A Phase I Study of Oral Ixabepilone in Subjects With Advanced Cancer

Study Overview
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Brief Summary
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This study will determine the maximum tolerated dose of oral ixabepilone administered for 5 successive days every 21 days in participants with advanced cancer. The safety, tolerability, and pharmacokinetics of ixabepilone in the body will be studied. In addition, this study will assess preliminary evidence of the effect of food and famotidine on the pharmacokinetics of oral ixabepilone.

Official Title
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A Phase I Study of Ixabepilone Administered as a Daily Oral Dose on 5 Successive Days Every 21 Days in Subjects With Advanced Cancer

Conditions
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Cancer

Intervention / Treatment
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* Drug: Ixabepilone, 5 mg/d
* Drug: Ixabepilone, 10 mg/d
* Drug: Ixabepilone, 15 mg/d
* Drug: Ixabepilone, 20 mg/d
* Drug: Ixabepilone, 25 mg/d
* Drug: Ixabepilone, 30 mg/d
* Drug: Ixabepilone, 25 mg, with famotidine
* Drug: Ixabepilone, 25 mg, with food


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of solid tumor malignancy unresponsive to current treatment options Measurable or nonmeasurable disease as defined by Response Evaluation Criteria in Solid Tumors Lapse of at least 1 week since minor surgery and of at least 3 weeks since major surgery and radiation therapy Eastern Cooperative Oncology Group performance status of 0-1 Lapse of at least 4 weeks since immunotherapy or chemotherapy Negative pregnancy test result within 72 hours of study drug administration for any woman of childbearing potential (WOCBP) Exclusion Criteria: WOCBP unable or unwilling to use birth control during study and for up to 4 weeks after study completion Women who are pregnant or breastfeeding Fertile men not using effective birth control with partners who are WOCBP Gastrointestinal(GI) disease or GI tract surgery that could impact drug absorption Inability to swallow capsules Inability to be venipunctured or to tolerate venous access Known symptomatic brain metastases Common Terminology Criteria for Adverse Events Grade 2 or greater neuropathy or history of Grade 3 or greater neuropathy Psychiatric conditions inhibiting compliance with protocol requirements Uncontrolled medical disorder or active infection that would impair participant's ability to receive protocol therapy or whose control may be jeopardized by the study treatment protocol Inadequate hematologic, hepatic, or renal function History of significant drug allergy Previous exposure to ixabepilone Exposure to any investigational drug or placebo within 4 weeks of enrollment Concurrent chemotherapy regimen Use of cytochrome P4503A4 inhibitors or inducers within 2 weeks of treatment initiation (unless approved by medical monitor) Use of steroids (except as antiemetic) Prisoners or subjects involuntarily detained for treatment

