Colorectal Cancer
Conditions
Keywords
GSI, Gilead, Gilead Sciences, GS-6624, Colorectal Cancer, KRAS, Oncology, monoclonal antibody
Brief summary
The primary objective of this study is to compare the additive efficacy of SIM versus placebo in combination with leucovorin (folinic acid), irinotecan, and fluorouracil (FOLFIRI) as measured by improvement in progression-free survival (PFS) in participants with metastatic KRAS mutant colorectal adenocarcinoma who have progressed following a first-line oxaliplatin- and fluoropyrimidine-containing regimen.
Interventions
BIOLOGICALSimtuzumab
SIM administered via intravenous infusion over 30 minutes
DRUGPlacebo to match SIM
Placebo to match SIM administered via intravenous infusion over 30 minutes
DRUGLeucovorin
l-Leucovorin 200 mg/m\^2 or dl-leucovorin 400 mg/m\^2 administered via intravenous infusion over 2 hours
DRUGIrinotecan
Irinotecan 180 mg/m\^2 administered via intravenous infusion over 90 minutes
DRUGFluorouracil
Fluorouracil 400 mg/m\^2 administered via intravenous bolus and 2400 mg/m\^2 via intravenous infusion over 46 hours
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Metastatic colorectal carcinoma with KRAS mutation * Received first line therapy and discontinued part or all of first line therapy * Estimated life expectancy \> 3 months * Stage IV disease * Eastern Cooperative Oncology Group (ECOG) performance status: 0-2 * Adequate hepatic and hematologic function * No major operations within 4 weeks prior to treatment start
Exclusion criteria
* More than 1 prior chemotherapy regimen for Stage 4 colorectal cancer * Experimental medical treatment within 30 days prior to study entry * Known or suspected cerebral metastases * History or presence of any form of cancer, other that colorectal cancer, within the 3 years prior to enrollment * Known dihydropyrimidine dehydrogenase-deficiency (special screening not required) * Subjects with angina pectoris, poorly controlled ventricular arrhythmias (does not include asymptomatic, occasional premature ventricular contractions), history of clinically significant coronary heart disease or cardiomyopathy, or electrocardiogram (ECG) abnormalities consistent with ischemia * Uncontrolled hypertension (seated systolic blood pressure \> 180 mm Hg or diastolic blood pressure \> 110 mm Hg) at screening * Clinically active liver disease, including active hepatitis (any etiology) or cirrhosis * Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy) within 21 days prior to randomization * Prior irinotecan therapy for metastatic disease is not permitted * Systemic fungal, bacterial, viral, or other infection Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Randomization up to 27 months | The PFS was defined as the time from the date of randomization to the earliest event time of: a) death regardless of cause, or b) first indication of disease progression. PFS was analyzed using Kaplan-Meier (KM) estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization up to 33 months | The OS is measured as time from date of randomization to death regardless of cause. The OS was analyzed using KM estimates. |
| Objective Response Rate (ORR) | Randomization up to 27 months | Objective response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). The ORR was defined as the percentage of participants who achieved a CR or PR. |
Countries
France, Germany, Italy, Poland, Russia, Spain, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, Russia, and Europe. The first participant was screened on 15 December 2011. The last study visit occurred on 27 February 2015.
Pre-assignment details
358 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| FOLFIRI + SIM 700 mg (Part A) Participants received SIM 700 mg via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycles for approximately 10 months. | 11 |
| FOLFIRI + Placebo (Part B) Participants received placebo to match SIM via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycles for approximately 27 months. | 84 |
| FOLFIRI + SIM 200 mg (Part B) Participants received SIM 200 mg via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycles for approximately 21 months. | 86 |
| FOLFIRI + SIM 700 mg (Part B) Participants received SIM 700 mg via intravenous infusion followed by FOLFIRI via intravenous infusion on Days 1 and 15 of each 28-day treatment cycles for approximately 19 months. | 85 |
| Total | 266 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 6 | 4 |
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Disease Progression | 9 | 61 | 65 | 70 |
| Overall Study | Investigator Discretion | 1 | 4 | 2 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 1 | 0 |
| Overall Study | Study Discontinued by Sponsor | 0 | 7 | 5 | 3 |
| Overall Study | Subject Request | 1 | 3 | 4 | 2 |
| Overall Study | Subject Withdrew Consent | 0 | 5 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | FOLFIRI + SIM 700 mg (Part A) | FOLFIRI + Placebo (Part B) | FOLFIRI + SIM 200 mg (Part B) | FOLFIRI + SIM 700 mg (Part B) |
|---|---|---|---|---|---|
