Trial Outcomes & Findings for Phase I Combination w/ Epirubicin (NCT NCT00322374)

NCT ID: NCT00322374

Last Updated: 2016-03-10

Results Overview

DLT: any of the following considered related to ixabepilone, epirubicin or combination occurring in Cycle 1: Absolute neutrophil count \<500 cells/mm\^3 for ≥7 consecutive days or febrile neutropenia of any duration;Grade(Gr)4 thrombocytopenia \<25,000 cells/mm\^3 or Gr3 w/bleeding requiring platelet transfusion;Any other drug-related Gr3/4 non-hematologic toxicity except Gr3 injection site reaction, fatigue, transient arthralgia/myalgia;Delayed recovery to Gr≤1 or baseline (except for alopecia) from toxicity related to treatment w/ ixabepilone + epirubicin delaying initiation of next cycle ≥3 wks

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 42 participants
• Primary outcome timeframe: From Baseline to the end of Cycle 1 (Day 21)
• Results posted on: 2016-03-10

Participant Flow

Participant milestones

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	All Participants
Enrollment STARTED	0	0	0	42
Enrollment COMPLETED	0	0	0	42
Enrollment NOT COMPLETED	0	0	0	0
Starting Dose STARTED	6	0	0	0
Starting Dose COMPLETED	0	0	0	0
Starting Dose NOT COMPLETED	6	0	0	0
First Escalation STARTED	0	30	0	0
First Escalation COMPLETED	0	0	0	0
First Escalation NOT COMPLETED	0	30	0	0
Second Escalation STARTED	0	0	6	0
Second Escalation COMPLETED	0	0	0	0
Second Escalation NOT COMPLETED	0	0	6	0

Reasons for withdrawal

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	All Participants
Starting Dose Physician Decision	2	0	0	0
Starting Dose Study Drug Toxicity	4	0	0	0
First Escalation Documented Disease Progression	0	6	0	0
First Escalation Physician Decision	0	12	0	0
First Escalation Study Drug Toxicity	0	11	0	0
First Escalation Participant Request	0	1	0	0
Second Escalation Physician Decision	0	0	5	0
Second Escalation Study Drug Toxicity	0	0	1	0

Baseline Characteristics

Phase I Combination w/ Epirubicin

Baseline characteristics by cohort

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=30 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Total n=42 Participants Total of all reporting groups
Age, Customized Between 18 and 65 years	6 participants n=5 Participants	24 participants n=7 Participants	5 participants n=5 Participants	35 participants n=4 Participants
Age, Customized >=65 years	0 participants n=5 Participants	6 participants n=7 Participants	1 participants n=5 Participants	7 participants n=4 Participants
Age, Continuous	57.5 years n=5 Participants	57.5 years n=7 Participants	53.5 years n=5 Participants	57 years n=4 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	30 Participants n=7 Participants	6 Participants n=5 Participants	42 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment France	5 participants n=5 Participants	16 participants n=7 Participants	3 participants n=5 Participants	24 participants n=4 Participants
Region of Enrollment Italy	1 participants n=5 Participants	14 participants n=7 Participants	3 participants n=5 Participants	18 participants n=4 Participants

PRIMARY outcome

Timeframe: From Baseline to the end of Cycle 1 (Day 21)

Population: The evaluable participant population consisted of participants who met the minimum safety evaluation requirements of the study: participant received ≥1 dose of ixabepilone and epirubicin in Cycle 1, completed adequate safety evaluations, and was observed for ≥21 days following the first dose or the participant experienced DLT.

