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A Study of Irinotecan Plus Cetuximab With or Without Enzastaurin in Participants With Colorectal Cancer

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00437268
Collaborator
(none)
26
Enrollment
20
Locations
2
Arms
26
Duration (Months)
1.3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To see how well enzastaurin in combination with irinotecan and cetuximab works versus irinotecan and cetuximab in participants who have progressed within 3 months.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
26 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Phase 2 Study of Irinotecan Plus Cetuximab With or Without Enzastaurin in Patients With Recurrent Colorectal Cancer
Study Start Date :
Mar 1, 2007
Actual Primary Completion Date :
May 1, 2009
Actual Study Completion Date :
May 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: enzastaurin + irinotecan + cetuximab

Drug: enzastaurin
1125 milligrams (mg) loading dose, then 500 mg orally, daily, of each 21-day cycle until progressive disease
Other Names:
  • LY317615

    • Drug: irinotecan
    300 milligrams per square meter (mg/m^2) intravenously on Day 1 of each 21-day cycle until progressive disease

    Drug: cetuximab
    400 mg/m^2, intravenously on Day 1, 250 mg/m^2 on Day 8, Day 15 Cycle 1 then 250 mg/m^2, on Day 1, 8 and 15 of each cycle, intravenously 21-day cycles until progressive disease
    Active Comparator: irinotecan + cetuximab

    Drug: irinotecan
    300 milligrams per square meter (mg/m^2) intravenously on Day 1 of each 21-day cycle until progressive disease

    Drug: cetuximab
    400 mg/m^2, intravenously on Day 1, 250 mg/m^2 on Day 8, Day 15 Cycle 1 then 250 mg/m^2, on Day 1, 8 and 15 of each cycle, intravenously 21-day cycles until progressive disease

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Progression-Free Survival (PFS) at 6 Months (PFS Rate) [At 6 months from randomization]

      PFS was defined as the time from the date of study enrollment to the first date of progressive disease or death from any cause. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy. The PFS probability values were multiplied by 100 to obtain the percentage values.

    Secondary Outcome Measures

    1. Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate) [Baseline to measured progressive disease up to 13.2 months]

      Tumor response rate was defined as number of participants with overall best response of complete response (CR) or partial response (PR) over number of protocol qualified participants using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) Guidelines. CR was defined as the disappearance of all tumor lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum of LDs or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions, with no new lesions appearing. Percentage of participants = (Number of participants with overall best response of CR or PR/Number of protocol qualified participants) x 100.

    2. Duration of Response [Time of response to progressive disease up to 13.2 months]

      The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of disease progression or death from any cause. According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, CR was defined as the disappearance of all tumor lesions and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum of LDs or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions, with no new lesions appearing. For participants who died, the duration of response was censored at death. For participants still alive, duration of response was censored at the last visit with adequate assessment.

    3. Overall Survival (OS) [Randomization to date of death from any cause up to 21.9 months]

      OS was defined as the time in months from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last contact date.

    4. Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate) [Baseline to disease progression (up to 13.2 months)]

      The overall disease control rate for each treatment arm was calculated as percent of participants with overall response of complete response (CR), partial response (PR) or stable disease (SD) over number of protocol qualified population. According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, CR was defined as the disappearance of all tumor lesions, PR was defined as at least a 30% decrease in sum of longest diameter (LD) of target lesions, progressive disease (PD) was defined as at least 20% increase in sum of LD of target lesions, and SD was defined as small changes that did not meet above criteria. Percentage of participants = (Number of participants with overall best response of CR, PR, or SD/Number of protocol qualified participants) x 100.

    5. Number of Participants With Adverse Events (AEs) or Who Died [Baseline to study completion (Cycle 31.5 [21 days/cycle] and 30-day safety follow-up)]

      Clinically significant events were defined as serious and other non-serious AEs. Participants who died due to progressive disease (PD) or and adverse events (AEs) while on treatment and or died during the 30 day post-treatment are included. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    Participants are eligible to be included in the study only if they meet all of the following criteria:

    1. Histologic diagnosis of colorectal cancer.

    2. Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) performance status schedule.

    3. Have had documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0; Therasse et al. 2000) within 3 months after receiving 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab as first-line therapy for locally advanced or metastatic disease, or within 6 months after receiving FOLFOX with or without bevacizumab in the adjuvant setting.

