Cancer
Conditions
Brief summary
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.
Interventions
DRUGIxabepilone, 5 mg/d
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.
DRUGIxabepilone, 10 mg/d
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.
DRUGIxabepilone, 15 mg/d
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.
DRUGIxabepilone, 20 mg/d
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.
DRUGIxabepilone, 25 mg/d
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.
DRUGIxabepilone, 30 mg/d
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.
DRUGIxabepilone, 25 mg, with famotidine
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.
DRUGIxabepilone, 25 mg, with food
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.
Sponsors
R-Pharm
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Ixabepilone | Days 1 through 21 (Cycle 1) | 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. |
| Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Days 1 through 21 (Cycle 1), continuously | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 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. |
| Time of Maximum Plasma Concentration (Tmax)of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 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. |
| Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Days 1 through 21 (Cycle 1), continuously | 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. |
| Maximum Plasma Concentration (Cmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 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. |
| Time of Maximum Plasma Concentration (Tmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 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. |
| Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 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. |
| Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | At screening and predose Day 1, Cycle 1 (21 days) | 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. |
| Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | At screening and predose Day 1, Cycle 1 (21 days) | 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. |
| Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) | 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. |
| Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Baseline and Days 1, 8, and 15 of Cycle 1 (21 days) | 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. |
Countries
United States
Participant flow
Pre-assignment details
Of 58 enrolled, 44 received treatment: 10 no longer met enrollment criteria (2 brain metastases, 2 bowel obstruction, 1 high aspartame aminotransferase \[AST\], 1 high AST/alanine transaminase, 2 low platelets, 1 hospitalized, 1 gastric adverse event \[AE\]); 2 withdrew consent/changed mind; 1 AE; 1 sponsor administrative reason.
Participants by arm
| Arm | Count |
|---|---|
| Ixabepilone, 5 mg/d Participants with advanced cancer received daily oral doses of ixabepilone, 5 mg, on Days 1 through 5 every 21 days. | 3 |
| Ixabepilone, 10 mg/d Participants with advanced cancer received daily oral doses of ixabepilone, 10 mg, on Days 1 through 5 every 21 days. | 6 |
| Ixabepilone, 15 mg/d Participants with advanced cancer received daily oral doses of ixabepilone, 15 mg, on Days 1 through 5 every 21 days. | 3 |
| Ixabepilone, 20 mg/d Participants with advanced cancer received daily oral doses of ixabepilone, 20 mg, on Days 1 through 5 every 21 days. | 3 |
| Ixabepilone, 25 mg/d Participants with advanced cancer received daily oral doses of ixabepilone, 25 mg, on Days 1 through 5 every 21 days. | 23 |
| Ixabepilone, 30 mg/d Participants with advanced cancer received daily oral doses of ixabepilone, 30 mg, on Days 1 through 5 every 21 days. | 6 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Dose Level 2 | Still on treatment | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Ixabepilone, 10 mg/d | Ixabepilone, 15 mg/d | Ixabepilone, 20 mg/d | Ixabepilone, 5 mg/d | Ixabepilone, 25 mg/d | Ixabepilone, 30 mg/d | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 21 Participants | 3 Participants | 32 Participants |
| Age, Continuous | 62 years | 60 years | 60 years | 64 years | 56 years | 69 years | 60 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 2 Participants | 3 Participants | 3 Participants | 17 Participants | 6 Participants | 36 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 12 Participants | 2 Participants | 23 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 11 Participants | 4 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 3 / 3 | 2 / 3 | 20 / 23 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 2 / 6 | 3 / 3 | 1 / 3 | 6 / 23 | 5 / 6 |
Outcome results
Primary
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.
Time frame: Days 1 through 21 (Cycle 1)
Population: All Treated Subjects: All subjects who received at least one dose of ixabepilone were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ixabepilone, 5 mg/d | Maximum Tolerated Dose (MTD) of Ixabepilone | 25 mg/d |
Primary
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.