DLT: any of the following considered related to ixabepilone, epirubicin or combination occurring in Cycle 1: Absolute neutrophil count <500 cells/mm^3 for ≥7 consecutive days or febrile neutropenia of any duration;Grade(Gr)4 thrombocytopenia <25,000 cells/mm^3 or Gr3 w/bleeding requiring platelet transfusion;Any other drug-related Gr3/4 non-hematologic toxicity except Gr3 injection site reaction, fatigue, transient arthralgia/myalgia;Delayed recovery to Gr≤1 or baseline (except for alopecia) from toxicity related to treatment w/ ixabepilone + epirubicin delaying initiation of next cycle ≥3 wks

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Number of Participants With a Dose Limiting Toxicity (DLT) Participants with DLT:Grade 4 (severe) neutropenia	1 Participants	1 Participants	2 Participants
Number of Participants With a Dose Limiting Toxicity (DLT) Total Participants with DLT	1 Participants	1 Participants	2 Participants
Number of Participants With a Dose Limiting Toxicity (DLT) Participants without DLT	5 Participants	5 Participants	4 Participants

PRIMARY outcome

Timeframe: Day 21 of Cycle 1

Population: The evaluable participant population consisted of participants who met the minimum safety evaluation requirements of the study: participant received ≥1 dose of ixabepilone and epirubicin in Cycle 1, completed adequate safety evaluations, and were observed for ≥21 days following the first dose or the participant experienced DLT.

The MTD was the highest dose in which 0/6 or 1/6 participants experienced DLT with at least 2 out of no more than 6 participants experiencing DLT at the next higher dose level. The RP2D was based on the MTD and the assessment of any relevant chronic toxicity. To obtain further confidence in the RP2D, a total maximum of 30 evaluable participants were enrolled at the MTD.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=42 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Ixabepilone Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) MTD	30 mg^m2	—	—
Ixabepilone Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) R2PD	30 mg^m2	—	—

SECONDARY outcome

Timeframe: Evaluated continuously on study from Baseline to ≤30 days after the last dose of study drug.

Population: All participants who received at least 1 cycle of therapy were evaluable for safety; adverse events and other symptoms were graded according to CTCAE Version 3.0.

AEs and SAEs considered possibly, probably, or certainly related to study treatment, graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death).SAE= any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization/prolongation of existing hospitalization, results in persistent/significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=30 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation Deaths (total)	0 participants	0 participants	0 participants
Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation Deaths within 30 days of last dose	0 participants	0 participants	0 participants
Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation AEs	6 participants	30 participants	6 participants
Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation SAEs	2 participants	8 participants	1 participants
Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation Grade 3/4 AEs	6 participants	28 participants	6 participants
Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation AEs leading to discontinuation of study treatment	4 participants	12 participants	1 participants

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

Pharmacokinetics (PK) is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. Cmax=maximum observed plasma concentration of single-dose ixabepilone administered with IV dose of epirubicin 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=28 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Maximum Plasma Concentration (Cmax) of Single-dose Ixabepilone	169.00 ng/ml Standard Deviation 44.42	217.86 ng/ml Standard Deviation 53.56	251.83 ng/ml Standard Deviation 48.56

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. AUC(INF)=area under the plasma concentration-time curve from time zero extrapolated to infinite time of single-dose ixabepilone administered with IV dose of epirubicin 75 mg/m^2.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=28 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Area Under the Curve, Extrapolated to Infinity (AUC[INF]) of Single-dose Ixabepilone	1760.42 ng·h/mL Standard Deviation 535.89	2072.43 ng·h/mL Standard Deviation 399.60	2100.56 ng·h/mL Standard Deviation 353.87

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. T-Half=terminal-phase elimination half-life in plasma of single-dose ixabepilone administered with IV dose of epirubicin 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=28 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Terminal Half-life (T-Half) of Single-dose Ixabepilone	51.82 hours Standard Deviation 15.47	34.07 hours Standard Deviation 11.75	44.15 hours Standard Deviation 18.41

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. CLT= Total body clearance from plasma of single-dose ixabepilone administered with IV dose of epirubicin 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=28 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Clearance (CLT) of Single-dose Ixabepilone	26.03 L/h Standard Deviation 5.45	24.62 L/h Standard Deviation 5.56	26.68 L/h Standard Deviation 2.83

