Metastatic Colorectal Cancer
Conditions
Keywords
Antibodies, Monoclonal, Colorectal Neoplasms
Brief summary
The purpose of this study is to determine if IMC-11F8 in combination with chemotherapy is effective in treating colorectal cancer (CRC).
Detailed description
The purpose of this study is to evaluate the anti-tumor activity (best overall response) of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody IMC-11F8 administered in combination with mFOLFOX-6 chemotherapy regimen in treatment-naive, locally-advanced or metastatic CRC participants.
Interventions
BIOLOGICALIMC-11F8 (necitumumab)
IMC-11F8 800 milligrams (mg) intravenous (IV) infusion over 50 minutes on Day 1
DRUGOxaliplatin
Oxaliplatin 85 milligrams per meter square (mg/m²) IV infusion over 2 hours on Day 1
DRUGFolinic acid (FA)
FA 400 mg/m² IV infusion bolus injection
DRUG5-FU
5-FU 400 mg/m² as a bolus followed by 2400 mg/m² IV continuous infusion over 46 hours
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically-confirmed, EGFR-detectable or EGFR-undetectable CRC * Locally-advanced unresectable or metastatic adenocarcinoma of the colon or rectum * At least 1 unidimensional-measurable target lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI); target lesion(s) must not lie within an irradiated area * Age ≥18 years * Life expectancy of ≥6 months * Eastern Cooperative Oncology Group (ECOG) performance status ≤2 at study entry * Adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥1.5 x 10\^9 liter (L), hemoglobin ≥10 grams per deciliter (g/dL), and platelets ≥100 x 10\^9/L * Adequate hepatic function as defined by a total bilirubin ≤1.5 milligrams per deciliter (mg/dL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) (or 5.0 x ULN in the case of liver metastases), and alkaline phosphatase (AP) ≤2.5 x ULN (or 5.0 x ULN in the case of liver metastases) * Adequate renal function as defined by a serum creatinine ≤1.5 x ULN, creatinine clearance ≥ 60 milliliters per minute (mL/min), or serum albumin ≥lower limit of normal (LLN) * Participant's relevant toxicities/effects of prior therapy \[surgery/radiation therapy (RT)\] must have recovered to a stable or chronic level * Participant agrees to use adequate contraception during the study period and for 4 weeks after the last dose of study treatment. Participants must notify the principal investigator if they themselves or their partner becomes pregnant. * Participant has provided signed Informed Consent
Exclusion criteria
* Has received prior systemic chemotherapy for locally-advanced unresectable or metastatic CRC. * Has received prior radiotherapy to \>25% of bone marrow * Has documented and/or symptomatic brain metastases * Has participated in clinical studies of non-approved experimental agents or procedures within 12 weeks of study entry * Has received previous therapy with monoclonal antibodies * Has received previous therapy with any agent that targets the EGFR * Has serious concomitant medical conditions including active uncontrolled infection or cardiac disease, which in the opinion of the investigator, could compromise the participant or study. * On chronic non-topical corticosteroid treatment for \>6 months at doses \>10 milligrams per day (mg/day) of prednisolone or equivalent before study entry, which in the opinion of the investigator could compromise the participant or the study * Has a known dihydropyrimidine dehydrogenase deficiency * Has a known allergy to any of the treatment components * Has an acute or subacute intestinal occlusion * Has peripheral neuropathy ≥Grade 2 * Has a history of other malignancies, with the exception of curatively treated non-melanoma skin cancer or carcinoma in situ of the cervix * If female, is pregnant (confirmed by urine or serum beta human chorionic gonadotropin test) or breast-feeding * Has received a prior autologous or allogeneic organ or tissue transplantation * Has interstitial pneumonia or interstitial fibrosis of the lung * Has pleural effusion or ascites that causes ≥Grade 2 dyspnea * Has psychological, familial, sociological, or geographical conditions which do not permit adequate study follow-up, compliance with the protocol, or signature of Informed Consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response ) | Up to 30 Months | CR and PR defined using Response Evaluation Criteria In Solid Tumors (RECIST) version (v) 1.0 criteria. CR was defined as the disappearance of all target and non-target lesions and PR defined as a ≥30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD. Percentage of participants was calculated as: (total number of participants with CR or PR from start of the treatment until disease progression or recurrence) / (total number of participants treated) \* 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | First dose to measured PD or death up to 30 months | PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause. Progressive disease (PD) was determined using RECIST v1.0 criteria. PD was defined as ≥20% increase in the sum of LD of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of new lesions and/or unequivocal progression of existing nontarget lesions. PFS was estimated by the Kaplan-Meier method. Participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last tumor assessment prior to the earliest of the following events: 2 or more missed visits, additional cancer treatment or the end of the follow-up period. |