Time frame: Days 1 through 21 (Cycle 1), continuously
Population: All Treated Participants: All participants who received at least one dose of ixabepilone were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Thrombocytopenia (Grade 4) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Fatigue (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Clostridium difficile colitis (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 4) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Ileus (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 4) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenia (Grade 4) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Vomiting (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypophosphatemia (Grade 4) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Nausea (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Diarrhea (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Abdominal pain (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Mucosal inflammation (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Dehydration (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 3) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Sudden death (Grade 5) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 4) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Mucosal inflammation (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Nausea (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Vomiting (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Abdominal pain (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Clostridium difficile colitis (Grade 3) | 1 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Thrombocytopenia (Grade 4) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Fatigue (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypophosphatemia (Grade 4) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Sudden death (Grade 5) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 4) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Dehydration (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Ileus (Grade 3) | 1 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenia (Grade 4) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Diarrhea (Grade 3) | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Ileus (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Fatigue (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Abdominal pain (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Vomiting (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Dehydration (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Mucosal inflammation (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenia (Grade 4) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Nausea (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Thrombocytopenia (Grade 4) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Diarrhea (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 4) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypophosphatemia (Grade 4) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Clostridium difficile colitis (Grade 3) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 4) | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Sudden death (Grade 5) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Vomiting (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Clostridium difficile colitis (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Ileus (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Abdominal pain (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Fatigue (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 4) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Dehydration (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Diarrhea (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Nausea (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Mucosal inflammation (Grade 3) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenia (Grade 4) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 4) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypophosphatemia (Grade 4) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Thrombocytopenia (Grade 4) | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Sudden death (Grade 5) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenia (Grade 4) | 1 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Fatigue (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Diarrhea (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypophosphatemia (Grade 4) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Mucosal inflammation (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 4) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Abdominal pain (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Dehydration (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Sudden death (Grade 5) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Thrombocytopenia (Grade 4) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Clostridium difficile colitis (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 4) | 1 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Nausea (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Vomiting (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Ileus (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 3) | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 3) | 0 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Fatigue (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Mucosal inflammation (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Dehydration (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Clostridium difficile colitis (Grade 3) | 0 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenia (Grade 4) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 4) | 2 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Neutropenic fever (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 4) | 0 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Diarrhea (Grade 3) | 2 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Sudden death (Grade 5) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypophosphatemia (Grade 4) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Abdominal pain (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Ileus (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Thrombocytopenia (Grade 4) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Nausea (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Vomiting (Grade 3) | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With DLTs by Worst Common Terminology Criteria (CTC) Grade | Hypokalemia (Grade 3) | 1 Participants |
Secondary
Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone
Time frame: Days 1 and 5 of Cycle 1
Population: All participants who received ixabepilone and who had adequate concentration profiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone, 5 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 1 (n=3, n=6, n=3, n=3, n=23, n=6) | 28.40 ng*h/mL | Standard Deviation 29.73 |
| Ixabepilone, 5 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 21.83 ng*h/mL | Standard Deviation 28.59 |
| Ixabepilone, 10 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 1 (n=3, n=6, n=3, n=3, n=23, n=6) | 91.79 ng*h/mL | Standard Deviation 62.45 |
| Ixabepilone, 10 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 143.85 ng*h/mL | Standard Deviation 134.15 |
| Ixabepilone, 15 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 1 (n=3, n=6, n=3, n=3, n=23, n=6) | 120.58 ng*h/mL | Standard Deviation 152.23 |
| Ixabepilone, 15 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 179.82 ng*h/mL | Standard Deviation 126.95 |
| Ixabepilone, 20 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 1 (n=3, n=6, n=3, n=3, n=23, n=6) | 120.82 ng*h/mL | Standard Deviation 73.62 |
| Ixabepilone, 20 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 222.73 ng*h/mL | Standard Deviation 136.49 |
| Ixabepilone, 25 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 1 (n=3, n=6, n=3, n=3, n=23, n=6) | 195.96 ng*h/mL | Standard Deviation 177.39 |
| Ixabepilone, 25 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 348.07 ng*h/mL | Standard Deviation 370.95 |
| Ixabepilone, 30 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 1 (n=3, n=6, n=3, n=3, n=23, n=6) | 252.01 ng*h/mL | Standard Deviation 153.26 |
| Ixabepilone, 30 mg/d | Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 545.42 ng*h/mL | Standard Deviation 441.93 |
Secondary
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.
Time frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days)
Population: All participants who received ixabepilone and who had adequate concentration profiles. Participants received MTD (25 mg).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone, 5 mg/d | Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Fasted (Cycle 1) | 190.22 ng*h/mL | Standard Deviation 128.14 |
| Ixabepilone, 5 mg/d | Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Fed (Cycle 2) | 243.46 ng*h/mL | Standard Deviation 99.91 |
Secondary
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.
