Phase 1 Trial of Oral Ixabepilone

• Number of Participants With a Dose-Limiting Toxicity (DLT) [ Time Frame: During Cycle 1 (Day 0 through Day 21) ] [ Designated as safety issue: Yes ]
  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.
• Ixabepilone Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (R2PD) [ Time Frame: At the end of Cycle 1 (21 days). ] [ Designated as safety issue: Yes ]
  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.

• Safety (Dose Limiting Toxicities) [ Time Frame: assessed at cycle 1 ]
• Drug-related adverse events [ Time Frame: from first study drug administration through 30 days post dose ]

• 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 [ Time Frame: From first study drug administration through 30 days post dose ] [ Designated as safety issue: Yes ]
  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.
• Number of Participants With Most Common Treatment-Related Nonhematologic AEs (>25%) [ Time Frame: From first study drug administration through 30 days post dose ] [ Designated as safety issue: Yes ]
  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.
• Number of Participants With Hematology Laboratory Abnormalities [ Time Frame: From first study drug administration through 30 days post dose ] [ Designated as safety issue: Yes ]
  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).
• Number Of Participants With Liver Function and Renal Laboratory Abnormalities [ Time Frame: From first study drug administration through 30 days post dose ] [ Designated as safety issue: Yes ]
  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).
• Maximum QTc Interval on Day 1 and Maximum Change From Baseline for QTc Interval [ Time Frame: Baseline (Day -1) and Day 1 ] [ Designated as safety issue: Yes ]
  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
• PK: Mean Plasma Concentration Of Ixabepilone By Nominal Collection Time [ Time Frame: 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 ] [ Designated as safety issue: No ]
  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).
• Best Overall Response [ Time Frame: Tumor assessments performed on Day 1 of every other cycle of therapy, until disease progression or toxicity ] [ Designated as safety issue: No ]
  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.

• Assess the plasma pharmacokinetic (PK) of oral Ixabepilone [ Time Frame: at cycle 1 only ]
• Describe any evidence of antitumor activity [ Time Frame: disease assessments after every other cycle of therapy ]

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

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