Fungal Infection, Leukemia
Conditions
Keywords
Cancer of the Blood, Cancer of Bone Marrow, Acute Leukemia, AML, Fungal infection, Prophylaxis, Posaconazole, SCH 56592, Noxafil, Chemotherapy
Brief summary
The goal of this clinical research study is to learn the amount of posaconazole that is in the body at different time points when given to patients with leukemia. The safety of this drug will also be studied. Objectives: Primary: To study the plasma pharmacokinetics of posaconazole in patients with newly diagnosed acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) undergoing induction chemotherapy or relapsed or refractory patients who will receive salvage chemotherapy. Secondary: To evaluate the safety of posaconazole given as prophylaxis.
Detailed description
Chemotherapy can lower immune system function, which can cause fungal infections to occur more easily. The standard treatment for prevention of such infections includes drugs such as voriconazole and liposomal amphotericin B that help prevent fungus from growing. The Study Drug: Posaconazole is designed to block the ergosterol synthesis (a part of the fungal membrane). This may help to prevent fungal infections. Study Drug Administration: If you are found to be eligible to take part in this study, you will take posaconazole by mouth 3 times per day. Posaconazole is a liquid. You should take the study drug after a full meal or with a liquid nutritional supplement (such as a protein shake). If you are not able to eat food, you should take it with a carbonated beverage (such as soda). Food and Drug Diary: You will be also be given a food and drug diary where you will write down the time you took each dose. You should also record the time eaten and describe what you ate or drank at each meal. This information will be used to find out the number of calories and amount of protein, carbohydrates, and fat you have consumed. You will be given a small bag where you can keep the drug and diary. You should return this diary after the last blood draw. Blood Draws for Pharmacokinetics (PK) Testing: While you are on study, blood (about 1 teaspoon each time) will be drawn for PK testing. PK testing measures the amount of study drug in the body at different time points. * Days 1, 3, and 10, before your first dose of study drug and 3, 5, and 10 hours after the first dose of the day * Days 2 and 4, about 24 hours after the first dose the day before Blood (about 1 teaspoon) will also be drawn for PK testing 1 time at any of the following time points: * Before you start a new dose of study drug, if the dose needs to be raised * If you stop taking the study drug due to intolerable side effects or a fungal infection Note that if you are not already in the hospital on the days of the PK blood draws, you will need to stay at the hospital for about 10 hours on these days. Length of the Study: You will take the study drug for up to 42 days. You will be taken off study if you experience intolerable side effects, if you develop an invasive fungal infection, or if the doctor thinks it is in your best interest. This is an investigational study. Posaconazole is FDA approved and commercially available for the prevention of fungal infections. Up to 25 patients will take part in the study. All will be enrolled at MD Anderson.
Interventions
DRUGPosaconazole
200 mg (liquid) by mouth 3 times per day.
