Phase 1 Trial of Oral Ixabepilone

Study Overview
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Brief Summary
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This Phase 1 study of oral ixabepilone given every 6 hours for 3 doses on Day 1, every 21 days, was a dose-finding study designed to determine the maximum tolerated dose (MTD) and safety of this dosing schedule in participants with advanced cancer

Official Title
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A Phase 1 Study of Ixabepilone Administered as 3 Oral Doses Each Separated by 6 Hours Every 21 Days in Subjects With Advanced Cancer

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Ixabepilone (oral formulation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, 18 or older Histologically or cytologically confirmed diagnosis of solid tumor malignancy Measurable or non-measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria Karnofsky Performance Status (KPS) of 70-100 Recovered from toxicities resulting from previous therapies Exclusion Criteria: More than 3 prior cytotoxic regimens in the metastatic setting Current or recent gastrointestinal (GI) disease that would impact the absorption of study drug Inability to swallow whole capsules Inadequate hepatic and renal function Function exposure to any epothilone

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: 1<br> | Drug: Ixabepilone (oral formulation)<br>* Capsules, Oral, Dose escalating (Phase 1), 3 doses on 1 day every 3 weeks, until disease progression or unacceptable toxicity<br>* Other names: BMS-247550;|

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, occurring in Cycle 1: Absolute neutrophil count (ANC) <500 cells/mm^3 for ≥5 consecutive days or febrile neutropenia of any duration; Grade(Gr)4 thrombocytopenia <25,000 cells/mm^3 or Gr3 with bleeding requiring platelet transfusion; Gr3/4 nausea, vomiting, or diarrhea despite use of adequate intervention, fatigue, any other clinically significant drug-related ≥Gr 3 non-hematologic toxicity, delayed recovery (to Gr ≤1 or baseline, except alopecia) from toxicity which delays initiation of Cycle 2 by ≥3 weeks. | During Cycle 1 (Day 0 through Day 21) | 
| Ixabepilone Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) | The MTD was defined as the maximum dose which could be given to 6 participants such that not more than 1 participant experienced a DLT (or fewer than one-third if there were more than 6 treated participants) with at least 2 participants experiencing a DLT at the next higher dose level. The R2PD was to be based on the MTD and the assessment of any relevant chronic toxicities. | At the end of Cycle 1 (21 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Event (AE), AE Leading to Discontinuation, Treatment-related AE, Treatment-related AE Leading to Discontinuation (DC), Most Common Treatment-Related Nonhematologic AE (>25%), Serious AE (SAE), or Treatment-related SAE | AEs graded according to Common Terminology Criteria Version 3.0 (CTC v 3.0). AE=any new untoward medical occurrence or worsening of a pre-existing medical condition not necessarily having a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization/causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, or is an important medical event. | From first study drug administration through 30 days post dose | 
| Number of Participants With Most Common Treatment-Related Nonhematologic AEs (>25%) | AEs graded according to Common Terminology Criteria Version 3.0 (CTC v 3.0). AE=any new untoward medical occurrence or worsening of a pre-existing medical condition not necessarily having a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization/causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, or is an important medical event. | From first study drug administration through 30 days post dose | 
| Number of Participants With Hematology Laboratory Abnormalities | Laboratory results were graded according to CTC v 3.0. Hematology laboratory evaluations included absolute neutrophil count (ANC), white blood cell count (WBC), platelets (PLT), and hemoglobin (HGB). | From first study drug administration through 30 days post dose | 
| Number Of Participants With Liver Function and Renal Laboratory Abnormalities | Laboratory results were graded according to CTC v 3.0. Clinical laboratory evaluations included liver function (alanine aminotransferase [ALT], Aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin), and renal function (creatinine). | From first study drug administration through 30 days post dose | 
| Maximum QTc Interval on Day 1 and Maximum Change From Baseline for QTc Interval | QTc interval was defined as the measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, corrected for heart rate | Baseline (Day -1) and Day 1 | 
| PK: Mean Plasma Concentration Of Ixabepilone By Nominal Collection Time | Pharmacokinetics (PK) of ixabepilone were derived from plasma concentration versus time data. Individual patient PK parameter values were derived by standard non-compartmental methods by a validated pharmacokinetic analysis program. PK parameters include Cmax (maximum plasma concentration), Cmin (minimum plasma concentration), Tmax (time of maximum plasma concentration), AUC (0-TAU) (area under the curve in one dosing interval), T-half (plasma half-life). | Time 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 12.5, 13, 14, 15, 16, 17, 18, 20, 48, 72, and 168 hours post dose | 
| Best Overall Response | Tumor assessment was performed according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR) = disappearance of all clinical and radiological evidence of target lesions; Partial Response (PR) = at least 30% reduction in the sum of the longest diameter of all target lesions; Progressive disease (PD) = at least 20% increase in the sum of the longest diameter of all target lesions; Stable Disease (SD) = neither PR nor PD criteria were met. | Tumor assessments performed on Day 1 of every other cycle of therapy, until disease progression or toxicity |