Advertisement

Topics

Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen

2014-08-27 03:16:40 | BioPortfolio

Summary

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.

Description

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.

Study Design

Allocation: Non-Randomized, Control: Active Control, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Acute Myeloid Leukemia

Intervention

Busulfan

Location

University of California Med. Center
San Francisco
California
United States
94143

Status

Recruiting

Source

University of California, San Francisco

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:16:40-0400

Clinical Trials [2212 Associated Clinical Trials listed on BioPortfolio]

Busulfan, Fludarabine, Clofarabine With Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia

Primary endpoint is to determine the efficacy and optimal dose levels of clofarabine and fludarabine in combination with busulfan for treatment of high risk patients with AML (Acute Myeloi...

Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)

The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplasti...

Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia

This phase II trial studies the side effects and how well giving busulfan and etoposide followed by peripheral blood stem cell transplant (PBSCT) and low-dose aldesleukin works in treating...

Busulfan Compared With Cyclophosphamide in Patients Undergoing Total-Body Irradiation Plus Peripheral Stem Cell Transplantation for Advanced Myelodysplastic Syndrome or Related Acute Myeloid Leukemia

RATIONALE: Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy used to kill tumor cells. It is not yet known i...

CAR-T Cells Therapy in Relapsed/Refractory Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a group of genetically highly heterogeneous malignant disease . The disease is the most common type of adult acute leukemia. Overall survival (OS) was less ...

PubMed Articles [6968 Associated PubMed Articles listed on BioPortfolio]

Effect of absolute monocyte count post-transplant on the outcome of patients with acute myeloid leukemia undergoing myeloablative allogeneic hematopoietic stem cell transplant with busulfan and cyclophosphamide conditioning.

Peripheral monocytes have recently been evaluated as a prognostic factor in different types of hematological malignancies. This study assessed the prognostic value of absolute monocyte count (AMC) pos...

Biologico-clinical significance of DNMT3A variants expression in acute myeloid leukemia.

DNA methyltransferase 3A (DNMT3A) catalyzes de novo DNA methylation and plays important roles in the pathogenesis of acute myeloid leukemia. However, the expression status of DNMT3A variants in acute ...

Acute external otitis as debut of acute myeloid leukemia - A case and review of the literature.

Acute leukemia is a well known childhood cancer. The relation between leukemia and otological symptoms has long been established but is highly rare as a debut symptom of leukemia. External otitis is a...

The importance of meaningful activity in people living with acute myeloid leukemia.

The symptom burden of acute myeloid leukemia (AML) and its treatment can accelerate physical deconditioning and impair mobility and quality of life. In the present study, we explore the subjective exp...

Widespread use of measurable residual disease in acute myeloid leukemia practice.

Measurable residual disease (MRD) has prognostic importance for patients with acute myeloid leukemia (AML). How leukemia providers incorporate MRD into routine practice remains undefined.

Medical and Biotech [MESH] Definitions

An alkylating agent having a selective immunosuppressive effect on BONE MARROW. It has been used in the palliative treatment of chronic myeloid leukemia (MYELOID LEUKEMIA, CHRONIC), but although symptomatic relief is provided, no permanent remission is brought about. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), busulfan is listed as a known carcinogen.

A pediatric acute myeloid leukemia involving both myeloid and monocytoid precursors. At least 20% of non-erythroid cells are of monocytic origin.

A rare acute myeloid leukemia characterized by abnormal EOSINOPHILS in the bone marrow.

An acute myeloid leukemia in which abnormal PROMYELOCYTES predominate. It is frequently associated with DISSEMINATED INTRAVASCULAR COAGULATION.

An acute leukemia exhibiting cell features characteristic of both the myeloid and lymphoid lineages and probably arising from MULTIPOTENT STEM CELLS.

More From BioPortfolio on "Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Transplantation
Organ transplantation is the moving of an organ from one body to another or from a donor site to another location on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative ...

Leukemia
Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader grou...


Searches Linking to this Trial