    4. Standard radiation therapy for rectal cancer is allowed. Participants must have recovered from the toxic effects (except for alopecia) of the treatment prior to study enrollment. Prior radiotherapy must be completed 4 weeks before study entry. Lesions that have been radiated in the advanced setting cannot be included as sites of measurable disease unless clear tumor progression has been documented in these lesions since the end of radiation therapy.

    5. At least one uni-dimensionally measurable lesion meeting RECIST v1.0 guidelines (at least 10 millimeters [mm] in longest diameter by spiral computerized tomography (CT) scan, or at least 20 mm by standard techniques). Positron emission tomography (PET) scans and ultrasounds may not be used.

    Exclusion Criteria:
    Participants will be excluded from the study if they meet any of the following criteria:

    1. Have received treatment within the last 4 weeks with a drug that has not received regulatory approval for any indication at the time of study entry.

    2. Have previously completed or withdrawn from this study or any other study investigating enzastaurin, irinotecan, or cetuximab.

    3. Have a serious concomitant systemic disorder [such as active infection including human immunodeficiency virus (HIV), or cardiac disease] that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol.

    4. Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV.

    5. Have a prior malignancy (other than colorectal cancer, or adequately treated carcinoma in-situ of the cervix or nonmelanoma skin cancer), unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Participants with a history of low grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Casa Grande Arizona United States 85222
    2 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tucson Arizona United States 85724
    3 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Los Angeles California United States 90033
    4 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Palm Springs California United States 92262
    5 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Washington District of Columbia United States 20007
    6 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Orlando Florida United States 32806
    7 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Atlanta Georgia United States 30309
    8 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Arlington Heights Illinois United States 60005
    9 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Chicago Illinois United States 60611
    10 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Indianapolis Indiana United States 46237
    11 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Louisville Kentucky United States 40202
    12 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Shreveport Louisiana United States 71101
    13 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Baltimore Maryland United States 21229
    14 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Detroit Michigan United States 48202
    15 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Kalamazoo Michigan United States 49048
    16 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Robbinsdale Minnesota United States 55422
    17 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Omaha Nebraska United States 68131
    18 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Valhalla New York United States 10595
    19 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Fort Worth Texas United States 76104
    20 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Lubbock Texas United States 79410

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours,EST), Eli Lilly and Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00437268
    Other Study ID Numbers:
    • 10538
    • H6Q-MC-S018
    First Posted:
    Feb 19, 2007
    Last Update Posted:
    Jul 21, 2020
    Last Verified:
    Jul 1, 2020
    Additional relevant MeSH terms:
    Colorectal Neoplasms
    Irinotecan
    Cetuximab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Participant flow reports those participants who discontinued from study drug.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 milligrams per square meter (mg/m^2), intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 of Cycle 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Period Title: Overall Study
    STARTED 13 13
    Received at Least 1 Dose of Study Drug 13 13
    Protocol Qualified (PQ) Participant 13 12
    COMPLETED 0 0
    NOT COMPLETED 13 13

