SYNOPSIS. Final Clinical Study Report for Study CA Final Clinical Study Report

Ixabepilone BMS-247550 CA163102 Final Clinical Study Report Name of Sponsor/Company: Bristol-Myers Squibb Individual Study Table Referring to the D...
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Ixabepilone BMS-247550

CA163102 Final Clinical Study Report

Name of Sponsor/Company: Bristol-Myers Squibb

Individual Study Table Referring to the Dossier

(For National Authority Use Only)

Name of Finished Product: IXEMPRA™ Name of Active Ingredient: Ixabepilone

SYNOPSIS Final Clinical Study Report for Study CA163102 TITLE OF STUDY: Effect of Rifampin on the Pharmacokinetics of Ixabepilone in Patients with Advanced Cancer INVESTIGATORS/STUDY CENTERS: Tarek Mekhail, MD / The Cleveland Clinic, Cleveland, Ohio PUBLICATIONS:

None

STUDY PERIOD:

Study Initiation Date:

28-Sep-2005

Study Completion Date:

11-Nov-2008

CLINICAL PHASE:

1

OBJECTIVES: Primary Objective: To assess the effect of rifampin on the pharmacokinetics of ixabepilone in patients with advanced cancer. Secondary Objectives: •

To evaluate the safety of ixabepilone co-administered with rifampin



To evaluate the safety of ixabepilone



To evaluate the impact of ixabepilone on the QTc interval

METHODOLOGY: This was an open-label, single sequence study to assess the effect of rifampin on the PK of ixabepilone in subjects with advanced cancer. Cycle 1 (Days 1 - 21): On Day 1, subjects were administered a 3-hour intravenous (IV) infusion of 2

ixabepilone at a dose of 40 mg/m . On Day 15, subjects were administered an oral dose of 600 mg rifampin at least 1 hour before or 2 hours after the ingestion of food. On Days 16 through 21, subjects self-administered a 600-mg oral dose of rifampin once daily at least 1 hour before or 2 hours after the ingestion of food. Cycle 2 (Days 22 - 42): On Day 22, subjects were administered an oral dose of 600 mg of rifampin while in a fasted state. Subjects were then administered a 3-hour IV infusion of ixabepilone at a dose of 40 2

mg/m . On Days 23 through 28, subjects self-administered a 600-mg oral dose of rifampin once daily at least 1 hour before or 2 hours after the ingestion of food.

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Cycle 3 and later: Subjects who completed Cycle 2 could continue receiving a therapeutic regimen of ixabepilone based on their safety data and agreement by the Investigator and Sponsor. During Cycle 3 and 2

beyond, subjects received a 3-hour IV infusion of ixabepilone at a dose of 40 mg/m (unless their dose had been reduced) on Day 1 of every 21-day cycle as long as they remained eligible. There was a minimum of 21 days between each dose of ixabepilone. Subjects were allowed to continue this treatment up a maximum of 6 full cycles. To prevent hypersensitivity, subjects were pre-medicated with an antihistamine treatment 1 hour before each ixabepilone infusion. Safety was assessed throughout the conduct of the study. Triplicate 12-lead serial electrocardiograms were performed during Cycle 1, and blood samples for PK analysis were collected at specified timepoints during Cycles 1 and 2. NUMBER OF SUBJECTS (Planned and Analyzed): Ten (10) to 15 subjects were planned; 19 subjects were enrolled; and 15 subjects were treated. Data from all 15 subjects were analyzed. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Male or female subjects with histologically or cytologically confirmed solid tumor malignancy, who satisfied all protocol inclusion and exclusion criteria. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT, BATCH NUMBERS: Drug information is provided in Table 1. Ixabepilone was administered as a 3-hour IV infusion at a dose of 40 mg/m2 up to a maximum of 8 full cycles. Rifampin at a dose of 600 mg was administered orally once daily for a total of 14 days; rifampin (300 mg capsules) was provided by the study site. Table 1:

Ixabepilone Drug Information

Treatment

Formulation

Product ID Number

Label Batch Number

Product Batch Number

Ixabepilone (BMS-247550), 15 mg/vial

Lyophilized powder

247550-P015-033-2

4F80160

2K71419

247550-P015-032-2

4J87831

2L57743

247550-P015-040-1

5M02841

5A01261

247550-N0X0-037-0

4F80292

2K65799

247550-N0X0-037-0

4J87832

2K65795

247550-N0X0-035

6B13281

4L80275

Vehicle for Constitution, 8 mL/vial

Solution

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT, BATCH NUMBERS: Not applicable.

