Phase I Combination w/ Epirubicin

Study Overview
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Brief Summary
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Tumor response information was obtained for all participants who received at least 2 cycles of study drug, underwent requisite baseline and on-treatment disease assessments and had at least one post-treatment assessment. Tumor response assessment in evaluable participants was done according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Official Title
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A Phase I Study of Ixabepilone in Combination With Epirubicin in Patients With Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Ixabepilone
* Drug: Epirubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women ≥18 years Histologically or cytologically confirmed diagnosis of metastatic breast cancer Measurable or nonmeasurable disease defined by Response Evaluation Criteria In Solid Tumors (RECIST) Exclusion Criteria: Number of prior chemotherapy lines of treatment in the metastatic setting ≥2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 25 mg/m^2 Ixabepilone plus 75 mg/m^2 Epirubicin<br>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. | Drug: Ixabepilone<br>* Infusion, intravenous (IV), Cycle = 21 days. Dose escalation study.<br>* Other names: Epothilone;Drug: Epirubicin<br>* Infusion, intravenous (IV): 75 mg/m^2. Cycle = 21 days, up to 10 cycles or cumulative dose of 800 mg/m².<br>|
| Experimental: 30 mg/m^2 Ixabepilone plus 75 mg/m^2 Epirubicin<br>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. | Drug: Ixabepilone<br>* Infusion, intravenous (IV), Cycle = 21 days. Dose escalation study.<br>* Other names: Epothilone;Drug: Epirubicin<br>* Infusion, intravenous (IV): 75 mg/m^2. Cycle = 21 days, up to 10 cycles or cumulative dose of 800 mg/m².<br>|
| Experimental: 35 mg/m^2 Ixabepilone plus 75 mg/m^2 Epirubicin<br>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. | Drug: Ixabepilone<br>* Infusion, intravenous (IV), Cycle = 21 days. Dose escalation study.<br>* Other names: Epothilone;Drug: Epirubicin<br>* Infusion, intravenous (IV): 75 mg/m^2. Cycle = 21 days, up to 10 cycles or cumulative dose of 800 mg/m².<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Dose Limiting Toxicity (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 | From Baseline to the end of Cycle 1 (Day 21) | 
| Ixabepilone Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) | 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. | Day 21 of Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death, Adverse Events (AEs), Serious Adverse Events (SAEs), Grade 3/4 AEs, or AEs Leading to Discontinuation | 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 | Evaluated continuously on study from Baseline to ≤30 days after the last dose of study drug. | 
| Maximum Plasma Concentration (Cmax) of Single-dose Ixabepilone | 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. | From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion. | 
| Area Under the Curve, Extrapolated to Infinity (AUC[INF]) of Single-dose Ixabepilone | 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. | From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion. | 
| Terminal Half-life (T-Half) of Single-dose Ixabepilone | 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. | From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion. | 
| Clearance (CLT) of Single-dose Ixabepilone | 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. | From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion. | 
| Volume of Distribution at Steady State (Vss) of Single-dose Ixabepilone | 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. | From the start of the ixabepilone infusion on Day 1 to 120 hours after the first infusion. | 
| Epirubicin Cmax | 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. | From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion. | 
| Epirubicin AUC(INF) | 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. | From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion. | 
| Epirubicin T-Half | 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. | From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion. | 
| Epirubicin CLT | 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. | From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion. | 
| Epirubicin Vss | 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. | From the start of the ixabepilone infusion on Day 1 to 24 hours after the first infusion. | 
| Number Of Participants With A Best Overall Tumor Response of Complete Response, Partial Response, Stable Disease, And Progressive Disease | 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. | From Baseline (up to 2 weeks prior to starting therapy) to the end Cycle 2 | 
| Duration of Tumor Response | 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. | Time (in months) when criteria for CR or PR are met (which ever occurs first) up to date of progressive disease. | 
| Number Of Participants With Tumor Response by Duration of Response Category | 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. | Time (in months) when criteria for CR or PR are met (which ever occurs first) up to date of progressive disease. |