    Baseline Characteristics

    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab Total
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Total of all reporting groups
    Overall Participants 13 13 26
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    52.5
    (12.45)
    59.5
    (10.28)
    56.0
    (11.75)
    Sex: Female, Male (Count of Participants)
    Female
    9
    69.2%
    9
    69.2%
    18
    69.2%
    Male
    4
    30.8%
    4
    30.8%
    8
    30.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    4
    30.8%
    3
    23.1%
    7
    26.9%
    Not Hispanic or Latino
    9
    69.2%
    10
    76.9%
    19
    73.1%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    White
    5
    38.5%
    10
    76.9%
    15
    57.7%
    Black or African American
    2
    15.4%
    0
    0%
    2
    7.7%
    Asian
    2
    15.4%
    0
    0%
    2
    7.7%
    Unknown or Not Reported
    4
    30.8%
    3
    23.1%
    7
    26.9%
    Region of Enrollment (Count of Participants)
    United States
    13
    100%
    13
    100%
    26
    100%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
    0 - Fully Active
    4
    30.8%
    6
    46.2%
    10
    38.5%
    1 - Ambulatory, Restricted Strenuous Activity
    9
    69.2%
    7
    53.8%
    16
    61.5%
    Adjuvant Therapy Status (Count of Participants)
    Yes
    7
    53.8%
    5
    38.5%
    12
    46.2%
    No
    6
    46.2%
    8
    61.5%
    14
    53.8%
    Basis for Initial Diagnosis (Count of Participants)
    Histopathologic
    10
    76.9%
    13
    100%
    23
    88.5%
    Cytologic
    3
    23.1%
    0
    0%
    3
    11.5%
    Stage of Disease at Initial Diagnosis (Count of Participants)
    Stage IIB
    1
    7.7%
    0
    0%
    1
    3.8%
    Stage IIIB
    1
    7.7%
    0
    0%
    1
    3.8%
    Stage IIIC
    0
    0%
    2
    15.4%
    2
    7.7%
    Stage IV
    11
    84.6%
    11
    84.6%
    22
    84.6%
    Disease Type at Initial Diagnosis (Count of Participants)
    Adenocarcinoma
    12
    92.3%
    10
    76.9%
    22
    84.6%
    Mucinous Adenocarcinoma
    1
    7.7%
    2
    15.4%
    3
    11.5%
    Other
    0
    0%
    1
    7.7%
    1
    3.8%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With Progression-Free Survival (PFS) at 6 Months (PFS Rate)
    Description PFS was defined as the time from the date of study enrollment to the first date of progressive disease or death from any cause. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy. The PFS probability values were multiplied by 100 to obtain the percentage values.
    Time Frame At 6 months from randomization

    Outcome Measure Data

    Analysis Population Description
    Protocol qualified population: All randomized participants who received at least 1 dose of study drug and did not develop a severe infusion reaction to cetuximab after the first dose. Participants censored: Irinotecan +Cetuximab+Enzastaurin = 1; Irinotecan +Cetuximab =2.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Measure Participants 13 12
    Number (95% Confidence Interval) [percentage of participants]
    26
    200%
    23
    176.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzastaurin+Irinotecan+Cetuximab, Irinotecan+Cetuximab
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.431
    Comments The type 1 error rate was set at 0.20
    Method Log Rank
    Comments
    2. Secondary Outcome
    Title Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate)
    Description Tumor response rate was defined as number of participants with overall best response of complete response (CR) or partial response (PR) over number of protocol qualified participants using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) Guidelines. CR was defined as the disappearance of all tumor lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum of LDs or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions, with no new lesions appearing. Percentage of participants = (Number of participants with overall best response of CR or PR/Number of protocol qualified participants) x 100.
    Time Frame Baseline to measured progressive disease up to 13.2 months

    Outcome Measure Data

    Analysis Population Description
    Protocol qualified population: All randomized participants who received at least 1 dose of study drug and did not develop a severe infusion reaction to cetuximab after the first dose.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 milligrams per square meter (mg/m^2), intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 of Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Measure Participants 13 12
    Number (95% Confidence Interval) [percentage of participants]
    7.7
    59.2%
    16.7
    128.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzastaurin+Irinotecan+Cetuximab, Irinotecan+Cetuximab
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.593
    Comments
    Method Fisher Exact
    Comments
    3. Secondary Outcome
    Title Duration of Response
    Description The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of disease progression or death from any cause. According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, CR was defined as the disappearance of all tumor lesions and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum of LDs or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions, with no new lesions appearing. For participants who died, the duration of response was censored at death. For participants still alive, duration of response was censored at the last visit with adequate assessment.
    Time Frame Time of response to progressive disease up to 13.2 months

    Outcome Measure Data

    Analysis Population Description
    Participants with a CR or PR. No participants were censored.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 milligrams per square meter (mg/m^2), intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 of Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Measure Participants 1 2
    Median (95% Confidence Interval) [months]
    6.9
    12.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzastaurin+Irinotecan+Cetuximab, Irinotecan+Cetuximab
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.157
    Comments
    Method Log Rank
    Comments
    4. Secondary Outcome
    Title Overall Survival (OS)
    Description OS was defined as the time in months from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last contact date.
    Time Frame Randomization to date of death from any cause up to 21.9 months