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CRITERIA FOR EVALUATION: •

Pharmacokinetic Measures: Single-dose pharmacokinetic parameters (Cmax, Tmax, AUC(INF), AUC(0-T), T-HALF, MRT(INF), CLT, and Vss) of ixabepilone were derived from plasma concentration versus time data.



Safety Measures: Safety assessments were based on medical review of adverse event reports and the results of vital sign measurements, electrocardiograms, physical examinations, and clinical laboratory tests. The incidence of adverse events was tabulated and reviewed for potential significance and clinical importance.



Electrocardiogram Measures: QT interval corrected for heart rate (QTcF) was assessed using triplicate 12-lead serial electrocardiograms 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.

STATISTICAL CONSIDERATIONS: Sample Size Determination: The sample size for this study was not based on statistical power considerations. However, data from 10 subjects provided 72% confidence that the estimate of the Day 22to-Day 1 ratio of geometric means for ixabepilone Cmax would be within 20% of its true population value, and 92% confidence that the Day 22-to-Day 1 ratio of geometric means for ixabepilone AUC(INF) would be within 20% of its true population value. These calculations were based on the assumption that Cmax and AUC(INF) were lognormally distributed with intra-subject standard deviations of 0.33 for log(Cmax) and 0.24 for log(AUC(INF)). Pharmacokinetic Analysis: Individual listings and tabulations of summary statistics by treatment were provided for all derived PK parameters. Geometric means and coefficients of variation (%CV) were reported for Cmax and AUC(INF); medians, minima, and maxima were reported for Tmax; and means and standard deviations were reported for all other parameters. To assess the effect of rifampin on the PK of ixabepilone, a general linear model was applied to log(AUC(INF)) and log(Cmax) using an unstructured covariance matrix to model within subject correlation. 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. Electrocardiogram Analysis: Summary statistics were presented for electrocardiogram parameters and corresponding time-matched changes from baseline by study day and timepoint. The mean ∆QTcF and corresponding 90% confidence interval were provided by timepoint. The frequency distribution of subjects’ maximum recorded QTcF and ∆QTcF was tabulated by study day. SUMMARY OF RESULTS: Disposition and Baseline Demographic Characteristics and Physical Measurements: Table 2 provides subject disposition of enrolled subjects and Table 3 provides baseline demographic characteristics and physical measurements of treated subjects.

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Table 2:

Subject Disposition - All Enrolled Subjects Number (%) of Subjects

No. of subjects enrolled No. of subjects treated No. of subjects excluded from analysis No. of subjects off treatment

19 (100) 15 (79) 0 15 (100)

a

Reason off treatment Disease progression/relapse Investigator request Study drug toxicity Subject request Other a

7 (47) 2 (13) 3 (20) 2 (13) 1 (7)

Percentages are based on the number of subjects who were treated.

Table 3:

Demographic Characteristics and Physical Measurements at Baseline - Treated Subjects Total N = 15

Age (years) Mean (SD) Median Range

62 (14) 65 38 - 90

Age category, n (%) < 65 years ≥ 65 years

7 (47) 8 (53)

Gender, n (%) Male Female

12 (80) 3 (20)

Race, n (%) White

15 (100)

Weight (kg) Mean (SD) Median Range

80 (19) 79 52 - 116

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Table 3:

Demographic Characteristics and Physical Measurements at Baseline - Treated Subjects Total N = 15

Height (cm) Mean (SD) Median Range

174 (9) 175 157 - 188 2

BSA calculated (m ) Mean (SD) Median Range

1.9 (0.3) 1.9 1.5 - 2.4

SD = standard deviation Pharmacokinetic Results:The PK of ixabepilone is affected by co-administration of rifampin (Table 4). The mean ixabepilone half-life when administered alone was 51 hours (range, 22 - 89 hours), and 36 hours (range, 20 - 63 hours) when administered in the presence of rifampin. Mean total body clearance increased from 28 L/h after ixabepilone alone to 50 L/h when administered with rifampin. As shown in Table 5, a decrease of approximately 9% in ixabepilone Cmax was observed when rifampin was co-administered with ixabepilone. Co-administration of rifampin with ixabepilone resulted in a 43% decrease in AUC(INF). Table 4:

Summary Statistics of Ixabepilone Pharmacokinetic Parameters

Treatment

Cmax (ng/mL) Geo. Mean (%CV)

T-HALF (h) Mean (SD)

AUC(INF) (ng•h/mL) Geo. Mean (%CV)

Vss (L) Mean (SD)

CLT (L/h) Mean (SD)

Ixa (n = 14)

338.23 (40)

50.85 (18.59)

