Colon Cancer, Rectal Cancer
Conditions
Keywords
Colonic Neoplasms, Rectal Neoplasms, Adenocarcinoma, Antibodies, Monoclonal
Brief summary
The purpose of this study is to determine if participants with metastatic colorectal cancer live longer without their cancer progressing when treated with standard chemotherapy, standard chemotherapy plus ramucirumab, or standard chemotherapy plus icrucumab.
Detailed description
The purpose of this study is to evaluate the progression-free survival (PFS) in participants with metastatic colorectal cancer when treated with 1 of 3 modified FOLFOX-6 (folinic acid \[FA\] + fluorouracil \[5-FU\] + oxaliplatin \[mFOLFOX-6\])-based regimens, as second-line therapy. During 2010, there has been an identified shortage of injectable folinic acid (FA) in the United States. Levo-folinic acid (LFA) will be allowed as a substitute for FA in the mFOLFOX-6 chemotherapy regimen in circumstances in which FA is not available, to facilitate continuity of participant care.
Interventions
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
* Disease progression on an irinotecan-based first-line chemotherapy regimen (ie FOLFIRI or CAPIRI \[capecitabine + irinotecan\], with or without bevacizumab) * Age ≥ 18 years * Life expectancy of ≥ 6 months * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 at study entry * Agrees to adequate contraception during the study period and for 12 weeks after the last dose of study medication * Provided signed informed consent
Exclusion criteria
* Has received prior oxaliplatin-based chemotherapy for locally advanced unresectable or metastatic Colorectal Cancer (CRC) (Prior oxaliplatin-based adjuvant chemotherapy is allowed if the last dose of oxaliplatin was administered \> 12 months prior to randomization) * Has documented and/or symptomatic brain or leptomeningeal metastases * Has an ongoing or active infection, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders * On chronic non-topical corticosteroid treatment. A participant discontinuing such treatment \> 3 months prior to randomization is eligible * Has uncontrolled or poorly controlled hypertension on a standard regimen of antihypertensive therapy * Has a concurrent active malignancy. A participant with previous history of malignancy is eligible, provided that he/she has been disease free for \> 3 years * If female, is pregnant (confirmed by serum beta human chorionic gonadotropin \[βHCG\] test) or lactating * Has received a prior autologous or allogeneic organ or tissue transplantation * Has undergone major surgery within 28 days prior to randomization * Has had a serious nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization * Has an elective or planned major surgery to be performed during the course of the trial * Has a history of inflammatory bowel disease requiring pharmacological and/or surgical intervention in the 12 months prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Baseline until Disease Progression or Death from Any Cause (Up to 95 Weeks) | PFS is defined as the time from baseline until the date of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1), or death from any cause, whichever was first. Participants who die without a reported prior progression will be considered to have progressed on the day of their death. Participants who did not progress, are lost to follow-up, or have missed two or more scheduled tumor assessments will be censored at the day of their last radiographic tumor assessment, if there are no post-baseline tumor measurements for a randomized and treated participant, the participant will be censored at the date of randomization. If death or progressive disease (PD) occurs after 2 or more missing radiographic visits, censoring will occur at the date of the last radiographic visit prior to the last visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Baseline Until Death from Any Cause (Up to 163 Weeks) | Overall survival is defined as the time from baseline to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive. |
| Duration of Response (DoR) | Criteria First Met for CR or PR until Disease Progression or Death from Any Cause (Up to 95 Weeks) | DoR was measured from the time measurement criteria are first met for Complete Response or Partial Response or until the first date that the criteria for disease progression or death from any cause. whichever is first recorded. As defined according to RECIST v1.1, CR is the disappearance of all non-nodal target lesions, and PR is the short axes of any target lymph nodes reduced to \< 10 mm and at least a 30% decrease in the sum of the diameters of target lesions including the short axes of any target lymph nodes.) |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) at Cycle 5 | Cycle 5, 1 Hour Post End of Infusion | Maximum concentration (1 hour post end of infusion, Cmax) is the concentration measured in serum. |
| Pharmacokinetics (PK): Trough Serum Concentrations (Ctrough) at Cycle 5 | Cycle 5, Prior to Infusion | Trough (prior to infusion, Ctrough) concentrations measured in serum. |
