Advanced Solid Tumors, Neoplasms
Conditions
Brief summary
The purpose of this study is to test how rifampin affects the removal of BMS-247550 (ixabepilone) from the body.
Interventions
DRUGixabepilone
ixabepilone solution, intravenous, 40 mg/m2, once every 3 weeks until disease progression
DRUGRifampin
rifampin tablets, oral, 600 mg once daily, only on Days 15 to 21 of Cycle 1 and Days 1 to 7 of Cycle 2
Sponsors
R-Pharm
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
19 participants were enrolled and 15 were treated with the study drug. 4 participants were not treated (1 participant due to an adverse event \[AE\] and 3 participants for no longer meeting study criteria)
Participants by arm
| Arm | Count |
|---|---|
| All Participants All treated participants who received at least 1 dose of study drug. On Day 1 of Cycle 1, each participant received a single 3-hour IV infusion of ixabepilone 40 mg/m\^2. On Day 15, participants were administered an oral dose of 600 mg rifampin in the clinic and on Days 16-21, participants self-administered rifampin once daily at least 1 hour before or 2 hours after the ingestion of food. On Day 22 (Cycle 2), participants were administered an oral dose of 600 mg of rifampin while in a fasted state in the clinic. Participants were then administered a single 3-hour IV infusion of ixabepilone 40 mg/m\^2. On Days 23-28, participants self-administered a 600-mg oral dose of rifampin once daily at least 1 hour before or 2 hours after the ingestion of food. During Cycle 3 and beyond, participants received a single 3-hour IV infusion of ixabepilone at a dose of 40 mg/m\^2 (unless their dose had been reduced) on Day 1 of each 21-day cycle for a maximum of 6 full cycles. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Chest wall mass larger | 1 |
| Overall Study | Disease progression/relapse | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Study drug toxicity | 3 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 14 |
| Age, Customized < 65 years | 7 participants |
| Age, Customized >=65 years | 8 participants |
| Body surface area (BSA) continuous | 1.9 square meter STANDARD_DEVIATION 0.3 |
| Height continuous | 173.5 centimeter STANDARD_DEVIATION 9 |
| Race/Ethnicity, Customized Not Hispanic/Latino | 15 participants |
| Race/Ethnicity, Customized White | 15 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 12 Participants |
| Weight continuous | 80.3 kilogram STANDARD_DEVIATION 18.5 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 15 |
| serious Total, serious adverse events | 4 / 15 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [INF])
AUC (INF) was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ixabepilone | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [INF]) | 3028.70 nanogram (ng)*hour(hr)/mL |
| Ixabepilone + Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [INF]) | 1713.07 nanogram (ng)*hour(hr)/mL |
Comparison: Two-way analyses of variance were performed on log-transformed values of (AUC \[INF\]). The factors in the analyses were participant and day. Point estimates and 90% confidence intervals for means and differences between means on the log scale were exponentiated to obtain estimates for geometric means and ratio of geometric means on the original scale.90% CI: [0.482, 0.664]
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-T])
AUC (0-T) was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixabepilone | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-T]) | 3015.45 nanogram (ng)*hr/mL | Standard Deviation 1383.85 |
| Ixabepilone + Rifampin | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-T]) | 1478.31 nanogram (ng)*hr/mL | Standard Deviation 486.57 |
Primary
Maximum Plasma Concentration (Cmax)
Cmax was obtained directly from the concentration-time data.
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.
Population: Of the 15 patients in each group, only those with evaluable pharmacokinetic (PK) results are presented.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ixabepilone | Maximum Plasma Concentration (Cmax) | 338.23 nanogram (ng)/millilter(mL) |
| Ixabepilone + Rifampin | Maximum Plasma Concentration (Cmax) | 308.37 nanogram (ng)/millilter(mL) |
Comparison: Two-way analyses of variance were performed on log-transformed values of Cmax. The factors in the analyses were participant and day. Point estimates and 90% confidence intervals for means and differences between means on the log scale were exponentiated to obtain estimates for geometric means and ratio of geometric means on the original scale.90% CI: [0.751, 1.106]
Primary
Mean Residence Time Adjusted for Infusion Time (MRT [INF])
(MRT \[INF\]) was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixabepilone | Mean Residence Time Adjusted for Infusion Time (MRT [INF]) | 50.93 Hrs | Standard Deviation 22.05 |
| Ixabepilone + Rifampin | Mean Residence Time Adjusted for Infusion Time (MRT [INF]) | 29.86 Hrs | Standard Deviation 15.31 |
Primary
Time Taken for Plasma Concentration to Reduce by 50 Percent or Apparent Terminal Plasma Elimination Half-life (T Half)
T half was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixabepilone | Time Taken for Plasma Concentration to Reduce by 50 Percent or Apparent Terminal Plasma Elimination Half-life (T Half) | 50.85 Hrs | Standard Deviation 18.59 |
| Ixabepilone + Rifampin | Time Taken for Plasma Concentration to Reduce by 50 Percent or Apparent Terminal Plasma Elimination Half-life (T Half) | 36.45 Hrs | Standard Deviation 15.29 |
Primary
Time to Reach Maximum Observed Concentration (T Max)
T max was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone | Time to Reach Maximum Observed Concentration (T Max) | 1.57 Hrs |
| Ixabepilone + Rifampin | Time to Reach Maximum Observed Concentration (T Max) | 1.50 Hrs |
Primary
Total Body Clearance (CLT)
CLT was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixabepilone | Total Body Clearance (CLT) | 28.36 Litres(L)/hr | Standard Deviation 15.04 |
| Ixabepilone + Rifampin | Total Body Clearance (CLT) | 49.99 Litres(L)/hr | Standard Deviation 17.19 |
Primary
Urine 6B-Hydroxycortisol to Cortisol Ratio on Day -1
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.
