Effect of Rifampin on the Pharmacokinetics of Ixabepilone in Patients With Advanced Cancer
- Conditions
- NeoplasmsAdvanced Solid Tumors
- Interventions
- Registration Number
- NCT00207090
- Lead Sponsor
- R-Pharm
- Brief Summary
The purpose of this study is to test how rifampin affects the removal of BMS-247550 (ixabepilone) from the body.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 19
- Up to three prior chemotherapy regimens
- Measurable or non-measurable disease
- Available for treatment and follow-up
- Neuropathy
- Uncontrolled cardiovascular disease
- Refusal to participate in genetic analysis
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ixabepilone + rifampin Rifampin - Ixabepilone + rifampin ixabepilone -
- Primary Outcome Measures
Name Time Method Maximum Plasma Concentration (Cmax) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. Cmax was obtained directly from the concentration-time data.
Total Body Clearance (CLT) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. CLT was obtained directly from the concentration-time data.
Volume of Distribution at Steady-state (Vss) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. Vss was obtained directly from the concentration-time data.
Time to Reach Maximum Observed Concentration (T Max) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. T max was obtained directly from the concentration-time data.
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [INF]) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. AUC (INF) was obtained directly from the concentration-time data.
Time Taken for Plasma Concentration to Reduce by 50 Percent or Apparent Terminal Plasma Elimination Half-life (T Half) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. T half was obtained directly from the concentration-time data.
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-T]) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. AUC (0-T) was obtained directly from the concentration-time data.
Urine 6B-Hydroxycortisol to Cortisol Ratio on Day -1 Day -1 (0-8 hours and 8-24 hours), 24 hours before starting of ixabepilone administration. The urine 6B-hydroxycortisol to cortisol ratio is a measure of hepatic CYP3A4/3A5 activity, which is a potential marker of the rate of clearance of ixabepilone. The urine 6B-hydroxycortisol to cortisol ratios were calculated on Day -1.
Mean Residence Time Adjusted for Infusion Time (MRT [INF]) Blood samples were collected on Day 1 (pre-dose, then 1h30, 3h, 3h15, 3h30, 4h, 6h and 8h), Day 2, Day 3, Day 4 and Day 8 during ixabepilone administration and repeated for Cycle 2 (Days 22-25 and 29) during ixabepilone and rifampin co-administration. (MRT \[INF\]) was obtained directly from the concentration-time data.
Urine 6B-Hydroxycortisol to Cortisol Ratio on Day 22 Day 22 (0-8 hours and 8-24 hours) during ixabepilone and rifampin co-administration. The urine 6B-hydroxycortisol to cortisol ratio is a measure of hepatic CYP3A4/3A5 activity, which is a potential marker of the rate of clearance of ixabepilone. The urine 6B-hydroxycortisol to cortisol ratios were calculated on Day -1.
- Secondary Outcome Measures
Name Time Method Number of Participants Who Died and Who Experienced Other Serious AEs (SAEs), Grade 3-4 AEs, Drug-related AEs and AEs Leading to Study Drug Discontinuation From Day 1 to 30 days after the last dose of study drug. AEs:new untoward medical occurrences/worsening of pre-existing medical condition,whether or not related to study drug.SAE:AE resulting in death;life threatening;resulted in persistent/significant disability/incapacity;resulted in/prolonged existing hospitalization;a congenital anomaly/birth defect;overdose.Drug-related AEs: relationship to drug of certain;probable;possible;or missing.Participants who discontinued study due to AE were also recorded.AEs graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC),v3:Grade 1=mild,2=moderate, 3=severe,4=life threatening,5=death.
Number of Participants With Grade 3-4 Hematology Abnormalities Screening, Day 1, Day 8, Day 15, Day 22 and Day 29-36. Abnormalities occurring at any time during the study were graded per NCI CTC, v3.0 criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening). Grade 3 and 4 criteria are given below. Neutrophils: Grade 3: 0.5 - \<1.0x10\^9/L, Grade 4: \<0.5x10\^9/L. Leukocytes: Grade 3: 1.0 - \<2.0x10\^9/L, Grade 4: \<1.0x10\^9/L. Neutrophils + bands (absolute): Grade 3: 0.5 - \<1.0x10\^9/L, Grade 4: \<0.5x10\^9/L. Hemoglobin: Grade 3:6.5 - \<8.0g/dL, Grade 4: \<6.5g/dL. Lymphocytes: Grade 3: 0.2 - \<0.5x10\^9/L, Grade 4: \<0.2x10\^9/L. Platelets: Grade 3: 25.0 - \<50.0x10\^9/L, Grade 4: \<25.0x10.
Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous Screening, Days 1 and 22. Abnormalities occurring at any time during the study were graded per the NCI CTC (1=mild, 2=moderate, 3=severe, 4=life threatening). Grade 3 and 4 criteria were as follows: Alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase: Grade 3: \>5-20 x upper limit of normal (ULN), Grade 4: \>20 x ULN. Bilirubin: Grade 3: \>3-10 x ULN, Grade 4: \>10 x ULN. Albumin: Grade 3: \<2g/dL (Grade 4 not defined in NCI CTC). Creatinine: Grade 3: \>3-6 x ULN, Grade 4: \>6 x ULN. Phosphorous: Grade 3: 1-\<2mg/dL, Grade 4: \<1mg/dL.
Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. Screening, Days 2 and 22. Abnormalities occurring at any time during the study were graded per NCI CTC (1=mild, 2=moderate, 3=severe, 4=life threatening). Grade 3 and 4 criteria were as follows:Calcium: Grade 3: 6-\<7 or \>12.5-13.5mg/dL, Grade 4:\<6 or \>13.5mg/dL. Magnesium: Grade 3:0.6-\<0.8 or \>2.46-6.6mEq/L, Grade 4:\<0.6 or \>6.6mEq/L. Potassium: Grade 3:2.5-\<3 or \>6-7mmol/L, Grade 4:\<2.5 or \>7.0 mmol/L. Sodium: Grade 3:120-\<130 or \>155-160 mEq/L, Grade 4:\<120 or \>160mEq/L. Glucose: Grade 3:30-\<40 or \>250-500mg/dL, Grade 4:\<30 or \>500mg/dL. Uric acid: Grade 3:\>ULN-10mg/dL with physiologic consequences, Grade 4:\>10mg/dL.
Number of Participants With Clinically Meaningful Vital Signs Measures From screening to the off treatment visit. Vital signs were recorded throughout the study and included investigations related to body temperature, respiratory rate, seated blood pressure (systolic and diastolic), and heart rate. Normal ranges for the above are as follows: heart rate: 40 - 125 beats per minute (bpm); systolic BP: 65 - 200 millimeters of mercury (mmHg); diastolic BP: 40 - 120 mmHg; respiratory rate: 10 - 25 breaths per minute; temperature: 95 - 105F or 35 - 40.5C. The abnormalities displayed here are those considered "clinically significant" by the investigator and include abnormalities recorded at any time during study.
Number of Participants With Abnormal Physical Examination Findings From screening to the off treatment visit. Physical examination included height (screening only),weight,BSA,Eastern Cooperative Oncology Group Performance Status (ECOG PS),tendon reflexes,sensory function,motor strength. ECOG PS used to assess disease severity:score of 0 is fully active;1 is restricted physically strenuous activity;2 is ambulatory but unable to work;3 is capable of only limited self care;4 is completely disabled;5 is dead. Normal ranges:height:137-200cm or 54-79 inches;weight:40-135kg or 88-298 pounds (lbs);ECOG Scale:0-4. Abnormalities displayed here are those considered "clinically significant" by the investigator.
QT Interval Corrected for Heart Rate (QTcF) Data collected at 0, 1.5, 3, 4, 6, 8 and 24 hours after start of infusion. QT interval corrected for heart rate (QTcF) was assessed using triplicate 12-lead serial electrocardiograms (ECGs) that were performed at selected times after the first dose of ixabepilone without rifampin and at matched times prior to the first dose of ixabepilone. Abnormalities occurring at any time during the study were recorded.
Number of Participants With Identified ECG Abnormalities Data collected at screening, Day -1 and Day 1 (at 0, 1.5, 3, 4, 6, 8 and 24 hours) after start of infusion. Triplicate 12-lead serial ECGs were performed pre-dose (just prior to infusion), 1.5, 3 (just prior to end of the infusion even if infusion lasted for less than or more than planned 3 hrs), 4, 6, 8 and 24 hrs after start of ixabepilone infusion. Triplicate 12-lead serial ECGs were also to be performed on the date prior to dosing at times approximating post-dose schedule (pre-dose triplicate set of ECGs also qualified as the 24-hr baseline ECGs). Normal ranges for ECG are as follows: heart rate: 40 - 125 bpm; PR: 0.1 - 0.2 msec; QRS: 0.06 - 0.12 msec; QTC: 0.3 - 0.45 msec; QT: 0.3 - 0.5 msec.
Trial Locations
- Locations (1)
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States