| Maximum Concentration (Cmax) at Day 8 | Day 8 (cycles 1 and 5) | Maximum concentration (Cmax) is the maximum peak concentration measured in blood plasma after drug infusion. |
| Maximum Concentration (Cmax) at Day 15 | Day 15 (Cycles 1 and 5) | Cmax is the maximum peak concentration measured in blood plasma after drug infusion. |
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | Baseline until Disease Progression (Up to 95 Weeks) | The ORR is the percentage of participants with Complete Response (CR, the disappearance of target lesions and any pathological lymph nodes \[target or non-target\] taking as reference the baseline sum of diameters in response to treatment) or Partial Response (PR, at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters in response to treatment) according to RECIST v1.1 from the start of the treatment until disease progression. |
| Minimum Concentration (Cmin) at Day 4 | Day 4 (cycles 1 and 5) | Cmin is the minimum peak concentration measured in blood plasma after drug infusion. |
| Minimum Concentration (Cmin) at Day 8 | Day 8 (cycles 1 and 5) | Minimum concentration (Cmin) is the minimum peak concentration measured in blood plasma after drug infusion. |
| Minimum Concentration (Cmin) at Day 15 | Day 15 (cycles 1 and 5) | Minimum concentration (Cmin) is the minimum peak concentration measured in blood plasma after drug infusion. |
| Number of Participants With Serum Ramucirumab Antibody Assessment | 31 Weeks | A sample will be considered positive for anti-Ramucirumab antibodies if it exhibits a post-baseline antibody level exceeding the normal anti-Ramucirumab antibody level seen in healthy untreated individuals. |
| Serum Anti-Icrucumab Antibody Assessment | 31 Weeks | A sample will be considered positive for anti-icrucumab antibodies if it exhibits a post-baseline antibody level exceeding the normal anti-icrucumab antibody level seen in healthy untreated individuals. |
| Number of Participants With Adverse Events | Baseline up to 165 weeks | A summary of serious AEs (SAEs) and all other non-serious AEs regardless of causality, is located in the Reported Adverse Events module. |
| Minimum Concentration (Cmin) at Day 1 | Day 1 (cycles 1, 5, 9, and 13) | Cmin is the minimum peak concentration measured in blood plasma after drug infusion. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Completers were defined as participants who had failure event (progressive disease, death), or were off treatment and censored due to study completion.
Participants by arm
| Arm | Count |
|---|---|
| mFOLFOX-6 mFOLFOX-6: Oxaliplatin: 85 mg/m² IV Q2W
FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m² Q2W if FA is unavailable).
5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W | 49 |
| mFOLFOX-6 + Ramucirumab mFOLFOX-6 + Ramucirumab
Ramucirumab: 8 mg/kg IV Q2W
mFOLFOX-6: Oxaliplatin: 85 mg/m² IV Q2W
FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m² Q2W if FA is unavailable).
5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W | 52 |
| mFOLFOX-6 + Icrucumab mFOLFOX-6 + Icrucumab
Icrucumab: 15 mg/kg IV Q2W
mFOLFOX-6: Oxaliplatin: 85 mg/m² IV Q2W
FA: 400 mg/m² IV Q2W (or LFA: 200 mg/m2 Q2W if FA is unavailable).
5FU: 400 mg/m² bolus + 2400 mg/m² IV Q2W | 52 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Met Exclusion Criteria | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 |
| Overall Study | Withdrew Consent | 3 | 0 | 2 |
Baseline characteristics
| Characteristic | mFOLFOX-6 | mFOLFOX-6 + Ramucirumab | mFOLFOX-6 + Icrucumab | Total |
|---|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 9.23 | 59.9 years STANDARD_DEVIATION 10.95 | 58.2 years STANDARD_DEVIATION 10.15 | 59.6 years STANDARD_DEVIATION 10.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 52 Participants | 51 Participants | 152 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 5 Participants | 7 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 35 Participants | 45 Participants | 45 Participants | 125 Participants |
| Sex: Female, Male Female | 21 Participants | 21 Participants | 29 Participants | 71 Participants |
| Sex: Female, Male Male | 28 Participants | 31 Participants | 23 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 37 / 49 | 41 / 52 | 40 / 52 |
| other Total, other adverse events | 48 / 49 | 52 / 52 | 52 / 52 |
| serious Total, serious adverse events | 11 / 49 | 18 / 52 | 12 / 52 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS is defined as the time from baseline until the date of disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1), or death from any cause, whichever was first. Participants who die without a reported prior progression will be considered to have progressed on the day of their death. Participants who did not progress, are lost to follow-up, or have missed two or more scheduled tumor assessments will be censored at the day of their last radiographic tumor assessment, if there are no post-baseline tumor measurements for a randomized and treated participant, the participant will be censored at the date of randomization. If death or progressive disease (PD) occurs after 2 or more missing radiographic visits, censoring will occur at the date of the last radiographic visit prior to the last visit.