    Outcome Measure Data

    Analysis Population Description
    Protocol qualified population: All randomized participants who received at least 1 dose of study drug and did not develop a severe infusion reaction to cetuximab after the first dose. Censored participants: Enzastaurin+Irinotecan+Cetuximab = 4; Irinotecan+Cetuximab = 4.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Measure Participants 13 12
    Median (95% Confidence Interval) [months]
    8.5
    8.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzastaurin+Irinotecan+Cetuximab, Irinotecan+Cetuximab
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.539
    Comments Kaplan-Meier analysis was used for statistical analysis.
    Method Log Rank
    Comments
    5. Secondary Outcome
    Title Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate)
    Description The overall disease control rate for each treatment arm was calculated as percent of participants with overall response of complete response (CR), partial response (PR) or stable disease (SD) over number of protocol qualified population. According to the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, CR was defined as the disappearance of all tumor lesions, PR was defined as at least a 30% decrease in sum of longest diameter (LD) of target lesions, progressive disease (PD) was defined as at least 20% increase in sum of LD of target lesions, and SD was defined as small changes that did not meet above criteria. Percentage of participants = (Number of participants with overall best response of CR, PR, or SD/Number of protocol qualified participants) x 100.
    Time Frame Baseline to disease progression (up to 13.2 months)

    Outcome Measure Data

    Analysis Population Description
    Protocol qualified population: All randomized participants who received at least 1 dose of study drug and did not develop a severe infusion reaction to cetuximab after the first dose.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Measure Participants 13 12
    Number (95% Confidence Interval) [percentage of participants]
    38.5
    296.2%
    50.0
    384.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzastaurin+Irinotecan+Cetuximab, Irinotecan+Cetuximab
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.695
    Comments
    Method Fisher Exact
    Comments
    6. Secondary Outcome
    Title Number of Participants With Adverse Events (AEs) or Who Died
    Description Clinically significant events were defined as serious and other non-serious AEs. Participants who died due to progressive disease (PD) or and adverse events (AEs) while on treatment and or died during the 30 day post-treatment are included. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
    Time Frame Baseline to study completion (Cycle 31.5 [21 days/cycle] and 30-day safety follow-up)

    Outcome Measure Data

    Analysis Population Description
    The safety population included all randomized and treated participants.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    Measure Participants 13 13
    Non-serious AEs
    13
    100%
    13
    100%
    Serious AEs
    8
    61.5%
    6
    46.2%
    Deaths Due to PD
    0
    0%
    0
    0%
    Deaths Due to AEs
    0
    0%
    1
    7.7%
    Deaths in 30-day follow-up
    0
    0%
    1
    7.7%

