Colorectal Cancer
Conditions
Brief summary
This study will evaluate the addition of enzastaurin to 5-FU (5-fluorouracil)/LV (leucovorin) plus bevacizumab in the maintenance of best response obtained with 6 cycles of first-line therapy consisting of 5-FU/LV + oxaliplatin (FOLFOX) or 5-FU/LV + irinotecan (FOLFIRI), plus bevacizumab in patients with Metastatic Colorectal Cancer.
Interventions
DRUGEnzastaurin
1125 milligram (mg) loading dose, then 250 mg twice daily, oral up to 1 year (yr) or until progressive disease
DRUGPlacebo
oral, daily (up to 1 yr or until progressive disease)
DRUGLeucovorin (LV)
400 milligram per meter squared (mg/m\^2) intravenously (IV), Day 1 of 14 day cycle (up to 1 yr or until progressive disease)
DRUG5-fluorouracil (5-FU)
400 mg/m\^2 bolus then 2400 mg/m\^2 IV over 46 hours, Day 1 of 14 day cycle (up to 1 yr or until progressive disease)
5 milligram per kilogram (mg/kg) IV, Day 1 of 14 day cycle (up to 1 yr or until progressive disease)
Sponsors
Roche Pharma AG
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic diagnosis of locally advanced or metastatic colorectal cancer (CRC) that is not curable. The histology types to be included are adenocarcinoma, mucinous adenocarcinoma, signet ring, and undifferentiated. Patients with neuroendocrine carcinomas will be excluded. * Received 6 cycles (3 months \[12 weeks\]) of first-line therapy with FOLFOX or FOLFIRI, plus bevacizumab for metastatic CRC. Patients have received at least 5 cycles with bevacizumab. Patients who received 6 cycles of first-line therapy with FOLFOX or FOLFIRI, plus bevacizumab for recurrent CRC that has relapsed at least 12 months after completion of adjuvant therapy will also be included. All standard FOLFOX (FOLFIRI) regimens given on a biweekly schedule will be permitted; however, 21-day regimens will not be allowed. * No more than 4 weeks may pass between the end of first-line therapy (that is, Day 14 of Cycle 6) and randomization. * Documented evidence of tumor response of complete response (CR), partial response (PR), or stable disease (SD) by computed tomography (CT) scan or magnetic resonance imaging (MRI). Confirmation of response is not required.
Exclusion criteria
* Are unable to swallow tablets. * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. * Have known central nervous system metastases. * Are receiving concurrent administration of any other antitumor therapy. * Patients who have significant heart, liver, kidney, or psychiatric disease or have an active infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Randomization to measured progressive disease or death up to 17.2 months | PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of Response Evaluation Criteria in Solid Tumor (RECIST) Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization up to 22.8 months | OS was the duration from enrollment to death due to any cause. For participants who are alive, OS is censored at the last contact. |
| Number of Participants With Adverse Events (AEs) | Randomization up to 17.2 months | A summary of serious and all other non-serious AEs is located in the Reported Adverse Event module. |
| Overall Survival (OS) From Start of First Line Therapy | Start of first line therapy (approximately 3 months prior to randomization) to date of death from any cause up to 27 months post randomization | OS was the duration from first line therapy to death due to any cause. For participants who are alive, OS is censored at the last contact. |
| PFS From Start of First Line Therapy | Start of first line therapy to measured progressive disease or death up to 24 months | PFS was defined as the time from first line therapy to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of RECIST Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause. |
Countries
Austria, France, Germany, Italy, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Enzastaurin + 5-FU/LV + Bev Enzastaurin: Loading dose of 1125 mg orally, 3 times during Day 1 of Cycle 1 (14-day cycle); 500 mg orally, twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles.
LV: 400 mg/m\^2 IV on Day 1 of each 14-day cycle, followed by 5-FU 400 mg/m\^2 IV bolus then 2400 mg/m\^2 IV over 46 hours, plus Bev: 5 mg/kg IV.
First-line therapy for metastatic CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-FU, and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev. | 58 |
| Placebo + 5-FU/LV + Bev Placebo: administered orally 3 times during Day 1 of Cycle 1 (14 day cycle); placebo administered orally twice daily on Day 2 to Day 14 of Cycle 1 and all subsequent cycles.
Leucovorin (LV): 400 mg/m\^2 administered by IV on Day 1 of each 14 day cycle, followed by 5-fluorouracil (5-FU) 400 mg/m\^2 IV bolus then 2400 mg/m\^2 IV over 46 hours, plus Bevacizumab (Bev): 5 milligrams/kilogram (mg/kg) IV.