Time frame: Baseline until Disease Progression or Death from Any Cause (Up to 95 Weeks)
Population: Modified Intent-to-Treatment (mITT) population includes all the randomized participants who received at least one dose study drug. In mFOLFOX-6, mFOLFOX-6+Ramucirumab and mFOLFOX-6 + Icrucumab, there were 13, 9 and 11 censored participants, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| mFOLFOX-6 | Progression-Free Survival (PFS) | 18.4 Weeks |
| mFOLFOX-6 + Ramucirumab | Progression-Free Survival (PFS) | 21.4 Weeks |
| mFOLFOX-6 + Icrucumab | Progression-Free Survival (PFS) | 15.9 Weeks |
Secondary
Duration of Response (DoR)
DoR was measured from the time measurement criteria are first met for Complete Response or Partial Response or until the first date that the criteria for disease progression or death from any cause. whichever is first recorded. As defined according to RECIST v1.1, CR is the disappearance of all non-nodal target lesions, and PR is the short axes of any target lymph nodes reduced to \< 10 mm and at least a 30% decrease in the sum of the diameters of target lesions including the short axes of any target lymph nodes.)
Time frame: Criteria First Met for CR or PR until Disease Progression or Death from Any Cause (Up to 95 Weeks)
Population: mITT population includes all the randomized participants who received at least one dose of study drug and had evaluable baseline and post baseline DoR data. 2 participants were censored in mFOLFOX-6 arm, 2 in mFOLFOX-6 + Ramucirumab arm and 1 in mFOLFOX-6 + Icrucumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| mFOLFOX-6 | Duration of Response (DoR) | 35.6 Weeks |
| mFOLFOX-6 + Ramucirumab | Duration of Response (DoR) | NA Weeks |
| mFOLFOX-6 + Icrucumab | Duration of Response (DoR) | NA Weeks |
Secondary
Maximum Concentration (Cmax) at Day 15
Cmax is the maximum peak concentration measured in blood plasma after drug infusion.
Time frame: Day 15 (Cycles 1 and 5)
Population: Zero participants analyzed. OM entered incorrectly and no data collected to report.
Secondary
Maximum Concentration (Cmax) at Day 8
Maximum concentration (Cmax) is the maximum peak concentration measured in blood plasma after drug infusion.
Time frame: Day 8 (cycles 1 and 5)
Population: Zero participants analyzed. Outcome Measure (OM) entered incorrectly and no data collected to report.
Secondary
Minimum Concentration (Cmin) at Day 1
Cmin is the minimum peak concentration measured in blood plasma after drug infusion.
Time frame: Day 1 (cycles 1, 5, 9, and 13)
Population: Zero participants analyzed. OM entered incorrectly and no data collected to report.
Secondary
Minimum Concentration (Cmin) at Day 15
Minimum concentration (Cmin) is the minimum peak concentration measured in blood plasma after drug infusion.
Time frame: Day 15 (cycles 1 and 5)
Population: Zero participants analyzed. OM entered incorrectly and no data collected to report.
Secondary
Minimum Concentration (Cmin) at Day 4
Cmin is the minimum peak concentration measured in blood plasma after drug infusion.
Time frame: Day 4 (cycles 1 and 5)
Population: Zero participants analyzed. OM entered incorrectly and no data collected to report.
Secondary
Minimum Concentration (Cmin) at Day 8
Minimum concentration (Cmin) is the minimum peak concentration measured in blood plasma after drug infusion.
Time frame: Day 8 (cycles 1 and 5)
Population: Zero participants analyzed. OM entered incorrectly and no data collected to report.
Secondary
Number of Participants With Adverse Events
A summary of serious AEs (SAEs) and all other non-serious AEs regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline up to 165 weeks
Population: Population includes all the randomized participants who received at least one dose study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| mFOLFOX-6 | Number of Participants With Adverse Events | Any TEAE | 49 Participants |
| mFOLFOX-6 | Number of Participants With Adverse Events | Any AE leading to discontinuation (any drug) | 6 Participants |
| mFOLFOX-6 | Number of Participants With Adverse Events | Any Grade ≥3 AE | 30 Participants |
| mFOLFOX-6 | Number of Participants With Adverse Events | Any SAE | 11 Participants |
| mFOLFOX-6 + Ramucirumab | Number of Participants With Adverse Events | Any SAE | 18 Participants |
| mFOLFOX-6 + Ramucirumab | Number of Participants With Adverse Events | Any Grade ≥3 AE | 37 Participants |
| mFOLFOX-6 + Ramucirumab | Number of Participants With Adverse Events | Any AE leading to discontinuation (any drug) | 18 Participants |
| mFOLFOX-6 + Ramucirumab | Number of Participants With Adverse Events | Any TEAE | 52 Participants |
| mFOLFOX-6 + Icrucumab | Number of Participants With Adverse Events | Any AE leading to discontinuation (any drug) | 11 Participants |
| mFOLFOX-6 + Icrucumab | Number of Participants With Adverse Events | Any TEAE | 52 Participants |
| mFOLFOX-6 + Icrucumab | Number of Participants With Adverse Events | Any Grade ≥3 AE | 31 Participants |
| mFOLFOX-6 + Icrucumab | Number of Participants With Adverse Events | Any SAE | 12 Participants |
Secondary
Number of Participants With Serum Ramucirumab Antibody Assessment
A sample will be considered positive for anti-Ramucirumab antibodies if it exhibits a post-baseline antibody level exceeding the normal anti-Ramucirumab antibody level seen in healthy untreated individuals.
