Colorectal Cancer, Colorectal Carcinoma, Colorectal Tumor
Conditions
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.
Interventions
DRUGenzastaurin
1125 milligrams (mg) loading dose, then 500 mg orally, daily, of each 21-day cycle until progressive disease
DRUGirinotecan
300 milligrams per square meter (mg/m\^2) intravenously on Day 1 of each 21-day cycle until progressive disease
DRUGcetuximab
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
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
Participant flow reports those participants who discontinued from study drug.
Participants by arm
| Arm | Count |
|---|---|
| Enzastaurin+Irinotecan+Cetuximab 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 | 13 |
| Irinotecan+Cetuximab 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 | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progressive disease | 9 | 9 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Enzastaurin+Irinotecan+Cetuximab | Irinotecan+Cetuximab | Total |
|---|---|---|---|
| Adjuvant Therapy Status No | 6 Participants | 8 Participants | 14 Participants |
| Adjuvant Therapy Status Yes | 7 Participants | 5 Participants | 12 Participants |
| Age, Continuous | 52.5 years STANDARD_DEVIATION 12.45 | 59.5 years STANDARD_DEVIATION 10.28 | 56.0 years STANDARD_DEVIATION 11.75 |
| Basis for Initial Diagnosis Cytologic | 3 Participants | 0 Participants | 3 Participants |
| Basis for Initial Diagnosis Histopathologic | 10 Participants | 13 Participants | 23 Participants |
| Disease Type at Initial Diagnosis Adenocarcinoma | 12 Participants | 10 Participants | 22 Participants |
| Disease Type at Initial Diagnosis Mucinous Adenocarcinoma | 1 Participants | 2 Participants | 3 Participants |
| Disease Type at Initial Diagnosis Other | 0 Participants | 1 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - Fully Active | 4 Participants | 6 Participants | 10 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 - Ambulatory, Restricted Strenuous Activity | 9 Participants | 7 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 10 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 10 Participants | 15 Participants |
| Region of Enrollment United States | 13 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
| Stage of Disease at Initial Diagnosis Stage IIB | 1 Participants | 0 Participants | 1 Participants |
| Stage of Disease at Initial Diagnosis Stage IIIB | 1 Participants | 0 Participants | 1 Participants |
| Stage of Disease at Initial Diagnosis Stage IIIC | 0 Participants | 2 Participants | 2 Participants |
| Stage of Disease at Initial Diagnosis Stage IV | 11 Participants | 11 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 13 / 13 |
| serious Total, serious adverse events | 8 / 13 | 6 / 13 |
Outcome results
Primary
Percentage of Participants With Progression-Free Survival (PFS) at 6 Months (PFS Rate)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin+Irinotecan+Cetuximab | Percentage of Participants With Progression-Free Survival (PFS) at 6 Months (PFS Rate) | 26 percentage of participants |
| Irinotecan+Cetuximab | Percentage of Participants With Progression-Free Survival (PFS) at 6 Months (PFS Rate) | 23 percentage of participants |
p-value: 0.431Log Rank
Secondary
Duration of Response
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
Population: Participants with a CR or PR. No participants were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin+Irinotecan+Cetuximab | Duration of Response | 6.9 months |
| Irinotecan+Cetuximab | Duration of Response | 12.6 months |
p-value: 0.157Log Rank
Secondary
Number of Participants With Adverse Events (AEs) or Who Died
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)
Population: The safety population included all randomized and treated participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzastaurin+Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Serious AEs | 8 Participants |
| Enzastaurin+Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Deaths Due to AEs | 0 Participants |
| Enzastaurin+Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Deaths Due to PD | 0 Participants |
| Enzastaurin+Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Deaths in 30-day follow-up | 0 Participants |
| Enzastaurin+Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Non-serious AEs | 13 Participants |
| Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Deaths in 30-day follow-up | 1 Participants |
| Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Non-serious AEs | 13 Participants |
| Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Serious AEs | 6 Participants |
| Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Deaths Due to PD | 0 Participants |
| Irinotecan+Cetuximab | Number of Participants With Adverse Events (AEs) or Who Died | Deaths Due to AEs | 1 Participants |
Secondary
Overall Survival (OS)
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin+Irinotecan+Cetuximab | Overall Survival (OS) | 8.5 months |
| Irinotecan+Cetuximab | Overall Survival (OS) | 8.0 months |
p-value: 0.539Log Rank
Secondary
Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate)
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin+Irinotecan+Cetuximab | Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate) | 38.5 percentage of participants |
| Irinotecan+Cetuximab | Percentage of Participants With a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate) | 50.0 percentage of participants |
p-value: 0.695Fisher Exact
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Enzastaurin+Irinotecan+Cetuximab | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate) | 7.7 percentage of participants |
| Irinotecan+Cetuximab | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Tumor Response Rate) | 16.7 percentage of participants |
p-value: 0.593Fisher Exact