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. Vss= Volume of distribution at steady-state of single-dose ixabepilone administered with IV dose of epirubicin 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=28 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Volume of Distribution at Steady State (Vss) of Single-dose Ixabepilone	1331.65 liters Standard Deviation 370.88	803.21 liters Standard Deviation 292.09	1001.70 liters Standard Deviation 317.23

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. Cmax=maximum observed plasma concentration of epirubicin administered IV 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=28 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Epirubicin Cmax	3306.53 ng/ml Standard Deviation 2125.45	4139.00 ng/ml Standard Deviation 2598.19	4533.08 ng/ml Standard Deviation 2490.83

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. AUC(INF)=the area under the plasma concentration-time curve from time zero extrapolated to infinity of epirubicin administered IV 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=27 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Epirubicin AUC(INF)	2489.37 ng·h/mL Standard Deviation 1488.39	3132.67 ng·h/mL Standard Deviation 1685.32	2595.44 ng·h/mL Standard Deviation 1017.64

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. T-Half=terminal-phase elimination half-life in plasma of epirubicin administered IV dose 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=27 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Epirubicin T-Half	13.61 hours Standard Deviation 3.33	19.41 hours Standard Deviation 6.31	15.55 hours Standard Deviation 2.92

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. CLT= Total body clearance from plasma of epirubicin administered IV 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=27 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Epirubicin CLT	81.33 L/h Standard Deviation 70.84	53.85 L/h Standard Deviation 32.87	58.00 L/h Standard Deviation 38.82

SECONDARY outcome

Timeframe: From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion.

Population: Participants who had received any treatment with ixabepilone and epirubicin and had adequate concentration profiles.

PK is a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and eliminated by the body. Vss= Volume of distribution at steady-state of epirubicin administered IV 75 mg/m^2, derived from plasma concentration versus time data.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=27 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 Participants Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Epirubicin Vss	912.83 liters Standard Deviation 1500.018	750.24 liters Standard Deviation 977.352	522.45 liters Standard Deviation 657.97

SECONDARY outcome

Timeframe: From Baseline (up to 2 weeks prior to starting therapy) to the end Cycle 2

Population: Participants with measurable disease who received any treatment, as well as response evaluable participants. Evaluations were based on tumor measurements collected on the case report form using RECIST incorporating the use of target/non-target lesions.

Information on all tumor lesions was obtained at baseline by radiologic techniques, or if appropriate by physical examination (e.g. subcutaneous nodules). Measurable tumors were evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) criteria, wherein complete response (CR) = disappearance of all target lesions; partial response (PR) = ≥30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD)= ≥20% increase in the sum of the longest diameter of target lesions, and stable disease (SD) = small changes that do not meet above criteria.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=32 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=22 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Number Of Participants With A Best Overall Tumor Response of Complete Response, Partial Response, Stable Disease, And Progressive Disease Complete Response	0 participants	0 participants	—
Number Of Participants With A Best Overall Tumor Response of Complete Response, Partial Response, Stable Disease, And Progressive Disease Partial Response	18 participants	9 participants	—
Number Of Participants With A Best Overall Tumor Response of Complete Response, Partial Response, Stable Disease, And Progressive Disease Stable Disease	11 participants	10 participants	—
Number Of Participants With A Best Overall Tumor Response of Complete Response, Partial Response, Stable Disease, And Progressive Disease Progressive Disease	3 participants	3 participants	—

SECONDARY outcome

Timeframe: Time (in months) when criteria for CR or PR are met (which ever occurs first) up to date of progressive disease.

Population: Participants with measurable disease who received any treatment, as well as response evaluable participants. Evaluations were based on tumor measurements collected on the case report form using RECIST incorporating the use of target/non-target lesions.

Defined as the interval measured from the time that the measurement criteria are first met for CR or PR, whichever occurs first, until the date of documented progressive disease or death. CR= disappearance of all target lesions; PR= ≥30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=18 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=9 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Duration of Tumor Response	6.45 months Interval 1.0 to 17.0	6.4 months Interval 2.0 to 10.0	—

SECONDARY outcome

Timeframe: Time (in months) when criteria for CR or PR are met (which ever occurs first) up to date of progressive disease.

