Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen
| Status: | Recruiting |
|---|---|
| Conditions: | Blood Cancer, Hematology |
| Therapuetic Areas: | Hematology, Oncology |
| Healthy: | No |
| Age Range: | 18 - 69 |
| Updated: | 2/7/2015 |
| Start Date: | November 2009 |
| End Date: | December 2017 |
| Contact: | Thomas Martin, MD |
| Email: | martint@medicine.ucsf.edu |
| Phone: | 415-353-9365 |
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
Busulfan and etoposide have been used as preparative therapy for autoSCT (stem cell
transplant) in adults with acute myeloid leukemia (AML) at UCSF for the past 10 years. Over
this period and together with collaborative transplant centers, over 200 patients have
received this treatment. By intent-to-treat analysis, and with median follow-up of 7.0
years, the 5-year DFS is 55%. The current protocol will utilize the combination of IV
Busulfan (BU) and etoposide. The busulfan dose will be escalated amongst 3 targeted dose
levels. All targeted dose levels represent higher busulfan dosing than standard
myeloablative dosing, with the lowest dose being approximately 14% higher than standard.
Busulfan levels will be monitored after the first, fourth and twelfth doses. Dose
adjustments will be made "in real time" based on AUC levels determined from the first and
fourth doses. This strategy of busulfan monitoring and dose adjustment has improved the
therapeutic widow of BU in previous clinical trials.
The current protocol will utilize the combination of intravenous busulfan and etoposide. The
busulfan dose will be escalated amongst 3 targeted dose levels (area under the curve (AUC)
levels at time 6 hours of 1250 uMol*min, 1400 uMol*min and 1550 uMol*min). All targeted
dose levels represent higher busulfan dosing than standard myeloablative dosing with the
lowest dose (1250 uMol*min) being approximately 14% higher than standard. In the absence of
dose-limiting toxicity, cohorts of 4-6 patients will be treated at each dose level and 10
additional patients will be treated at the maximum tolerated dose (MTD) to confirm safety.
The busulfan dosing will begin at 1 mg/kg based on historical plasma levels obtained from
patients receiving BU at a starting dose of 0.8 mg/kg at UCSF Medical Center.
The highest dose level proposed for this study will exceed the reported toxic level for
busulfan in the alloSCT setting. Patients will be followed closely for toxicity and strict
stopping rules have been included. Eligibility criteria will exclude patients with prior
history of hepatotoxicity or viral hepatitis. Potential hepatotoxic agents will not be
allowed just prior to and during the busulfan dosing period. In addition, patients who
experience hepatotoxicty during pre-transplant mobilization therapy may be excluded from
receiving dose-escalated busulfan therapy. Every attempt will be made to prevent or avoid
hepatotoxicity.
transplant) in adults with acute myeloid leukemia (AML) at UCSF for the past 10 years. Over
this period and together with collaborative transplant centers, over 200 patients have
received this treatment. By intent-to-treat analysis, and with median follow-up of 7.0
years, the 5-year DFS is 55%. The current protocol will utilize the combination of IV
Busulfan (BU) and etoposide. The busulfan dose will be escalated amongst 3 targeted dose
levels. All targeted dose levels represent higher busulfan dosing than standard
myeloablative dosing, with the lowest dose being approximately 14% higher than standard.
Busulfan levels will be monitored after the first, fourth and twelfth doses. Dose
adjustments will be made "in real time" based on AUC levels determined from the first and
fourth doses. This strategy of busulfan monitoring and dose adjustment has improved the
therapeutic widow of BU in previous clinical trials.
The current protocol will utilize the combination of intravenous busulfan and etoposide. The
busulfan dose will be escalated amongst 3 targeted dose levels (area under the curve (AUC)
levels at time 6 hours of 1250 uMol*min, 1400 uMol*min and 1550 uMol*min). All targeted
dose levels represent higher busulfan dosing than standard myeloablative dosing with the
lowest dose (1250 uMol*min) being approximately 14% higher than standard. In the absence of
dose-limiting toxicity, cohorts of 4-6 patients will be treated at each dose level and 10
additional patients will be treated at the maximum tolerated dose (MTD) to confirm safety.
The busulfan dosing will begin at 1 mg/kg based on historical plasma levels obtained from
patients receiving BU at a starting dose of 0.8 mg/kg at UCSF Medical Center.
The highest dose level proposed for this study will exceed the reported toxic level for
busulfan in the alloSCT setting. Patients will be followed closely for toxicity and strict
stopping rules have been included. Eligibility criteria will exclude patients with prior
history of hepatotoxicity or viral hepatitis. Potential hepatotoxic agents will not be
allowed just prior to and during the busulfan dosing period. In addition, patients who
experience hepatotoxicty during pre-transplant mobilization therapy may be excluded from
receiving dose-escalated busulfan therapy. Every attempt will be made to prevent or avoid
hepatotoxicity.
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.
- 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.
Inclusion Criteria:
Before Consolidation Chemotherapy
- Age 18-69 years
- Diagnosis of AML
- CR with ≤2 courses of induction chemotherapy.
- Out of the hospital for a minimum of 4 weeks from induction chemotherapy or 3 weeks
if consolidation chemotherapy has been administered.
- Remission bone marrow bx w/i 2 wks of beginning post remission rx.
- One cycle of post-remission consolidation w/standard dose cytarabine or HDAC with <8
doses of HDAC.
- Benign CSF: Lumbar puncture with cell count, differential and protein to determine
lack of extramedullary leukemia required w/i 2 weeks of post- remission therapy IF
CSF status is unknown or has been positive at dx.
- No active infection
- No evidence of prior liver disease.
- Creatinine <2.0 mg/dl.
- Cardiac ejection fraction ≥40%.
- Adequate pulmonary function with DLCO ≥40% of predicted.
- No co-morbid medical condition that would jeopardize the chance of tolerating
aggressive chemotherapy.
- ECOG 0-2
- Signed informed consent.
Eligibility to be Re-assessed Before Autologous SCT
- Minimum of 4 weeks out of hospital after post-remission rx.
- Continued CR documented by bone marrow morphology and cytogenetics (if previously
abnormal), performed within 2 wks of admission for autologous transplantation.
- Adequate marrow recovery from post-remission therapy as demonstrated by an ANC ≥
500/µl, platelets ≥ 50,000/µl and stable or improving hemoglobin (transfusion
independent).
- Adequate peripheral stem cells collected and stored;
- No evidence of liver dysfunction as determined within 2 weeks of transplant
admission. Bilirubin must be < 2.0 mg/dl and the AST and alkaline phosphatase < 3x
the upper limit of normal.
- Creatinine < 2.0 mg/dl.
- No active infection or need for ongoing antibiotics.
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