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) or Death | First dose to end of treatment and 30-day post treatment follow-up up to 31 months | The number of participants who experienced AEs, SAEs or death during the study and within 30 days of last dose. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
| Duration of Response | Time of response to time of measured PD or death up to 30 months | The duration of response was defined as the time from first confirmed CR or PR to the first time of PD or death due to any cause. CR, PR and PD were defined using RECIST v1.0 criteria. CR was defined as the disappearance of all target and non-target lesions; PR was defined as a ≥30% decrease in the sum of the LD of the target lesions, taking as reference the baseline sum of the LD; PD was defined as a ≥20% increase in the sum of LD of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of new lesions and/or unequivocal progression of existing nontarget lesions. Participants with CR or PR who had no PD or death at the time of the data inclusion cutoff, the duration of response was censored at their last contact. |
| Serum Anti-IMC-11F8 Antibody Assessment (Immunogenicity) | Baseline up to last day of treatment plus 45 days after last treatment (127 weeks) | A participant was considered to have an anti-IMC-11F8 response if there were 2 consecutive positive samples or if the final sample tested is positive. Participants with a baseline sample positive for anti-IMC-11F8 antibodies were considered unevaluable for immunogenicity. A sample was considered positive for IMC-11F8 antibodies if it exhibited a post-baseline treatment emergent antibody level that exceeded the upper 95% confidence interval of the mean determined from the normal anti-IMC 11F8 level found in healthy treatment-naïve individuals. |
| Maximum Concentration (Cmax) of IMC-11F8 at Study Day 1 of Cycle 1 | Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose | — |
| Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of IMC-11F8 at Study Day 1 of Cycle 1 | Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose | — |
| Half-Life (t1/2) of IMC-11F8 at Study Day 1 of Cycle 1 | Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose | The t1/2 is the time measured for the plasma concentration of the drug to decrease by one half. |
| Clearance (CL) of IMC-11F8 at Study Day 1 of Cycle 1 | Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose | CL is the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time. |
| Overall Survival (OS) | First dose to date of death from any cause up to 30 months | OS was defined as the duration from the date of first dose to the date of death from any cause. OS was estimated by the Kaplan-Meier method. Participants who were alive at the time of the data inclusion cutoff or lost to follow-up, OS was censored at the last contact. |
| Cmax at Study Day 1 of Cycles 2 Through 6 | Day 1 Cycles 2 through 6 predose and 1 hour postdose | — |
| Area Under the Curve (AUC) at Study Day 1 of Cycles 2 Through 6 | Day 1 Cycles 2 through 6 predose and 1 hour postdose | — |
| t1/2 at Study Day 1 of Cycles 2 Through 6 | Day 1 Cycles 2 through 6 predose and 1 hour post dose | — |
| CL at Study Day 1 of Cycles 2 Through 6 | Day 1 Cycles 2 through 6 predose and 1 hour postdose | — |
| Vss at Study Day 1 of Cycles 2 Through 6 | Day 1 Cycles 2 through 6 predose and 1 hour postdose | — |
| Change From Baseline in Tumor Size | Baseline, 29 Months | — |
| Kirsten Rat Sarcoma (KRAS) Mutation Status | Baseline | Tumor tissues collected prior to study drug administration were evaluated for the presence or absence of KRAS mutations by a retrospective analysis. |
| Volume of Distribution (Vss) of IMC-11F8 at Study Day 1 of Cycle 1 | Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose | Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug at steady-state. |
Countries
Belgium, Spain
Participant flow
Pre-assignment details
Participants with known best overall response and off study treatment were considered to be completed.