3028.70 (45)

1323.26 (684.63)

28.36 (15.04)

Ixa + Rif (n = 10)

294.96 (45)

36.45 (15.29)

1615.44 (29)

1447.54 (763.15)

49.99 (17.19)

Treatment: Ixa = 40 mg/m2 ixabepilone; Ixa + Rif = 40 mg/m2 ixabepilone and 600 mg rifampin CV = coefficient of variation; h = hours; L = liters; SD = standard deviation

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Ixabepilone BMS-247550 Table 5:

CA163102 Final Clinical Study Report Results of Statistical Analysis on Ixabepilone Cmax and AUC(INF)

Pharmacokinetic Parameter

Cmax (ng/mL)

AUC(INF) (ng•h/mL)

Geometric Means

Ratio of Adjusted Geometric Means

Treatment

Geo. Mean (%CV)

Ixa

338.23 (40)

Ixa + Rif

294.96 (45)

Ixa

3028.70 (45)

Ixa + Rif

1615.44 (29)

Ratio

Point Estimate

90% Confidence Limits

Ixa + Rif vs Ixa

0.912

(0.751,1.106)

Ixa + Rif vs Ixa

0.566

(0.482,0.664)

Treatment: Ixa = 40 mg/m2 ixabepilone; Ixa + Rif = 40 mg/m2 ixabepilone and 600 mg rifampin CV = coefficient of variation

Safety Results: An adverse event summary is shown in Table 6. There were no deaths reported during treatment or within 30 days of the last dose of study drug. Four (4) subjects (27%) had a total of 7 serious adverse events. Three (3) subjects (20%) had a total of 9 adverse events that led to the discontinuation of study treatment; 2 of the adverse events were considered serious (Grade 3 hypersensitivity and Grade 2 myocardial ischemia). No subjects discontinued from the study as a result of hematologic or serum chemistry abnormalities and no laboratory abnormalities were considered to be serious. All 15 treated subjects had 1 or more adverse events, and 10 subjects (67%) had Grade 3 - 4 events. Across all dose cycles, a total of 212 adverse events were reported: 188 (89%) were Grade 1 - 2 and 24 (11%) were Grade 3 - 4 in intensity. The most commonly reported adverse events were fatigue (87%), anorexia (73%), alopecia (60%), diarrhea (53%), arthralgia (47%), chills (40%), nausea (40%), and dysgeusia (40%). The most commonly reported Grade 3 - 4 adverse events were neutropenia/neutrophil decrease (27%) and white blood cell decrease (13%). Across all dose cycles, a total of 159 treatment-related AEs were reported. The most commonly reported treatment-related adverse events were fatigue (80%), anorexia (60%), alopecia (53%), chills (40%), dysgeusia (40%), nausea (40%), and arthralgia (40%). There was no evidence that ixabepilone administered as a single agent or co-administered with rifampin had any clinically meaningful effects on systolic and diastolic blood pressures, heart rate, respiration, or body temperature.

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Table 6:

Adverse Event Summary Number (%) of Subjects N = 15

Adverse event(s)

15 (100%)

Grade 3 - 4 adverse event(s)

10 (67%)

Death

0

Serious adverse event(s)

4 (27%)

Discontinuation due to adverse event(s)

3 (20%)

Electrocardiogram Results: 2

Ixabepilone at a dose of 40 mg/m administered as a 3-hour IV infusion was not associated with clinically 2

meaningful QTcF interval prolongation. The maximum mean ∆QTcF for 40 mg/m ixabepilone was 7.82 msec, observed 4 hours after the start of ixabepilone infusion. The maximum upper bound of the 90% confidence interval for ∆QTcF was 12.014 msec observed 4 hours after the start of ixabepilone infusion. No subjects had a QTcF interval > 450 msec or ∆QTcF > 30 msec or an ECG abnormality related to QT/QTc interval after ixabepilone administration. No concentration-dependent effect for ixabepilone on ∆QTcF was apparent. No subject had a QT interval > 500 msec, a PR interval > 200 msec, or a QRS interval > 120 msec. CONCLUSIONS: •

Co-administration of rifampin resulted in a clinically meaningful decrease in exposure to ixabepilone as measured by AUC(INF).



Co-administration of rifampin had no clinically relevant effect on the Cmax of ixabepilone.



The safety profile of ixabepilone as a single agent and when co-administered with rifampin was acceptable.



Ixabepilone was not associated with clinically meaningful QTcF interval prolongation.



There was no apparent concentration-dependent effect of ixabepilone on QTcF interval.

DATE OF REPORT: 10-Sep-2009

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