    Adverse Events

    Time Frame Baseline to study completion (Cycle 31.5 [21 days/cycle] and 30-day safety follow-up)
    Adverse Event Reporting Description Study-specific clinical outcomes due to progressive disease were not considered to be a serious adverse event (SAE) unless the investigator deemed it related to the use of the study drug.
    Arm/Group Title Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Arm/Group Description Enzastaurin: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1, then 500 mg orally, daily, of each 21-day cycle until progressive disease Irinotecan: 300 milligrams per square meter (mg/m^2), intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 of Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease Irinotecan: 300 mg/m^2 intravenously on Day 1 of each 21-day cycle until progressive disease Cetuximab: 400 mg/m^2 intravenously on Day 1, then 250 mg/m^2 on Days 8 and 15 in Cycle 1, then 250 mg/m^2 intravenously on Days 1, 8 and 15 of each 21-day cycle until progressive disease
    All Cause Mortality
    Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/13 (61.5%) 6/13 (46.2%)
    Blood and lymphatic system disorders
    Anaemia 0/13 (0%) 0 1/13 (7.7%) 1
    Febrile neutropenia 2/13 (15.4%) 2 1/13 (7.7%) 1
    Neutropenia 2/13 (15.4%) 3 0/13 (0%) 0
    Pancytopenia 0/13 (0%) 0 1/13 (7.7%) 1
    Gastrointestinal disorders
    Abdominal pain 0/13 (0%) 0 2/13 (15.4%) 2
    Ascites 1/13 (7.7%) 1 0/13 (0%) 0
    Diarrhoea 1/13 (7.7%) 1 0/13 (0%) 0
    Nausea 1/13 (7.7%) 1 0/13 (0%) 0
    Rectal haemorrhage 1/13 (7.7%) 1 0/13 (0%) 0
    Small intestinal obstruction 1/13 (7.7%) 1 1/13 (7.7%) 1
    Vomiting 1/13 (7.7%) 1 0/13 (0%) 0
    General disorders
    Fatigue 0/13 (0%) 0 1/13 (7.7%) 1
    Multi-organ failure 0/13 (0%) 0 1/13 (7.7%) 1
    Hepatobiliary disorders
    Gallbladder obstruction 0/13 (0%) 0 1/13 (7.7%) 1
    Infections and infestations
    Anorectal cellulitis 1/13 (7.7%) 1 0/13 (0%) 0
    Bacteraemia 0/13 (0%) 0 1/13 (7.7%) 1
    Clostridium difficile colitis 0/13 (0%) 0 1/13 (7.7%) 1
    Injury, poisoning and procedural complications
    Rib fracture 0/13 (0%) 0 1/13 (7.7%) 1
    Metabolism and nutrition disorders
    Dehydration 1/13 (7.7%) 1 0/13 (0%) 0
    Hyperkalaemia 1/13 (7.7%) 1 0/13 (0%) 0
    Hypoglycaemia 0/13 (0%) 0 1/13 (7.7%) 1
    Psychiatric disorders
    Mental status changes 0/13 (0%) 0 1/13 (7.7%) 1
    Reproductive system and breast disorders
    Vaginal haemorrhage 1/9 (11.1%) 1 1/9 (11.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 1/13 (7.7%) 1 0/13 (0%) 0
    Vascular disorders
    Hypotension 1/13 (7.7%) 2 0/13 (0%) 0
    Other (Not Including Serious) Adverse Events
    Enzastaurin+Irinotecan+Cetuximab Irinotecan+Cetuximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/13 (100%) 13/13 (100%)
    Blood and lymphatic system disorders
    Anaemia 3/13 (23.1%) 3 4/13 (30.8%) 4
    Leukopenia 2/13 (15.4%) 2 3/13 (23.1%) 6
    Neutropenia 5/13 (38.5%) 7 5/13 (38.5%) 10
    Thrombocytopenia 1/13 (7.7%) 4 0/13 (0%) 0
    Ear and labyrinth disorders
    Ear discomfort 0/13 (0%) 0 1/13 (7.7%) 1