| Age, Customized ≥ 65 years | 91 Participants | 4 Participants | 23 Participants | 36 Participants | 28 Participants |
| Age, Customized Between 18 and 65 years | 169 Participants | 7 Participants | 57 Participants | 49 Participants | 56 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic/Latino | 23 Participants | 3 Participants | 5 Participants | 7 Participants | 8 Participants |
| Race/Ethnicity, Customized Ethnicity Non-Hispanic/Latino | 226 Participants | 8 Participants | 70 Participants | 75 Participants | 73 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 11 Participants | 0 Participants | 5 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 8 Participants | 1 Participants | 1 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 22 Participants | 2 Participants | 8 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Missing | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 7 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 220 Participants | 8 Participants | 67 Participants | 74 Participants | 71 Participants |
| Region of Enrollment France | 8 Participants | 0 Participants | 4 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Germany | 16 Participants | 0 Participants | 5 Participants | 4 Participants | 7 Participants |
| Region of Enrollment Italy | 18 Participants | 0 Participants | 7 Participants | 7 Participants | 4 Participants |
| Region of Enrollment Poland | 17 Participants | 0 Participants | 5 Participants | 7 Participants | 5 Participants |
| Region of Enrollment Russia | 29 Participants | 0 Participants | 9 Participants | 7 Participants | 13 Participants |
| Region of Enrollment Spain | 30 Participants | 0 Participants | 9 Participants | 13 Participants | 8 Participants |
| Region of Enrollment United States | 148 Participants | 11 Participants | 45 Participants | 47 Participants | 45 Participants |
| Sex: Female, Male Female | 127 Participants | 6 Participants | 41 Participants | 32 Participants | 48 Participants |
| Sex: Female, Male Male | 133 Participants | 5 Participants | 39 Participants | 53 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 11 | 76 / 80 | 80 / 85 | 79 / 84 |
| serious Total, serious adverse events | 4 / 11 | 27 / 80 | 24 / 85 | 17 / 84 |
Outcome results
Primary
Progression Free Survival (PFS)
The PFS was defined as the time from the date of randomization to the earliest event time of: a) death regardless of cause, or b) first indication of disease progression. PFS was analyzed using Kaplan-Meier (KM) estimates.
Time frame: Randomization up to 27 months
Population: Full Analysis Set included participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRI + SIM 700 mg (Part A) | Progression Free Survival (PFS) | 5.7 months |
| FOLFIRI + Placebo (Part B) | Progression Free Survival (PFS) | 5.8 months |
| FOLFIRI + SIM 200 mg (Part B) | Progression Free Survival (PFS) | 5.4 months |
| FOLFIRI + SIM 700 mg (Part B) | Progression Free Survival (PFS) | 5.5 months |
Comparison: The null hypothesis was that the hazard ratio (HR) equals to 1 between SIM treatment arm and placebo, while the alternative hypothesis was that HR was less than 1.~The HR (95% confidence interval \[CI\]) and p-value (for comparison between SIM treatment arm and placebo) were based on two-sided log-rank test, stratified based on the 2-level Eastern Cooperative Oncology Group (ECOG) performance status (0 or \> 0) at randomization.p-value: 0.039595% CI: [1.01, 2.06]Log Rank
Comparison: The null hypothesis was that the HR equals to 1 between SIM treatment arm and placebo, while the alternative hypothesis was that HR was less than 1.~The HR (95% CI) and p-value (for comparison between SIM treatment arm and placebo) were based on two-sided log-rank test, stratified based on the 2-level ECOG performance status (0 or \> 0) at randomization.p-value: 0.104295% CI: [0.92, 1.89]Log Rank
Secondary
Objective Response Rate (ORR)
Objective response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (version 1.1) as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). The ORR was defined as the percentage of participants who achieved a CR or PR.
Time frame: Randomization up to 27 months
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFIRI + SIM 700 mg (Part A) | Objective Response Rate (ORR) | 9.1 percentage of participants |
| FOLFIRI + Placebo (Part B) | Objective Response Rate (ORR) | 10.0 percentage of participants |
| FOLFIRI + SIM 200 mg (Part B) | Objective Response Rate (ORR) | 5.9 percentage of participants |
| FOLFIRI + SIM 700 mg (Part B) | Objective Response Rate (ORR) | 11.9 percentage of participants |
Secondary
Overall Survival (OS)
The OS is measured as time from date of randomization to death regardless of cause. The OS was analyzed using KM estimates.
Time frame: Randomization up to 33 months
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRI + SIM 700 mg (Part A) | Overall Survival (OS) | 9.8 months |
| FOLFIRI + Placebo (Part B) | Overall Survival (OS) | 16.3 months |
| FOLFIRI + SIM 200 mg (Part B) | Overall Survival (OS) | 10.5 months |
| FOLFIRI + SIM 700 mg (Part B) | Overall Survival (OS) | 11.4 months |