Time frame: Day -1 (0-8 hours and 8-24 hours), 24 hours before starting of ixabepilone administration.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone | Urine 6B-Hydroxycortisol to Cortisol Ratio on Day -1 | 0-8 hours | 10.04 Ratio | Standard Deviation 5.76 |
| Ixabepilone | Urine 6B-Hydroxycortisol to Cortisol Ratio on Day -1 | 8-24 hours | 9.29 Ratio | Standard Deviation 5.84 |
Primary
Urine 6B-Hydroxycortisol to Cortisol Ratio on Day 22
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.
Time frame: Day 22 (0-8 hours and 8-24 hours) during ixabepilone and rifampin co-administration.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone | Urine 6B-Hydroxycortisol to Cortisol Ratio on Day 22 | 0-8 hours | 110.88 Ratio | Standard Deviation 101.91 |
| Ixabepilone | Urine 6B-Hydroxycortisol to Cortisol Ratio on Day 22 | 8-24 hours | 62.42 Ratio | Standard Deviation 54.35 |
Primary
Volume of Distribution at Steady-state (Vss)
Vss was obtained directly from the concentration-time data.
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.
Population: All treated participants who were evaluable for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixabepilone | Volume of Distribution at Steady-state (Vss) | 1323.26 L | Standard Deviation 684.63 |
| Ixabepilone + Rifampin | Volume of Distribution at Steady-state (Vss) | 1447.54 L | Standard Deviation 763.15 |
Secondary
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
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.
Time frame: From Day 1 to 30 days after the last dose of study drug.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | 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 | Death | 0 participants |
| Ixabepilone | 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 | Other SAEs | 4 participants |
| Ixabepilone | 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 | Treatment-related AEs | 15 participants |
| Ixabepilone | 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 | Grade 3-4 AEs | 10 participants |
| Ixabepilone | 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 | Discontinuation due to AEs | 3 participants |
Secondary
Number of Participants With Abnormal Physical Examination Findings
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.
Time frame: From screening to the off treatment visit.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Number of Participants With Abnormal Physical Examination Findings | Weight-related abnormalities | 3 participants |
| Ixabepilone | Number of Participants With Abnormal Physical Examination Findings | Other physical examination abnormalities | 0 participants |
Secondary
Number of Participants With Clinically Meaningful Vital Signs Measures
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.
Time frame: From screening to the off treatment visit.
Population: All treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixabepilone | Number of Participants With Clinically Meaningful Vital Signs Measures | 0 participants |
Secondary
Number of Participants With Grade 3-4 Hematology Abnormalities
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.
Time frame: Screening, Day 1, Day 8, Day 15, Day 22 and Day 29-36.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Number of Participants With Grade 3-4 Hematology Abnormalities | Neutrophils (absolute) | 5 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Hematology Abnormalities | Leukocytes | 6 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Hematology Abnormalities | Neutrophils + bands (absolute) | 5 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Hematology Abnormalities | Hemoglobin | 1 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Hematology Abnormalities | Lymphocytes (absolute) | 6 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Hematology Abnormalities | Platelet count | 0 participants |
Secondary
Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous
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.
Time frame: Screening, Days 1 and 22.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Alanine Aminotransferase | 0 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Aspartate Aminotransferase | 0 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Alkaline Phosphatase | 0 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Bilirubin | 0 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Albumin | 0 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Creatinine | 0 participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous | Phosphorous (inorganic) | 1 participants |
Secondary
Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid.
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.
Time frame: Screening, Days 2 and 22.
Population: All treated participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. | Calcium (total) | 0 Participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. | Magnesium (serum) | 0 Participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. | Potassium (serum) | 0 Participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. | Sodium (serum) | 1 Participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. | Glucose (serum) | 0 Participants |
| Ixabepilone | Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid. | Uric acid | 0 Participants |
Secondary
Number of Participants With Identified ECG Abnormalities
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.
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.
Population: All participants treated with ixabepilone.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone | Number of Participants With Identified ECG Abnormalities | Newly identified ECG abnormalities | 13 Participants |
| Ixabepilone | Number of Participants With Identified ECG Abnormalities | Discontinuation due to ECG abnormalities | 1 Participants |
| Ixabepilone | Number of Participants With Identified ECG Abnormalities | Abnormalities related to QT/QTc interval | 0 Participants |
| Ixabepilone | Number of Participants With Identified ECG Abnormalities | Total number of ECG abnormalities | 13 Participants |
Secondary
QT Interval Corrected for Heart Rate (QTcF)
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.
Time frame: Data collected at 0, 1.5, 3, 4, 6, 8 and 24 hours after start of infusion.
Population: All participants treated with ixabepilone. The 'n' is signifying those participants who received study drug and were evaluated for this measure at the timepoint for each group respectively.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 0 hour (n=9) | 3.44 millisecond |
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 1.5 hour (n=14) | 5.64 millisecond |
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 3 hour (n=14) | 0.57 millisecond |
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 4 hour (n=11) | 7.82 millisecond |
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 6 hour (n=13) | 6.54 millisecond |
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 8 hour (n=3) | -10.70 millisecond |
| Ixabepilone | QT Interval Corrected for Heart Rate (QTcF) | 24 hour (n=10) | -1.90 millisecond |