Population: Participants with measurable disease who received any treatment, as well as response evaluable participants. Evaluations were based on tumor measurements collected on the case report form using RECIST incorporating the use of target/non-target lesions.

Duration of response was defined as the interval measured from the time that the measurement criteria are first met for CR or PR, whichever occurs first, until the date of documented progressive disease or death; PR= ≥30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=18 Participants Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=9 Participants Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Number Of Participants With Tumor Response by Duration of Response Category Response Duration < 4 Months	5 participants	1 participants	—
Number Of Participants With Tumor Response by Duration of Response Category Response Duration ≥4 Months	13 participants	8 participants	—
Number Of Participants With Tumor Response by Duration of Response Category Response Duration ≥6 Months	11 participants	6 participants	—

Adverse Events

Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2

Serious events: 8 serious events

Other events: 30 other events

Deaths: 0 deaths

Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 participants at risk Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=30 participants at risk Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 participants at risk Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Investigations PLATELET COUNT DECREASED	0.00% 0/6	0.00% 0/30	16.7% 1/6
Immune system disorders HYPERSENSITIVITY	16.7% 1/6	0.00% 0/30	0.00% 0/6
Nervous system disorders SYNCOPE	0.00% 0/6	0.00% 0/30	16.7% 1/6
Nervous system disorders CEREBROVASCULAR ACCIDENT	0.00% 0/6	3.3% 1/30	0.00% 0/6
Gastrointestinal disorders NAUSEA	0.00% 0/6	6.7% 2/30	0.00% 0/6
Gastrointestinal disorders VOMITING	16.7% 1/6	0.00% 0/30	0.00% 0/6
Blood and lymphatic system disorders ANAEMIA	0.00% 0/6	3.3% 1/30	0.00% 0/6
Blood and lymphatic system disorders NEUTROPENIA	0.00% 0/6	0.00% 0/30	16.7% 1/6
Blood and lymphatic system disorders FEBRILE NEUTROPENIA	0.00% 0/6	3.3% 1/30	0.00% 0/6
Blood and lymphatic system disorders FEBRILE BONE MARROW APLASIA	0.00% 0/6	6.7% 2/30	0.00% 0/6
Musculoskeletal and connective tissue disorders BACK PAIN	0.00% 0/6	3.3% 1/30	0.00% 0/6
General disorders PYREXIA	0.00% 0/6	6.7% 2/30	0.00% 0/6

