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

This study has been completed.
Sponsor:
Information provided by:
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00422097
First received: January 12, 2007
Last updated: May 17, 2011
Last verified: May 2011
  Purpose

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.


Condition Intervention Phase
Cancer
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
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Ixabepilone Administered as a Daily Oral Dose on 5 Successive Days Every 21 Days in Subjects With Advanced Cancer

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Ixabepilone [ Time Frame: Days 1 through 21 (Cycle 1) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Days 1 through 21 (Cycle 1), continuously ] [ Designated as safety issue: Yes ]
    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:
  • Number of Participants With Death as Outcome, Treatment-related Adverse Events (AEs), and AEs Leading to Discontinuation [ Time Frame: Days 1 through 21 (Cycle 1), continuously ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Abnormal Laboratory Values by Worst CTC Grade [ Time Frame: Baseline and Days 1, 8, and 15 of Cycle 1 (21 days) ] [ Designated as safety issue: Yes ]
    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.

  • Maximum Plasma Concentration (Cmax) of Ixabepilone [ Time Frame: Days 1 and 5 of Cycle 1 ] [ Designated as safety issue: No ]
  • Time of Maximum Plasma Concentration (Tmax) of Ixabepilone [ Time Frame: Days 1 and 5 of Cycle 1 ] [ Designated as safety issue: No ]
  • Area Under the Concentration-time Curve in 1 Dosing Interval (AUC[TAU])of Ixabepilone [ Time Frame: Days 1 and 5 of Cycle 1 ] [ Designated as safety issue: No ]
  • Plasma Half-life (T-Half) of Ixabepilone [ Time Frame: Day 5 of Cycle 1 ] [ Designated as safety issue: No ]
  • Maximum Plasma Concentration (Cmax) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts [ Time Frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) ] [ Designated as safety issue: No ]
    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.

  • Area Under the Curve in 1 Dosing Interval (AUC[TAU]) of Oral Ixabepilone at MTD in Fasted and Fed Participants in Crossover Cohorts [ Time Frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) ] [ Designated as safety issue: No ]
    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.

  • Maximum Plasma Concentration (Cmax) of Oral Ixabepilone With and Without Famotidine in Crossover Cohorts [ Time Frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 hours postdose Day 1 of Cycle 1 (21 days) and Day 1 of Cycle 2 (21 days) ] [ Designated as safety issue: No ]
    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) [ Time Frame: At screening and predose Day 1, Cycle 1 (21 days) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: At screening and predose Day 1, Cycle 1 (21 days) ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 40
Study Start Date: January 2007
Study Completion Date: April 2011
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.
Experimental: 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.
Drug: Ixabepilone, 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00422097

Locations
United States, District of Columbia
Georgetown University Medical Center Lombardi Cancer Center
Washington, District of Columbia, United States, 20007
United States, Michigan
Wayne State University (Hwcrc)
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00422097     History of Changes
Other Study ID Numbers: CA163-111
Study First Received: January 12, 2007
Results First Received: January 27, 2011
Last Updated: May 17, 2011
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Famotidine
Epothilones
Anti-Ulcer Agents
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Histamine H2 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 20, 2014