Time frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days)
Population: Participants who received ixabepilone, at the MTD of 25 mg, alone in Cycle 1 and had adequate concentration profiles. Participants then were crossed over to a cycle in which they received MTD (25 mg) ixabepilone with famotidine,40 mg, on Day 1 of Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone, 5 mg/d | Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | Without Famotidine (Cycle 1) | 218.36 ng*h/mL | Standard Deviation 260.55 |
| Ixabepilone, 5 mg/d | Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | With Famotidine (Cycle 2) | 276.30 ng*h/mL | Standard Deviation 179.2 |
Secondary
Maximum Plasma Concentration (Cmax) of Ixabepilone
Time frame: Days 1 and 5 of Cycle 1
Population: All participants who received ixabepilone and who had adequate concentration profiles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone, 5 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 4.02 ng/mL | Standard Deviation 1.99 |
| Ixabepilone, 5 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 2.45 ng/mL | Standard Deviation 0.42 |
| Ixabepilone, 10 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 25.93 ng/mL | Standard Deviation 20.47 |
| Ixabepilone, 10 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 20.34 ng/mL | Standard Deviation 23.07 |
| Ixabepilone, 15 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 16.04 ng/mL | Standard Deviation 16.76 |
| Ixabepilone, 15 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 22.17 ng/mL | Standard Deviation 12.4 |
| Ixabepilone, 20 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 24.10 ng/mL | Standard Deviation 19.96 |
| Ixabepilone, 20 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 32.73 ng/mL | Standard Deviation 24.97 |
| Ixabepilone, 25 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 36.14 ng/mL | Standard Deviation 25.18 |
| Ixabepilone, 25 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 57.99 ng/mL | Standard Deviation 99.77 |
| Ixabepilone, 30 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 43.67 ng/mL | Standard Deviation 20.87 |
| Ixabepilone, 30 mg/d | Maximum Plasma Concentration (Cmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 66.48 ng/mL | Standard Deviation 62.64 |
Secondary
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.
Time frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days)
Population: All participants who received ixabepilone and who had adequate concentration profiles. Participants received MTD (25 mg) ixabepilone without famotidine (Cycle 1) and then were crossed over to a cycle in which they received MTD (25 mg) ixabepilone with famotidine (Cycle 2).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone, 5 mg/d | Maximum Plasma Concentration (Cmax) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Fasted (Cycle 1) | 38.11 ng/mL | Standard Deviation 29.48 |
| Ixabepilone, 5 mg/d | Maximum Plasma Concentration (Cmax) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Fed (Cycle 2) | 44.76 ng/mL | Standard Deviation 38.69 |
Secondary
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.
Time frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days)
Population: Participants who received ixabepilone, at the MTD of 25 mg, alone in Cycle 1 and had adequate concentration profiles. Participants then were crossed over to a cycle in which they received MTD (25 mg) ixabepilone with famotidine,40 mg, on Day 1 of Cycle 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ixabepilone, 5 mg/d | Maximum Plasma Concentration (Cmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | Without Famotidine (Cycle 1) | 36.91 ng/mL | Standard Deviation 29.79 |
| Ixabepilone, 5 mg/d | Maximum Plasma Concentration (Cmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | With Famotidine (Cycle 2) | 66.16 ng/mL | Standard Deviation 63.91 |
Secondary
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.
Time frame: At screening and predose Day 1, Cycle 1 (21 days)
Population: All Treated Subjects: All subjects who received at least one dose of ixabepilone were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low sodium (Grade 3) | 4 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | High sodium (Grade 3) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low albumin (Grade 3) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low alkaline phosphatase (Grade 3) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low potassium (Grade 3) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low potassium (Grade 4) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low total calcium (Grade 4) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal (CTC Grade 3 or Greater) Serum Chemistry Levels | Low inorganic phosphorus (Grade 4) | 1 Participants |
Secondary
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.
Time frame: Baseline and Days 1, 8, and 15 of Cycle 1 (21 days)
Population: All Treated Subjects: All subjects who received at least one dose of ixabepilone were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils + Bands (Absolute) (Grade 3) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Hemoglobin (Grade 1) | 19 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Hemoglobin (Grade 2) | 15 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Hemoglobin (Grade 3) | 5 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Hemoglobin (Grade 4) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Leukocytes (Grade 1) | 7 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Leukocytes (Grade 2) | 4 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Leukocytes (Grade 3) | 2 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Leukocytes (Grade 4) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Lymphocytes (Absolute) (Grade 1) | 14 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Lymphocytes (Absolute) (Grade 2) | 14 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Lymphocytes (Absolute) (Grade 3) | 12 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Lymphocytes (Absolute) (Grade 4) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils (Absolute) (Grade 1) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils (Absolute) (Grade 2) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils (Absolute) (Grade 3) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils (Absolute) (Grade 4) | 4 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils + Bands (Absolute) (Grade 1) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils + Bands (Absolute) (Grade 2) | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Neutrophils + Bands (Absolute) (Grade 4) | 4 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Platelet Count (Grade 1) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Platelet Count (Grade 2) | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Platelet Count (Grade 3) | 1 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Abnormal Laboratory Values by Worst CTC Grade | Platelet Count (Grade 4) | 1 Participants |
Secondary
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.