Other adverse events

Measure	Ixabepilone 25 mg^m2 + Epirubicin 75 mg^m2 n=6 participants at risk Participants received 25 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 30 mg^m2 + Epirubicin 75 mg^m2 n=30 participants at risk Participants received 30 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.	Ixabepilone 35 mg^m2 + Epirubicin 75 mg^m2 n=6 participants at risk Participants received 35 mg/m\^2 Ixabepilone as a 3-hour IV infusion following a 3- to 5-minute IV infusion of 75 mg/m\^2 epirubicin every 21 days.
Blood and lymphatic system disorders LEUKOPENIA	50.0% 3/6	36.7% 11/30	50.0% 3/6
Blood and lymphatic system disorders NEUTROPENIA	100.0% 6/6	100.0% 30/30	100.0% 6/6
Blood and lymphatic system disorders THROMBOCYTOPENIA	16.7% 1/6	6.7% 2/30	0.00% 0/6
Eye disorders CONJUNCTIVITIS	0.00% 0/6	6.7% 2/30	16.7% 1/6
Eye disorders LACRIMATION INCREASED	16.7% 1/6	0.00% 0/30	0.00% 0/6
Investigations WEIGHT DECREASED	33.3% 2/6	20.0% 6/30	16.7% 1/6
Investigations HAEMOGLOBIN DECREASED	16.7% 1/6	26.7% 8/30	50.0% 3/6
Investigations PLATELET COUNT DECREASED	16.7% 1/6	3.3% 1/30	16.7% 1/6
Investigations BLOOD CREATININE INCREASED	0.00% 0/6	6.7% 2/30	0.00% 0/6
Investigations ALANINE AMINOTRANSFERASE INCREASED	16.7% 1/6	6.7% 2/30	16.7% 1/6
Investigations ASPARTATE AMINOTRANSFERASE INCREASED	0.00% 0/6	10.0% 3/30	33.3% 2/6
Investigations BLOOD ALKALINE PHOSPHATASE INCREASED	0.00% 0/6	0.00% 0/30	16.7% 1/6
Investigations ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED	0.00% 0/6	0.00% 0/30	16.7% 1/6
Cardiac disorders TACHYCARDIA	16.7% 1/6	3.3% 1/30	0.00% 0/6
Cardiac disorders LEFT VENTRICULAR DYSFUNCTION	16.7% 1/6	0.00% 0/30	0.00% 0/6
Vascular disorders HOT FLUSH	0.00% 0/6	6.7% 2/30	16.7% 1/6
Vascular disorders VENOUS INSUFFICIENCY	16.7% 1/6	3.3% 1/30	0.00% 0/6
Psychiatric disorders ANXIETY	16.7% 1/6	3.3% 1/30	0.00% 0/6
Immune system disorders HYPERSENSITIVITY	0.00% 0/6	10.0% 3/30	0.00% 0/6
Nervous system disorders HEADACHE	33.3% 2/6	20.0% 6/30	16.7% 1/6
Nervous system disorders AREFLEXIA	16.7% 1/6	10.0% 3/30	0.00% 0/6
Nervous system disorders DYSGEUSIA	0.00% 0/6	30.0% 9/30	33.3% 2/6
Nervous system disorders DYSAESTHESIA	0.00% 0/6	16.7% 5/30	16.7% 1/6
Nervous system disorders HYPOREFLEXIA	50.0% 3/6	33.3% 10/30	33.3% 2/6
Nervous system disorders PARAESTHESIA	83.3% 5/6	50.0% 15/30	50.0% 3/6
Nervous system disorders SENSORY LOSS	33.3% 2/6	30.0% 9/30	0.00% 0/6
Nervous system disorders HYPOAESTHESIA	16.7% 1/6	6.7% 2/30	33.3% 2/6
Nervous system disorders HYPERAESTHESIA	0.00% 0/6	10.0% 3/30	0.00% 0/6
Nervous system disorders CRANIAL NEUROPATHY	0.00% 0/6	0.00% 0/30	16.7% 1/6
Nervous system disorders PERIPHERAL SENSORY NEUROPATHY	16.7% 1/6	6.7% 2/30	16.7% 1/6
Gastrointestinal disorders NAUSEA	83.3% 5/6	83.3% 25/30	66.7% 4/6
Gastrointestinal disorders VOMITING	50.0% 3/6	70.0% 21/30	66.7% 4/6
Gastrointestinal disorders DIARRHOEA	0.00% 0/6	23.3% 7/30	50.0% 3/6
Gastrointestinal disorders DYSPEPSIA	16.7% 1/6	0.00% 0/30	16.7% 1/6
Gastrointestinal disorders GASTRITIS	0.00% 0/6	16.7% 5/30	33.3% 2/6
Gastrointestinal disorders STOMATITIS	0.00% 0/6	16.7% 5/30	0.00% 0/6
