9 for busulfan sampling)

- After the busulfan is administered on Day -10, and the serial serum samples have been
obtained, the patient will be discharged from the ACC infusion center.

- Busulfan dosing will resume starting on day -8 and will be given IV q6h for an
additional 15 doses (total 16 doses). Patients at UCSF will receive busulfan
chemotherapy on the 11 Long Adult Inpatient Unit. Dose #2 will be administered at
approximately 8 pm. This dose will be adjusted based on target dose level and PK data
results following dose #1. The second dose will not be given until the PK data is
available from dose #1.

- PK studies will also be performed following the 4th and 12th doses. The final busulfan
dose-adjustment will be made at approximately dose #10 as determined by PK data. In
some cases, the dose-adjustment may be delayed due to travel time or problems at the
reference lab. No dose-adjustment will be made from data obtained from samplings made
following the 12th dose.

- Dose adjustments will be based on a standard formula as recommended by the reference
laboratory. Adjustments will be made to achieve the target AUC level from doses 2 until
16. Dose adjustments will be calculated and confirmed by two physicians (including one
of the co-PI's, if possible) at UCSF Medical Center.

Dose adjustments and busulfan laboratory values will also be reviewed regularly by Jeanine
McCune Ph D., at the University of Washington, in Seattle, WA. Dr. McCune is a collaborator
on this trial and manages the Busulfan pharmacokinetics laboratory in Seattle. She is a
leader in the field of Busulfan metabolism, pharmacokinetics and administration.