Time frame: Days 1 through 21 (Cycle 1), continuously
Population: All Treated Subjects: All subjects who received at least 1 dose of ixabepilone.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Death | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Treatment-related AEs | 2 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs | 3 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs leading to discontinuation | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs | 6 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Treatment-related AEs | 6 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Death | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs leading to discontinuation | 1 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs leading to discontinuation | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs | 3 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Treatment-related AEs | 3 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Death | 2 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Death | 1 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs leading to discontinuation | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Treatment-related AEs | 1 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs | 2 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs | 20 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs leading to discontinuation | 1 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Treatment-related AEs | 12 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Death | 1 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Treatment-related AEs | 5 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs | 6 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | AEs leading to discontinuation | 0 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation | Death | 1 Participants |
Secondary
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.
Time frame: At screening and predose Day 1, Cycle 1 (21 days)
Population: Although physical examinations and ECGs were performed, the findings were not summarized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal physical examination findings | 0 Participants |
| Ixabepilone, 5 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal ECG results | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal physical examination findings | 0 Participants |
| Ixabepilone, 10 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal ECG results | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal physical examination findings | 0 Participants |
| Ixabepilone, 15 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal ECG results | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal physical examination findings | 0 Participants |
| Ixabepilone, 20 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal ECG results | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal physical examination findings | 0 Participants |
| Ixabepilone, 25 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal ECG results | 0 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal physical examination findings | 0 Participants |
| Ixabepilone, 30 mg/d | Number of Participants With Significant Findings on Physical Examination or Electrocardiogram (ECG) | With abnormal ECG results | 0 Participants |
Secondary
Plasma Half-life (T-Half) of Ixabepilone
Time frame: Day 5 of Cycle 1
Population: All participants who received ixabepilone and who had adequate concentration profiles
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Plasma Half-life (T-Half) of Ixabepilone | 18.56 Hours | — |
| Ixabepilone, 10 mg/d | Plasma Half-life (T-Half) of Ixabepilone | 47.00 Hours | Standard Deviation 82.68 |
| Ixabepilone, 15 mg/d | Plasma Half-life (T-Half) of Ixabepilone | 24.32 Hours | Standard Deviation 17.68 |
| Ixabepilone, 20 mg/d | Plasma Half-life (T-Half) of Ixabepilone | 35.25 Hours | Standard Deviation 20.63 |
| Ixabepilone, 25 mg/d | Plasma Half-life (T-Half) of Ixabepilone | 35.62 Hours | Standard Deviation 17.48 |
| Ixabepilone, 30 mg/d | Plasma Half-life (T-Half) of Ixabepilone | 34.14 Hours | Standard Deviation 14.16 |
Secondary
Time of Maximum Plasma Concentration (Tmax) of Ixabepilone
Time frame: Days 1 and 5 of Cycle 1
Population: All participants who received ixabepilone and who had adequate concentration profiles
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 2.0 Hour |
| Ixabepilone, 5 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 2.3 Hour |
| Ixabepilone, 10 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 1.8 Hour |
| Ixabepilone, 10 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 2.5 Hour |
| Ixabepilone, 15 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 4.0 Hour |
| Ixabepilone, 15 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 5.0 Hour |
| Ixabepilone, 20 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 2.0 Hour |
| Ixabepilone, 20 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 1.5 Hour |
| Ixabepilone, 25 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 2.0 Hour |
| Ixabepilone, 25 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 1.8 Hour |
| Ixabepilone, 30 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day1 (n=3, n=6, n=3, n=3, n=23, n=6) | 3.0 Hour |
| Ixabepilone, 30 mg/d | Time of Maximum Plasma Concentration (Tmax) of Ixabepilone | Day 5 (n=2, n=6, n=3, n=3, n=22, n=6) | 3.5 Hour |
Secondary
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.
Time frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days)
Population: All participants who received ixabepilone and who had adequate concentration profiles. Participants received MTD (25 mg).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Time of Maximum Plasma Concentration (Tmax)of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Fasted (Cycle 1) | 2.0 ng/mL |
| Ixabepilone, 5 mg/d | Time of Maximum Plasma Concentration (Tmax)of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts | Fed (Cycle 2) | 4.0 ng/mL |
Secondary
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.
Time frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days)
Population: Participants who received ixabepilone, at the MTD of 25 mg, alone in Cycle 1 and had adequate concentration profiles. Participants then were crossed over to a cycle in which they received MTD (25 mg) ixabepilone with famotidine,40 mg, on Day 1 of Cycle 2.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ixabepilone, 5 mg/d | Time of Maximum Plasma Concentration (Tmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | Without Famotidine (Cycle 1) | 3.0 ng/mL |
| Ixabepilone, 5 mg/d | Time of Maximum Plasma Concentration (Tmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts | With Famotidine (Cycle 2) | 4.0 ng/mL |