Time frame: 31 Weeks
Population: Participants in mFOLFOX-6 +Ramucirumab who received at least one dose of study drug and had at least 1 post treatment assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| mFOLFOX-6 | Number of Participants With Serum Ramucirumab Antibody Assessment | 0 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from baseline to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive.
Time frame: Baseline Until Death from Any Cause (Up to 163 Weeks)
Population: mITT population includes all the randomized participants who received at least one dose of study drug. In mFOLFOX-6, mFOLFOX-6 + Ramucirumab, and mFOLFOX-6 + Icrucumab there were 12, 11, and 12 censored participants, respectively.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| mFOLFOX-6 | Overall Survival (OS) | 53.6 Weeks |
| mFOLFOX-6 + Ramucirumab | Overall Survival (OS) | 41.7 Weeks |
| mFOLFOX-6 + Icrucumab | Overall Survival (OS) | 42.0 Weeks |
Secondary
Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])
The ORR is the percentage of participants with Complete Response (CR, the disappearance of target lesions and any pathological lymph nodes \[target or non-target\] taking as reference the baseline sum of diameters in response to treatment) or Partial Response (PR, at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters in response to treatment) according to RECIST v1.1 from the start of the treatment until disease progression.
Time frame: Baseline until Disease Progression (Up to 95 Weeks)
Population: mITT population includes all the randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mFOLFOX-6 | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | 14 percentage of participants |
| mFOLFOX-6 + Ramucirumab | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | 3.8 percentage of participants |
| mFOLFOX-6 + Icrucumab | Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR]) | 3.8 percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) at Cycle 5
Maximum concentration (1 hour post end of infusion, Cmax) is the concentration measured in serum.
Time frame: Cycle 5, 1 Hour Post End of Infusion
Population: All randomized participants assigned to the mFOLFOX-6 + Ramucirumab or mFOLFOX-6 + Icrucumab who received at least one dose of study drug and had evaluable ramucirumab or icrucumab PK data to calculate Cmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| mFOLFOX-6 | Pharmacokinetics (PK): Maximum Concentration (Cmax) at Cycle 5 | NA microgram/milliliter (µg/mL) | — |
| mFOLFOX-6 + Ramucirumab | Pharmacokinetics (PK): Maximum Concentration (Cmax) at Cycle 5 | 201 microgram/milliliter (µg/mL) | Geometric Coefficient of Variation 88 |
Secondary
Pharmacokinetics (PK): Trough Serum Concentrations (Ctrough) at Cycle 5
Trough (prior to infusion, Ctrough) concentrations measured in serum.
Time frame: Cycle 5, Prior to Infusion
Population: All randomized participants assigned to the mFOLFOX-6 + Ramucirumab or mFOLFOX-6 + Icrucumab who received at least one dose of study drug and had evaluable Ramucirumab or Icrucumab PK data to calculate Ctrough.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| mFOLFOX-6 | Pharmacokinetics (PK): Trough Serum Concentrations (Ctrough) at Cycle 5 | 53.6 µg/mL | Geometric Coefficient of Variation 123 |
| mFOLFOX-6 + Ramucirumab | Pharmacokinetics (PK): Trough Serum Concentrations (Ctrough) at Cycle 5 | 146 µg/mL | Geometric Coefficient of Variation 32 |
Secondary
Serum Anti-Icrucumab Antibody Assessment
A sample will be considered positive for anti-icrucumab antibodies if it exhibits a post-baseline antibody level exceeding the normal anti-icrucumab antibody level seen in healthy untreated individuals.
Time frame: 31 Weeks
Population: Zero participants analyzed. No data collected to report.