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ixabepilone, 5 mg/d<br>If none of first 3 participants experiences a dose-limiting toxicity (DLT) during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the maximum tolerated dose (MTD). If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD. | Drug: Ixabepilone, 5 mg/d<br>* Ixabepilone, 5 mg, administered orally once daily on Days 1 through 5 every 21 days. Dose increased by 5 mg for each subsequent treatment group until disease progression, unacceptable toxicity, or participant refusal. No dose escalation within each treatment group. On all dosing days in Cycle 1, participants must fast at least 4 hours before and 4 hours after treatment.<br>|
| Experimental: Ixabepilone, 10 mg/d<br>If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD. | Drug: Ixabepilone, 10 mg/d<br>* Ixabepilone, 10 mg, administered orally once daily on Days 1 through 5 every 21 days. Dose increased by 5 mg for each subsequent treatment group until disease progression, unacceptable toxicity, or participant refusal. No dose escalation within each treatment group. On all dosing days in Cycle 1, participants must fast at least 4 hours before and 4 hours after treatment.<br>|
| Experimental: Ixabepilone, 15 mg/d<br>If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD. | Drug: Ixabepilone, 15 mg/d<br>* Ixabepilone, 15 mg, administered orally once daily on Days 1 through 5 every 21 days. Dose increased by 5 mg for each subsequent treatment group until disease progression, unacceptable toxicity, or participant refusal. No dose escalation within each treatment group. On all dosing days in Cycle 1, participants must fast at least 4 hours before and 4 hours after treatment.<br>|
| Experimental: Ixabepilone, 20 mg/d<br>If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD. | Drug: Ixabepilone, 20 mg/d<br>* Ixabepilone, 20 mg, administered orally once daily on Days 1 through 5 every 21 days. Dose increased by 5 mg for each subsequent treatment group until disease progression, unacceptable toxicity, or participant refusal. No dose escalation within each treatment group. On all dosing days in Cycle 1, participants must fast at least 4 hours before and 4 hours after treatment.<br>|
| Experimental: Ixabepilone, 25 mg/d<br>If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD. | Drug: Ixabepilone, 25 mg/d<br>* Ixabepilone, 25 mg, administered orally once daily on Days 1 through 5 every 21 days. Dose increased by 5 mg for each subsequent treatment group until disease progression, unacceptable toxicity, or participant refusal. No dose escalation within each treatment group. On all dosing days in Cycle 1, participants must fast at least 4 hours before and 4 hours after treatment.<br>|
| Experimental: Ixabepilone, 30 mg/d<br>If none of first 3 participants experiences a DLT during the first 21-day cycle, a new cohort is opened at the next dose level (5-mg increments). If 2 or more of the first 3 participants experience a DLT within the first 21-day course, the dose level will be considered above the MTD. If 1 of the first 3 participants experiences a DLT, an additional 3 participants will be enrolled at this dose level for a total of 6 participants. If 2 or more of the 6 participants (or 1/3 or more of a cohort with more than 6 participants) experience a DLT, this dose level will be considered above the MTD. | Drug: Ixabepilone, 30 mg/d<br>* Ixabepilone, 30 mg, administered orally once daily on Days 1 through 5 every 21 days. Dose increased by 5 mg for each subsequent treatment group until disease progression, unacceptable toxicity, or participant refusal. No dose escalation within each treatment group. On all dosing days in Cycle 1, participants must fast at least 4 hours before and 4 hours after treatment.<br>|
| Experimental: Ixabepilone, 25 mg, with famotidine<br>Following identification of MTD, participants who completed Cycle 1 and treated at the ixabepilone MTD (25 mg/d) will crossover to Cycle 2 in which they receive famotidine, 40 mg on Day 1. | Drug: Ixabepilone, 25 mg, with famotidine<br>* Participants crossed over from Cycle 1 to receive famotidine, 40 mg, in an oral dose given 2 hours before ixabepilone, 25 mg, on Day 1 of Cycle 2 only.<br>|
| Experimental: Ixabepilone, 25 mg, with food<br>Following identification of MTD, participants who completed Cycle 1 and treated at the ixabepilone MTD (25 mg/d) will crossover to Cycle 2 in which they receive a low-fat meal on Day 1. | Drug: Ixabepilone, 25 mg, with food<br>* Participants consume a low-fat meal starting 30 minutes before dose administration on Day 1 of Cycle 2. Food consumed within 30 minutes. Administration of the total oral dose should not exceed more than 10 minutes from start to finish.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Ixabepilone | MTD is based on Cycle 1 data only and defined as the maximum dose that can be administered to 6 participants with no more than 1 experiencing a dose-limiting toxicity (DLT) (or fewer than one third of participants if more than 6 receive treatment) with at least 2 participants experiencing a DLT at the next higher dose level. DLT=an event, such as neutropenia; thrombocytopenia; Gr 3 or 4 nausea or diarrhea; Gr 3 fatigue or asthenia; transient arthralgia or recalcitrant myalgia; and prolonged recovery from a toxicity, that occurs during the first course of treatment. | Days 1 through 21 (Cycle 1) | 
| Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Adverse events (AEs) graded by CTC version 3. Grade (Gr) 1=mild; Gr 2=moderate; Gr 3=severe; Gr 4=life threatening; Gr 5=Death related to AE. DLT is defined as an event related to ixabepilone that occurs during the first course of treatment. Includes neutropenia; thrombocytopenia; Gr 3 or 4 nausea, vomiting, or diarrhea despite adequate medical intervention and prophylaxis; Gr 3 fatigue or asthenia; transient arthralgia or myalgia unresponsive to medical intervention; any Gr 3 nonhematologic toxicity; and prolonged recovery from a toxicity. | Days 1 through 21 (Cycle 1), continuously | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with treatment. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment. | Days 1 through 21 (Cycle 1), continuously | 
| Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Lower limit of normal (LLN)=lowest level of normal among all laboratory ranges. Hemoglobin (g/dL): Gr 1: 10.0-<LLN; Gr 2: 8.0-<10.0; Gr 3:6.5-<8.0; Gr 4: 6.5. Leukocytes (c/uL): Gr 1: 3.0-<LLN; Gr 2: 2.0-<3.0; Gr 3: 1.0-<2.0; Gr 4: <1.0. Lymphocytes (c/uL): Gr 1: 0.8-<1.5; Gr 2: 0.5-<0.8; Gr 3: 0.2-<0.5; Gr 4: <0.2. Neutrophils (Absolute)(c/uL): Gr 1: 1.5-<2.0; Gr 2: 1.0-<1.5; Gr 3: 0.5-<1.0; Gr 4: <0.5. Neutrophils + Bands (c/uL): Gr 1: 1.5-<2.0; Gr 2: 1.0-<1.5; Gr 3: 0.5-<1.0; Gr 4: <0.5. Platelet Count (c/uL):Gr 1: 75.0-<LLN; Gr 2: 50.0-<75.0; Gr 3: 25.0-<50.0; Gr 4: <25.0. | Baseline and Days 1, 8, and 15 of Cycle 1 (21 days) | 
| Maximum Plasma Concentration (Cmax) of Ixabepilone |  | Days 1 and 5 of Cycle 1 | 
| Time of Maximum Plasma Concentration (Tmax) of Ixabepilone |  | Days 1 and 5 of Cycle 1 | 
| Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone |  | Days 1 and 5 of Cycle 1 | 
| Plasma Half-life (T-Half) of Ixabepilone |  | Day 5 of Cycle 1 | 
| Maximum Plasma Concentration (Cmax) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | After the MTD has been defined, participants who completed Cycle 1 (ixabepilone, 25 mg, given once daily orally on Days 1 through 5 of 21-day cycle, with participants fasting at least 4 hours before and 4 hours after treatment on all dosing days) then cross over to Cycle 2, during which they consume a standard lowfat meal starting 30 minutes prior to ixabepilone, 25 mg, administration on Day 1 of Cycle 2 only. Meal is consumed within a 30-minute period. Administration of the total oral dose should not exceed more than 10 minutes from start to finish. | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 
| Time of Maximum Plasma Concentration (Tmax)of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | After the ixabepilone MTD (25 mg) has been defined, participants who completed Cycle 1 (ixabepilone, 25 mg, given once daily orally on Days 1 through 5 of 21-day cycle, with participants fasting at least 4 hours before and 4 hours after treatment on all dosing days) then cross over to Cycle 2, during which they consume a standard lowfat meal starting 30 minutes prior to ixabepilone, 25 mg, administration on Day 1 of Cycle 2 only. Meal is consumed within a 30-minute period. Administration of the total oral dose should not exceed more than 10 minutes from start to finish. | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 
| Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | After the ixabepilone MTD (25 mg) has been defined, participants who completed Cycle 1 (ixabepilone, 25 mg, given once daily orally on Days 1 through 5 of 21-day cycle, with participants fasting at least 4 hours before and 4 hours after treatment on all dosing days) then cross over to Cycle 2, during which they consume a standard lowfat meal starting 30 minutes prior to ixabepilone, 25 mg, administration on Day 1 of Cycle 2 only. Meal is consumed within a 30-minute period. Administration of the total oral dose should not exceed more than 10 minutes from start to finish. | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 
| Maximum Plasma Concentration (Cmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | After the ixabepilone MTD (25 mg) has been defined, participants who completed Cycle 1 (ixabepilone, 25 mg, given once daily orally on Days 1 through 5 of 21-day cycle, with participants fasting at least 4 hours before and 4 hours after treatment on all dosing days) then cross over to Cycle 2, during which they receive famotidine, 40 mg. Prior to dosing on Day 1 of Cycle 2, famotidine administered in an oral dose 2 hours before ixabepilone 25-mg dose. | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 
| Time of Maximum Plasma Concentration (Tmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | After the ixabepilone MTD (25 mg) has been defined, participants who completed Cycle 1 (ixabepilone, 25 mg, given once daily orally on Days 1 through 5 of 21-day cycle, with participants fasting at least 4 hours before and 4 hours after treatment on all dosing days) then cross over to Cycle 2, during which they receive famotidine, 40 mg. Prior to dosing on Day 1 of Cycle 2, famotidine administered in an oral dose 2 hours before ixabepilone 25-mg dose. | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 
| Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | After the ixabepilone MTD (25 mg) has been defined, participants who completed Cycle 1 (ixabepilone, 25 mg, given alone once daily orally on Days 1 through 5 of 21-day cycle, with participants fasting at least 4 hours before and 4 hours after treatment on all dosing days) then cross over to Cycle 2, during which they receive famotidine, 40 mg. Prior to dosing on Day 1 of Cycle 2, famotidine administered in an oral dose 2 hours before ixabepilone 25-mg dose. | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 
| Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | Physical examination evaluated height, weight, Eastern Cooperative Oncology Group performance status, adverse events, and abnormal laboratory findings and included a neurologic examination to evaluate deep tendon reflexes, sensory modalities, and motor strength. Participants also underwent a 12-lead ECG screening. Physical examination findings and ECG findings were considered clinically significant at the investigator's discretion. | At screening and predose Day 1, Cycle 1 (21 days) | 
| Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Upper limit of normal (ULN)=upper level of normal among all laboratory ranges. Alkaline phosphatase(U/L): Gr 3: >5.0-20.0*ULN; Gr 4: >20.0*ULN. Sodium (mEq/L): Gr 3: 120-<130 or >155-160; Gr 4 <120. Potassium (mEq/L): Gr 3: 2.5-<3.0 or >6.0-7.0; Gr 4: <2.5 or >7.0. Calcium (mg/dL): Gr 3: 6.0-<7.0 or >12.5-13.5; Gr 4: <6.0 or >13.5. Inorganic phosphorus (mg/dL): Gr 3: 1.0-<2.0; Gr 4: <1.0. Albumin (g/dL): Gr 3: <2.0. | At screening and predose Day 1, Cycle 1 (21 days) |