    Vertigo 1/13 (7.7%) 1 0/13 (0%) 0
    Eye disorders
    Erythema of eyelid 0/13 (0%) 0 1/13 (7.7%) 1
    Eye irritation 0/13 (0%) 0 1/13 (7.7%) 1
    Gastrointestinal disorders
    Abdominal discomfort 0/13 (0%) 0 1/13 (7.7%) 1
    Abdominal distension 0/13 (0%) 0 4/13 (30.8%) 4
    Abdominal pain 3/13 (23.1%) 3 6/13 (46.2%) 6
    Abdominal pain upper 0/13 (0%) 0 1/13 (7.7%) 1
    Ascites 1/13 (7.7%) 1 1/13 (7.7%) 1
    Breath odour 1/13 (7.7%) 1 0/13 (0%) 0
    Colitis 0/13 (0%) 0 1/13 (7.7%) 1
    Constipation 4/13 (30.8%) 8 2/13 (15.4%) 2
    Diarrhoea 8/13 (61.5%) 11 9/13 (69.2%) 18
    Dry mouth 4/13 (30.8%) 5 2/13 (15.4%) 2
    Dyspepsia 1/13 (7.7%) 1 0/13 (0%) 0
    Dysphagia 1/13 (7.7%) 1 0/13 (0%) 0
    Flatulence 2/13 (15.4%) 2 0/13 (0%) 0
    Haemorrhoids 2/13 (15.4%) 2 0/13 (0%) 0
    Nausea 8/13 (61.5%) 10 11/13 (84.6%) 20
    Oral pain 1/13 (7.7%) 1 0/13 (0%) 0
    Rectal haemorrhage 1/13 (7.7%) 2 2/13 (15.4%) 2
    Stomatitis 3/13 (23.1%) 3 1/13 (7.7%) 1
    Vomiting 5/13 (38.5%) 5 6/13 (46.2%) 7
    General disorders
    Asthenia 1/13 (7.7%) 1 3/13 (23.1%) 4
    Chills 1/13 (7.7%) 1 1/13 (7.7%) 1
    Cyst 0/13 (0%) 0 1/13 (7.7%) 1
    Fatigue 8/13 (61.5%) 9 9/13 (69.2%) 13
    Influenza like illness 0/13 (0%) 0 1/13 (7.7%) 1
    Non-cardiac chest pain 1/13 (7.7%) 1 0/13 (0%) 0
    Oedema peripheral 1/13 (7.7%) 2 2/13 (15.4%) 2
    Pain 1/13 (7.7%) 1 0/13 (0%) 0
    Pyrexia 2/13 (15.4%) 2 0/13 (0%) 0
    Xerosis 0/13 (0%) 0 1/13 (7.7%) 1
    Infections and infestations
    Abscess limb 0/13 (0%) 0 1/13 (7.7%) 1
    Candidiasis 0/13 (0%) 0 1/13 (7.7%) 1
    Localised infection 0/13 (0%) 0 1/13 (7.7%) 1
    Nasopharyngitis 0/13 (0%) 0 1/13 (7.7%) 1
    Rash pustular 1/13 (7.7%) 1 0/13 (0%) 0
    Rectal abscess 1/13 (7.7%) 1 0/13 (0%) 0
    Rhinitis 1/13 (7.7%) 1 0/13 (0%) 0
    Sinusitis 0/13 (0%) 0 1/13 (7.7%) 1
    Upper respiratory tract infection 0/13 (0%) 0 1/13 (7.7%) 1
    Injury, poisoning and procedural complications
    Contusion 1/13 (7.7%) 1 0/13 (0%) 0
    Sunburn 1/13 (7.7%) 1 0/13 (0%) 0
    Investigations
    Alanine aminotransferase increased 1/13 (7.7%) 1 1/13 (7.7%) 1
    Aspartate aminotransferase increased 1/13 (7.7%) 1 1/13 (7.7%) 1
    Blood alkaline phosphatase increased 2/13 (15.4%) 2 1/13 (7.7%) 1
    Blood creatinine increased 1/13 (7.7%) 1 0/13 (0%) 0
    Blood lactate dehydrogenase increased 0/13 (0%) 0 1/13 (7.7%) 1
    Blood pressure increased 0/13 (0%) 0 1/13 (7.7%) 1
    Blood urea increased 1/13 (7.7%) 1 0/13 (0%) 0
    Carcinoembryonic antigen increased 1/13 (7.7%) 1 1/13 (7.7%) 1
    Haemoglobin decreased 1/13 (7.7%) 1 0/13 (0%) 0
    Liver function test abnormal 0/13 (0%) 0 1/13 (7.7%) 2
    Neutrophil count decreased 1/13 (7.7%) 1 0/13 (0%) 0
    Platelet count decreased 0/13 (0%) 0 1/13 (7.7%) 1
    Weight decreased 2/13 (15.4%) 2 2/13 (15.4%) 2
    Weight increased 0/13 (0%) 0 1/13 (7.7%) 1
    Metabolism and nutrition disorders
    Decreased appetite 4/13 (30.8%) 4 6/13 (46.2%) 7
    Dehydration 1/13 (7.7%) 1 3/13 (23.1%) 3
    Hypercalcaemia 1/13 (7.7%) 1 0/13 (0%) 0