Gastrointestinal disorders CONSTIPATION	16.7% 1/6	33.3% 10/30	16.7% 1/6
Gastrointestinal disorders HAEMORRHOIDS	0.00% 0/6	6.7% 2/30	16.7% 1/6
Gastrointestinal disorders GINGIVAL PAIN	16.7% 1/6	0.00% 0/30	0.00% 0/6
Gastrointestinal disorders ABDOMINAL PAIN UPPER	0.00% 0/6	10.0% 3/30	0.00% 0/6
Infections and infestations ONYCHOMYCOSIS	16.7% 1/6	0.00% 0/30	0.00% 0/6
Infections and infestations NASOPHARYNGITIS	0.00% 0/6	0.00% 0/30	16.7% 1/6
Infections and infestations URINARY TRACT INFECTION	0.00% 0/6	0.00% 0/30	16.7% 1/6
Infections and infestations VULVOVAGINAL MYCOTIC INFECTION	16.7% 1/6	0.00% 0/30	0.00% 0/6
Renal and urinary disorders DYSURIA	16.7% 1/6	0.00% 0/30	0.00% 0/6
Metabolism and nutrition disorders ANOREXIA	16.7% 1/6	16.7% 5/30	33.3% 2/6
Metabolism and nutrition disorders HYPERGLYCAEMIA	0.00% 0/6	10.0% 3/30	16.7% 1/6
Blood and lymphatic system disorders ANAEMIA	83.3% 5/6	66.7% 20/30	50.0% 3/6
Skin and subcutaneous tissue disorders RASH	0.00% 0/6	0.00% 0/30	16.7% 1/6
Skin and subcutaneous tissue disorders BLISTER	16.7% 1/6	0.00% 0/30	0.00% 0/6
Skin and subcutaneous tissue disorders ALOPECIA	100.0% 6/6	70.0% 21/30	100.0% 6/6
Skin and subcutaneous tissue disorders DRY SKIN	33.3% 2/6	0.00% 0/30	0.00% 0/6
Skin and subcutaneous tissue disorders HYPERHIDROSIS	0.00% 0/6	0.00% 0/30	16.7% 1/6
Skin and subcutaneous tissue disorders NAIL DISORDER	50.0% 3/6	13.3% 4/30	0.00% 0/6
Skin and subcutaneous tissue disorders PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	33.3% 2/6	3.3% 1/30	0.00% 0/6
Reproductive system and breast disorders BARTHOLINITIS	0.00% 0/6	0.00% 0/30	16.7% 1/6
Musculoskeletal and connective tissue disorders MYALGIA	0.00% 0/6	36.7% 11/30	66.7% 4/6
Musculoskeletal and connective tissue disorders ARTHRITIS	16.7% 1/6	0.00% 0/30	0.00% 0/6
Musculoskeletal and connective tissue disorders BACK PAIN	0.00% 0/6	6.7% 2/30	0.00% 0/6
Musculoskeletal and connective tissue disorders BONE PAIN	0.00% 0/6	10.0% 3/30	0.00% 0/6
Musculoskeletal and connective tissue disorders ARTHRALGIA	33.3% 2/6	30.0% 9/30	50.0% 3/6
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	16.7% 1/6	10.0% 3/30	0.00% 0/6
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	16.7% 1/6	13.3% 4/30	16.7% 1/6
Respiratory, thoracic and mediastinal disorders COUGH	16.7% 1/6	6.7% 2/30	0.00% 0/6
Respiratory, thoracic and mediastinal disorders DYSPHONIA	0.00% 0/6	10.0% 3/30	0.00% 0/6
Respiratory, thoracic and mediastinal disorders RHINORRHOEA	16.7% 1/6	10.0% 3/30	0.00% 0/6
Respiratory, thoracic and mediastinal disorders LUNG INFILTRATION	16.7% 1/6	0.00% 0/30	0.00% 0/6
General disorders FATIGUE	0.00% 0/6	13.3% 4/30	16.7% 1/6
General disorders PYREXIA	16.7% 1/6	10.0% 3/30	16.7% 1/6
General disorders ASTHENIA	66.7% 4/6	53.3% 16/30	33.3% 2/6
General disorders HYPERTHERMIA	16.7% 1/6	0.00% 0/30	0.00% 0/6
General disorders MUCOSAL INFLAMMATION	0.00% 0/6	33.3% 10/30	16.7% 1/6

Additional Information

BMS Study Director

Bristol-Myers Squibb

Email: Clinical.Trials@bms.com

Results disclosure agreements

• Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
• Publication restrictions are in place

Restriction type: OTHER