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

Phase 1

Completed

Conditions: Cancer

Interventions: Drug: Ixabepilone, 25 mg, with food
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

Registration Number: NCT00422097

Lead Sponsor: R-Pharm

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Ixabepilone, 25 mg, with food	Ixabepilone, 25 mg, with food	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.
Ixabepilone, 5 mg/d	Ixabepilone, 5 mg/d	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.
Ixabepilone, 10 mg/d	Ixabepilone, 10 mg/d	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.
Ixabepilone, 15 mg/d	Ixabepilone, 15 mg/d	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.
Ixabepilone, 20 mg/d	Ixabepilone, 20 mg/d	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.
Ixabepilone, 25 mg/d	Ixabepilone, 25 mg/d	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.
Ixabepilone, 30 mg/d	Ixabepilone, 30 mg/d	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.
Ixabepilone, 25 mg, with famotidine	Ixabepilone, 25 mg, with famotidine	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax) of Ixabepilone	Days 1 and 5 of Cycle 1
Plasma Half-life (T-Half) of Ixabepilone	Day 5 of Cycle 1
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.
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.
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
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.
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.
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.
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.

Trial Locations

Locations (2): Wayne State University (Hwcrc)
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Detroit, Michigan, United States
Georgetown University Medical Center Lombardi Cancer Center
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Washington, District of Columbia, United States