Sponsors
Schering-Plough
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients newly diagnosed with AML or high-risk MDS undergoing induction chemotherapy or refractory or relapsed patients with AML or high-risk MDS who will receive first or second salvage chemotherapy. (Salvage patients are defined as patients that achieved remission and relapsed or patients who were refractory to initial frontline chemotherapy) 2. Age \> 18 years and able to take oral intake. 3. Patients must sign an informed consent. 4. Patients agree to medically approved forms of contraception 5. Patients on prior antifungal prophylaxis with voriconazole, itraconazole or fluconazole are eligible if they completed 3 days wash-out period if on voriconazole, or 14 days wash-out period if on itraconazole or 7 days wash-out period if on fluconazole
Exclusion criteria
1. Patients with history of anaphylaxis attributed to azole compounds 2. Patients with clinical or other evidence that indicates that they have proven or probable invasive fungal infection prior to enrollment (EORTC criteria) 3. Patients with baseline total bilirubin levels \> 3 times the upper normal limits (i.e. \> 3.0 mg/dl); or baseline SGPT \> 5 times upper limit normal. 4. Patients receiving any medication that is contraindicated with the use of posaconazole 5. Patients with baseline creatinine levels NCI grade 3 or above (\> 3.0 - 6.0 X ULN) 6. Patients with baseline QTc prolongation NCI grade 1 or above (QTc \> 0.45 - 0.47 seconds).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration in Plasma (Cmax) | Pharmacokinetics: Day 1, Day 3 and Day 10 of prophylaxis. | Pharmacokinetic samples were obtained on day 1, day 3 and day 10 of prophylaxis. A total of 15 samples (3 ml each sample) per participant were obtained, with thrice daily dosing planned around standard meal times. On day 1 and day 3 of prophylaxis sampling was done pre dose (0), and at 3, 5, 10 and 24 hours (±10 minutes) post dose from the time of the first dose of the day. On day 10 of prophylaxis sampling was done pre dose (0), and at 3, 5, and 10 hours (±10 minutes) post dose from the time of the first dose of the day. Posaconazole levels were assayed by high performance liquid chromatography (HPLC). The testing range for posaconazole is from 125 - 5000 ng/ml. There are no established therapeutic ranges for posaconazole. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: September 30, 2009 to January 3, 2011. From January 2010 through August 2010, adult with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) undergoing induction chemotherapy or first salvage therapy were recruited at The University of Texas (UT) MD Anderson Cancer Center.
Pre-assignment details
Of the 25 participants enrolled, five participants were excluded from the trial -- two were ineligible, one withdrew consent before start of treatment, another two were excluded from the study for other reasons.
Participants by arm
| Arm | Count |
|---|---|
| Posaconazole Posaconazole 200 mg (liquid) by mouth 3 times per day. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Unable to continue oral medication | 3 |
Baseline characteristics
| Characteristic | Posaconazole |
|---|---|
| Age, Continuous | 65 years |
| Chemotherapy Received Clofarabine-containing regimen | 8 participants |
| Chemotherapy Received Cytarabine-containing regimen | 9 participants |
| Chemotherapy Received Miscellaneous* | 3 participants |
| Participant Diagnosis AML, Induction | 19 participants |
| Participant Diagnosis AML, Relapse | 1 participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Maximum Observed Concentration in Plasma (Cmax)
Pharmacokinetic samples were obtained on day 1, day 3 and day 10 of prophylaxis. A total of 15 samples (3 ml each sample) per participant were obtained, with thrice daily dosing planned around standard meal times. On day 1 and day 3 of prophylaxis sampling was done pre dose (0), and at 3, 5, 10 and 24 hours (±10 minutes) post dose from the time of the first dose of the day. On day 10 of prophylaxis sampling was done pre dose (0), and at 3, 5, and 10 hours (±10 minutes) post dose from the time of the first dose of the day. Posaconazole levels were assayed by high performance liquid chromatography (HPLC). The testing range for posaconazole is from 125 - 5000 ng/ml. There are no established therapeutic ranges for posaconazole.
Time frame: Pharmacokinetics: Day 1, Day 3 and Day 10 of prophylaxis.
Population: Of the 11 females enrolled, one was not evaluable for the outcome thus excluded from analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Posaconazole (Females) | Maximum Observed Concentration in Plasma (Cmax) | Day 2, Hour 24 | 200 ng/ml |
| Posaconazole (Females) | Maximum Observed Concentration in Plasma (Cmax) | Day 4, Hour 24 | 300 ng/ml |
| Posaconazole (Females) | Maximum Observed Concentration in Plasma (Cmax) | Day 9, Hour 24 | 770 ng/ml |
| Posaconazole (Males) | Maximum Observed Concentration in Plasma (Cmax) | Day 2, Hour 24 | 290 ng/ml |
| Posaconazole (Males) | Maximum Observed Concentration in Plasma (Cmax) | Day 4, Hour 24 | 580 ng/ml |
| Posaconazole (Males) | Maximum Observed Concentration in Plasma (Cmax) | Day 9, Hour 24 | 800 ng/ml |