    Hyperkalaemia 1/13 (7.7%) 4 0/13 (0%) 0
    Hypoalbuminaemia 0/13 (0%) 0 1/13 (7.7%) 1
    Hypocalcaemia 0/13 (0%) 0 1/13 (7.7%) 1
    Hypoglycaemia 1/13 (7.7%) 1 0/13 (0%) 0
    Hypokalaemia 1/13 (7.7%) 1 0/13 (0%) 0
    Hypomagnesaemia 2/13 (15.4%) 3 4/13 (30.8%) 9
    Hyponatraemia 1/13 (7.7%) 1 0/13 (0%) 0
    Iron deficiency 0/13 (0%) 0 1/13 (7.7%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/13 (7.7%) 1 0/13 (0%) 0
    Back pain 4/13 (30.8%) 4 4/13 (30.8%) 4
    Flank pain 0/13 (0%) 0 2/13 (15.4%) 2
    Musculoskeletal chest pain 0/13 (0%) 0 1/13 (7.7%) 1
    Musculoskeletal pain 0/13 (0%) 0 1/13 (7.7%) 1
    Pain in extremity 0/13 (0%) 0 1/13 (7.7%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma 0/13 (0%) 0 1/13 (7.7%) 1
    Oral neoplasm benign 0/13 (0%) 0 1/13 (7.7%) 1
    Skin papilloma 0/13 (0%) 0 1/13 (7.7%) 1
    Nervous system disorders
    Dizziness 5/13 (38.5%) 5 2/13 (15.4%) 2
    Headache 1/13 (7.7%) 1 2/13 (15.4%) 2
    Peripheral sensory neuropathy 2/13 (15.4%) 2 0/13 (0%) 0
    Psychiatric disorders
    Anxiety 0/13 (0%) 0 1/13 (7.7%) 1
    Depression 1/13 (7.7%) 1 0/13 (0%) 0
    Insomnia 1/13 (7.7%) 1 1/13 (7.7%) 1
    Renal and urinary disorders
    Chromaturia 3/13 (23.1%) 3 0/13 (0%) 0
    Haematuria 1/13 (7.7%) 1 0/13 (0%) 0
    Pollakiuria 0/13 (0%) 0 1/13 (7.7%) 1
    Urinary bladder haemorrhage 1/13 (7.7%) 1 0/13 (0%) 0
    Urinary retention 0/13 (0%) 0 1/13 (7.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Cough 1/13 (7.7%) 1 0/13 (0%) 0
    Dyspnoea 1/13 (7.7%) 1 1/13 (7.7%) 1
    Dyspnoea exertional 0/13 (0%) 0 1/13 (7.7%) 1
    Epistaxis 2/13 (15.4%) 2 1/13 (7.7%) 1
    Hyperventilation 0/13 (0%) 0 1/13 (7.7%) 1
    Pleural effusion 1/13 (7.7%) 1 0/13 (0%) 0
    Productive cough 0/13 (0%) 0 1/13 (7.7%) 1
    Respiratory distress 1/13 (7.7%) 1 0/13 (0%) 0
    Rhinalgia 1/13 (7.7%) 2 0/13 (0%) 0
    Sinus congestion 1/13 (7.7%) 1 0/13 (0%) 0
    Skin and subcutaneous tissue disorders
    Acne 0/13 (0%) 0 1/13 (7.7%) 1
    Alopecia 4/13 (30.8%) 4 5/13 (38.5%) 5
    Dermatitis acneiform 6/13 (46.2%) 7 7/13 (53.8%) 7
    Drug eruption 2/13 (15.4%) 2 0/13 (0%) 0
    Dry skin 3/13 (23.1%) 3 2/13 (15.4%) 2
    Exfoliative rash 0/13 (0%) 0 1/13 (7.7%) 2
    Hyperhidrosis 1/13 (7.7%) 1 1/13 (7.7%) 1
    Nail disorder 0/13 (0%) 0 1/13 (7.7%) 1
    Night sweats 0/13 (0%) 0 1/13 (7.7%) 1
    Onychoclasis 0/13 (0%) 0 1/13 (7.7%) 1
    Petechiae 1/13 (7.7%) 1 0/13 (0%) 0
    Pruritus 1/13 (7.7%) 1 3/13 (23.1%) 3
    Rash 5/13 (38.5%) 9 5/13 (38.5%) 6
    Skin exfoliation 0/13 (0%) 0 1/13 (7.7%) 1
    Skin fissures 0/13 (0%) 0 1/13 (7.7%) 1
    Vascular disorders
    Hypotension 0/13 (0%) 0 1/13 (7.7%) 1

    Limitations/Caveats

    Results from other studies showed participants with mutant K-RAS tumors did not respond to Cetuximab. Due to issues with confounding of results the decision was to stop the study early.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00437268
    Other Study ID Numbers:
    • 10538
    • H6Q-MC-S018
    First Posted:
    Feb 19, 2007
    Last Update Posted:
    Jul 21, 2020
    Last Verified:
    Jul 1, 2020