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Rifampin

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ixabepilone solution, intravenous, 40 mg/m2, once every 3 weeks until disease progression

ixabepilone

rifampin tablets, oral, 600 mg once daily, only on Days 15 to 21 of Cycle 1 and Days 1 to 7 of Cycle 2

Bristol-Myers Squibb

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

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

Cmax was obtained directly from the concentration-time data.

AUC (INF) was obtained directly from the concentration-time data.

T half was obtained directly from the concentration-time data.

(MRT \[INF\]) was obtained directly from the concentration-time data.

CLT was obtained directly from the concentration-time data.

Vss was obtained directly from the concentration-time data.

T max was obtained directly from the concentration-time data.

AUC (0-T) was obtained directly from the concentration-time data.

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.

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.

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.

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.

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.

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.

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) 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.

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.

R-Pharm

Study Director

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.

All Participants

Age, Continuous

< 65 years

>=65 years

Age, Customized

Sex: Female, Male

White

Race/Ethnicity, Customized

Not Hispanic/Latino

BSA is the measured or calculated surface of a human body.

Body surface area (BSA) continuous

Height continuous

Weight continuous

Bristol-Myers Squibb Study Director

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.

On Day 1 of Cycle 1, each participant received a single 3-hour IV infusion of ixabepilone 40 mg/m\^2. (Participants then proceeded through the rest of Cycle 1 and on to further cycles - see the "ixabepilone + rifampin" treatment arm).

Ixabepilone

Having already received ixabepilone on Day 1 of Cycle 1 (see the "ixabepilone" treatment arm), participants were administered an oral dose of 600 mg rifampin on in the clinic on Day 15. 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.

Ixabepilone + Rifampin

Of the 15 patients in each group, only those with evaluable pharmacokinetic (PK) results are presented.

Maximum Plasma Concentration (Cmax)

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.

All treated participants who were evaluable for PK analysis.

Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time (AUC [INF])

Death

Other SAEs

Treatment-related AEs

Grade 3-4 AEs

Discontinuation due to AEs

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

Neutrophils (absolute)

Leukocytes

Neutrophils + bands (absolute)

Hemoglobin

Lymphocytes (absolute)

Platelet count

Number of Participants With Grade 3-4 Hematology Abnormalities

Alanine Aminotransferase

Aspartate Aminotransferase

Alkaline Phosphatase

Bilirubin

Albumin

Creatinine

Phosphorous (inorganic)

Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Alanine Aminotransferase, Aspartate Aminotransferase, Bilirubin, Albumin and Phosphorous

Time Taken for Plasma Concentration to Reduce by 50 Percent or Apparent Terminal Plasma Elimination Half-life (T Half)

Mean Residence Time Adjusted for Infusion Time (MRT [INF])

Total Body Clearance (CLT)

Volume of Distribution at Steady-state (Vss)

Time to Reach Maximum Observed Concentration (T Max)

Calcium (total)

Magnesium (serum)

Potassium (serum)

Sodium (serum)

Glucose (serum)

Uric acid

Number of Participants With Grade 3-4 Serum Chemistry Abnormalities in Calcium, Magnesium, Potassium, Sodium, Glucose and Uric Acid.

Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-T])

0-8 hours

8-24 hours

All participants who were enrolled into the study, 24 hours before ixabepilone administration on Day -1. Each participant received a single 3-hour IV infusion of ixabepilone 40 mg/m\^2 on Day 1 of Cycle 1. Each participant was administered an oral dose of 600 mg of rifampin while in a fasted state on Day 22 (Cycle 2). Participants were then administered a single 3-hour IV infusion of ixabepilone 40 mg/m\^2. On Days 23 through 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 2.

Urine 6B-Hydroxycortisol to Cortisol Ratio on Day -1

Number of Participants With Clinically Meaningful Vital Signs Measures

Each participant was administered an oral dose of 600 mg of rifampin while in a fasted state on Day 22 (Cycle 2). Participants were then administered a single 3-hour IV infusion of ixabepilone 40 mg/m\^2.

Urine 6B-Hydroxycortisol to Cortisol Ratio on Day 22

Weight-related abnormalities

Other physical examination abnormalities

Number of Participants With Abnormal Physical Examination Findings

0 hour (n=9)

1.5 hour (n=14)

3 hour (n=14)

4 hour (n=11)

6 hour (n=13)

8 hour (n=3)

24 hour (n=10)

On Day 1 of Cycle 1, each participant received a single 3-hour IV infusion of ixabepilone 40 mg/m\^2.

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.

Spots Global Cancer Trial Database for Effect of Rifampin on the Pharmacokinetics of Ixabepilone in Patients With Advanced Cancer

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

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