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Effect of Rifampin on the Pharmacokinetics of Ixabepilone in Patients With Advanced Cancer

This study has been completed.
Sponsor:
Information provided by:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00207090
First received: September 12, 2005
Last updated: October 27, 2010
Last verified: October 2010
  Purpose

The purpose of this study is to test how rifampin affects the removal of BMS-247550 (ixabepilone) from the body.


Condition Intervention Phase
Advanced Solid Tumors
Neoplasms
Drug: ixabepilone
Drug: Rifampin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effect of Rifampin on the Pharmacokinetics of Ixabepilone in Patients With Advanced Cancer

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Maximum Plasma Concentration (Cmax) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Cmax was obtained directly from the concentration-time data.

  • Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [INF]) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    T half was obtained directly from the concentration-time data.

  • Mean Residence Time Adjusted for Infusion Time (MRT [INF]) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    (MRT [INF]) was obtained directly from the concentration-time data.

  • Total Body Clearance (CLT) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    CLT was obtained directly from the concentration-time data.

  • Volume of Distribution at Steady-state (Vss) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    Vss was obtained directly from the concentration-time data.

  • Time to Reach Maximum Observed Concentration (T Max) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    T max 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]) [ Time Frame: 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. ] [ Designated as safety issue: No ]
    AUC (0-T) was obtained directly from the concentration-time data.

  • Urine 6B-Hydroxycortisol to Cortisol Ratio on Day -1 [ Time Frame: Day -1 (0-8 hours and 8-24 hours), 24 hours before starting of ixabepilone administration. ] [ Designated as safety issue: No ]
    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.

  • Urine 6B-Hydroxycortisol to Cortisol Ratio on Day 22 [ Time Frame: Day 22 (0-8 hours and 8-24 hours) during ixabepilone and rifampin co-administration. ] [ Designated as safety issue: No ]
    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:
  • 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 [ Time Frame: From Day 1 to 30 days after the last dose of study drug. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Screening, Day 1, Day 8, Day 15, Day 22 and Day 29-36. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Screening, Days 1 and 22. ] [ Designated as safety issue: Yes ]
    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. [ Time Frame: Screening, Days 2 and 22. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From screening to the off treatment visit. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From screening to the off treatment visit. ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Data collected at 0, 1.5, 3, 4, 6, 8 and 24 hours after start of infusion. ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Data collected at screening, Day -1 and Day 1 (at 0, 1.5, 3, 4, 6, 8 and 24 hours) after start of infusion. ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 19
Study Start Date: September 2005
Study Completion Date: November 2008
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ixabepilone + rifampin Drug: ixabepilone
ixabepilone solution, intravenous, 40 mg/m2, once every 3 weeks until disease progression
Other Names:
  • IXEMPRA®
  • BMS-247550
Drug: Rifampin
rifampin tablets, oral, 600 mg once daily, only on Days 15 to 21 of Cycle 1 and Days 1 to 7 of Cycle 2

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Up to three prior chemotherapy regimens
  • Measurable or non-measurable disease
  • Available for treatment and follow-up

Exclusion Criteria:

  • Neuropathy
  • Uncontrolled cardiovascular disease
  • Refusal to participate in genetic analysis
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00207090

Locations
United States, Ohio
The Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00207090     History of Changes
Other Study ID Numbers: CA163-102
Study First Received: September 12, 2005
Results First Received: September 3, 2010
Last Updated: October 27, 2010
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Epothilones
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antimitotic Agents
Antineoplastic Agents
Antitubercular Agents
Enzyme Inhibitors
Leprostatic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses
Tubulin Modulators

ClinicalTrials.gov processed this record on November 27, 2014