First-line therapy for CRC received prior to entering the study: six 14-day cycles (12 weeks) folinic acid, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX) or folinic acid, 5-FU, and irinotecan (FOLFIRI), plus Bev. | 59 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Entry Criteria Not Met | 0 | 2 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Progressive Disease | 26 | 24 |
| Overall Study | Randomized and Not Treated | 1 | 1 |
| Overall Study | Sponsor Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 9 |
Baseline characteristics
| Characteristic | Placebo + 5-FU/LV + Bev | Total | Enzastaurin + 5-FU/LV + Bev |
|---|---|---|---|
| Age, Continuous | 62.49 years STANDARD_DEVIATION 9.48 | 62.52 years STANDARD_DEVIATION 10.16 | 62.55 years STANDARD_DEVIATION 10.9 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 45 Participants | 87 Participants | 42 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 13 Participants | 29 Participants | 16 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 1 Participants | 1 Participants | 0 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Colon | 54 Participants | 109 Participants | 55 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Mucinous, Not Otherwise Specified | 4 Participants | 7 Participants | 3 Participants |
| Initial Pathological Diagnosis Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized African | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 54 Participants | 109 Participants | 55 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Austria | 8 Participants | 13 Participants | 5 Participants |
| Region of Enrollment France | 3 Participants | 9 Participants | 6 Participants |
| Region of Enrollment Germany | 17 Participants | 29 Participants | 12 Participants |
| Region of Enrollment Italy | 16 Participants | 29 Participants | 13 Participants |
| Region of Enrollment United States | 15 Participants | 37 Participants | 22 Participants |
| Sex: Female, Male Female | 21 Participants | 42 Participants | 21 Participants |
| Sex: Female, Male Male | 38 Participants | 75 Participants | 37 Participants |
| Stage of Disease at Study Entry I | 0 Participants | 0 Participants | 0 Participants |
| Stage of Disease at Study Entry IIa | 1 Participants | 1 Participants | 0 Participants |
| Stage of Disease at Study Entry IIb | 0 Participants | 0 Participants | 0 Participants |
| Stage of Disease at Study Entry IIIa | 0 Participants | 0 Participants | 0 Participants |
| Stage of Disease at Study Entry IIIb | 0 Participants | 4 Participants | 4 Participants |
| Stage of Disease at Study Entry IIIc | 1 Participants | 3 Participants | 2 Participants |
| Stage of Disease at Study Entry IV | 52 Participants | 99 Participants | 47 Participants |
| Stage of Disease at Study Entry Unknown or Not Reported | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 53 / 57 | 52 / 58 |
| serious Total, serious adverse events | 15 / 57 | 11 / 58 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of Response Evaluation Criteria in Solid Tumor (RECIST) Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause.
Time frame: Randomization to measured progressive disease or death up to 17.2 months
Population: Intent-to-Treat (ITT) Population: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin + 5-FU/LV + Bev | Progression Free Survival (PFS) | 5.8 months |
| Placebo + 5FU/LV + Bev | Progression Free Survival (PFS) | 8.1 months |
p-value: 0.8956Log Rank
Secondary
Number of Participants With Adverse Events (AEs)
A summary of serious and all other non-serious AEs is located in the Reported Adverse Event module.
Time frame: Randomization up to 17.2 months
Population: Safety Population: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Enzastaurin + 5-FU/LV + Bev | Number of Participants With Adverse Events (AEs) | Serious AEs | 15 Participants |
| Enzastaurin + 5-FU/LV + Bev | Number of Participants With Adverse Events (AEs) | Other Non-Serious AEs | 53 Participants |
| Placebo + 5FU/LV + Bev | Number of Participants With Adverse Events (AEs) | Serious AEs | 11 Participants |
| Placebo + 5FU/LV + Bev | Number of Participants With Adverse Events (AEs) | Other Non-Serious AEs | 52 Participants |
Secondary
Overall Survival (OS)
OS was the duration from enrollment to death due to any cause. For participants who are alive, OS is censored at the last contact.
Time frame: Randomization up to 22.8 months
Population: ITT Population: All randomized participants; Number of participants censored was 54 in Placebo + 5-FU/LV + Bev treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin + 5-FU/LV + Bev | Overall Survival (OS) | NA months |
| Placebo + 5FU/LV + Bev | Overall Survival (OS) | NA months |
p-value: 0.9865Log Rank
Secondary
Overall Survival (OS) From Start of First Line Therapy
OS was the duration from first line therapy to death due to any cause. For participants who are alive, OS is censored at the last contact.
Time frame: Start of first line therapy (approximately 3 months prior to randomization) to date of death from any cause up to 27 months post randomization
Population: ITT Population: All randomized participants; Number of participants censored were 45 in Enzastaurin + 5-FU/LV + Bev treatment group and 54 in Placebo + 5-FU/LV + Bev treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin + 5-FU/LV + Bev | Overall Survival (OS) From Start of First Line Therapy | 20.0 months |
| Placebo + 5FU/LV + Bev | Overall Survival (OS) From Start of First Line Therapy | NA months |
Secondary
PFS From Start of First Line Therapy
PFS was defined as the time from first line therapy to the first observation of disease progression or death due to any cause. Progressive disease was determined using a modified version of RECIST Assessment and was defined as at least a 20% increase in sum of longest diameter of target lesions. Time to disease progression was censored at the date of death if death was due to other cause.
Time frame: Start of first line therapy to measured progressive disease or death up to 24 months
Population: ITT Population: All randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enzastaurin + 5-FU/LV + Bev | PFS From Start of First Line Therapy | 8.9 months |
| Placebo + 5FU/LV + Bev | PFS From Start of First Line Therapy | 11.3 months |