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

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

Official Title
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A Randomized Phase 2 Study of Irinotecan Plus Cetuximab With or Without Enzastaurin in Patients With Recurrent Colorectal Cancer

Conditions
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Colorectal Cancer, Colorectal Carcinoma, Colorectal Tumor

Intervention / Treatment
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* Drug: enzastaurin
* Drug: irinotecan
* Drug: cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if they meet all of the following criteria: Histologic diagnosis of colorectal cancer. Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) performance status schedule. 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. 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. 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: 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. Have previously completed or withdrawn from this study or any other study investigating enzastaurin, irinotecan, or cetuximab. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: enzastaurin + irinotecan + cetuximab<br> | Drug: enzastaurin<br>* 1125 milligrams (mg) loading dose, then 500 mg orally, daily, of each 21-day cycle until progressive disease<br>* Other names: LY317615;Drug: irinotecan<br>* 300 milligrams per square meter (mg/m^2) intravenously on Day 1 of each 21-day cycle until progressive disease<br>Drug: cetuximab<br>* 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<br>|
| Active Comparator: irinotecan + cetuximab<br> | Drug: irinotecan<br>* 300 milligrams per square meter (mg/m^2) intravenously on Day 1 of each 21-day cycle until progressive disease<br>Drug: cetuximab<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At 6 months from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to measured progressive disease up to 13.2 months | 
| 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 of response to progressive disease up to 13.2 months | 
| 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. | Randomization to date of death from any cause up to 21.9 months | 
| 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. | Baseline to disease progression (up to 13.2 months) | 
| 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. | Baseline to study completion (Cycle 31.5 [21 days/cycle] and 30-day safety follow-up) |