Participants by arm
| Arm | Count |
|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 On Day 1 of each 2-week cycle, each participant received IMC-11F8 (necitumumab) in combination with the mFOLFOX-6 regimen (oxaliplatin/5-FU/FA) in the order shown:
* 800 mg IMC-11F8 IV infusion over 50 minutes
* 85 mg/m² oxaliplatin IV infusion over 2 hours
* 400 mg/m² folinic acid
* 400 mg/m² 5-FU as an IV bolus injection; and immediately followed by
* A 46-hour continuous IV infusion of 5-FU at 2400 mg/m² All treatments were administered every 2 weeks until disease progression, the development of unacceptable toxicity, noncompliance, withdrawal of consent, investigator decision, or until other criteria for treatment discontinuation were met. | 44 |
| Total | 44 |
Baseline characteristics
| Characteristic | IMC-11F8 (Necitumumab) + mFOLFOX-6 |
|---|---|
| Age, Continuous | 63.3 years STANDARD_DEVIATION 11.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Region of Enrollment Belgium | 13 participants |
| Region of Enrollment Spain | 31 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 44 / 44 |
| serious Total, serious adverse events | 16 / 44 |
Outcome results
Primary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response )
CR and PR defined using Response Evaluation Criteria In Solid Tumors (RECIST) version (v) 1.0 criteria. CR was defined as the disappearance of all target and non-target lesions and PR defined as a ≥30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD. Percentage of participants was calculated as: (total number of participants with CR or PR from start of the treatment until disease progression or recurrence) / (total number of participants treated) \* 100.
Time frame: Up to 30 Months
Population: All enrolled participants who received any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response ) | 63.6 percentage of participants |
Secondary
Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of IMC-11F8 at Study Day 1 of Cycle 1
Time frame: Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose
Population: All enrolled participants who received any quantity of study drug and had PK data available to calculate AUC(0-∞).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of IMC-11F8 at Study Day 1 of Cycle 1 | 39400 micrograms*hour/milliliter (µg*h/mL)] | Geometric Coefficient of Variation 35 |
Secondary
Area Under the Curve (AUC) at Study Day 1 of Cycles 2 Through 6
Time frame: Day 1 Cycles 2 through 6 predose and 1 hour postdose
Population: Zero participants were analyzed, AUC results were not collected.
Secondary
Change From Baseline in Tumor Size
Time frame: Baseline, 29 Months
Population: Zero participants were analyzed, the outcome measure was registered in error.
Secondary
CL at Study Day 1 of Cycles 2 Through 6
Time frame: Day 1 Cycles 2 through 6 predose and 1 hour postdose
Population: Zero participants were analyzed, CL results were not collected.
Secondary
Clearance (CL) of IMC-11F8 at Study Day 1 of Cycle 1
CL is the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time.
Time frame: Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose
Population: All enrolled participants who received any quantity of study drug and had PK data available to calculate CL.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Clearance (CL) of IMC-11F8 at Study Day 1 of Cycle 1 | 20.3 milliliters/hour (mL/h) | Geometric Coefficient of Variation 35 |
Secondary
Cmax at Study Day 1 of Cycles 2 Through 6
Time frame: Day 1 Cycles 2 through 6 predose and 1 hour postdose
Population: Zero participants were analyzed, Cmax results were not collected.
Secondary
Duration of Response
The duration of response was defined as the time from first confirmed CR or PR to the first time of PD or death due to any cause. CR, PR and PD were defined using RECIST v1.0 criteria. CR was defined as the disappearance of all target and non-target lesions; PR was defined as a ≥30% decrease in the sum of the LD of the target lesions, taking as reference the baseline sum of the LD; PD was defined as a ≥20% increase in the sum of LD of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of new lesions and/or unequivocal progression of existing nontarget lesions. Participants with CR or PR who had no PD or death at the time of the data inclusion cutoff, the duration of response was censored at their last contact.
Time frame: Time of response to time of measured PD or death up to 30 months
Population: All enrolled participants who received any quantity of study drug and had confirmed CR or PR. Participants censored =2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Duration of Response | 10.0 months |
Secondary
Half-Life (t1/2) of IMC-11F8 at Study Day 1 of Cycle 1
The t1/2 is the time measured for the plasma concentration of the drug to decrease by one half.
Time frame: Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose
Population: All enrolled participants who received any quantity of study drug and had PK data available to calculate t1/2.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Half-Life (t1/2) of IMC-11F8 at Study Day 1 of Cycle 1 | 142 hours (h) |
Secondary
Kirsten Rat Sarcoma (KRAS) Mutation Status
Tumor tissues collected prior to study drug administration were evaluated for the presence or absence of KRAS mutations by a retrospective analysis.
Time frame: Baseline
Population: All enrolled participants who had assessment of tumor tissue samples at baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Kirsten Rat Sarcoma (KRAS) Mutation Status | KRAS Mutation Positive | 9 participants |
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Kirsten Rat Sarcoma (KRAS) Mutation Status | KRAS Mutation Negative | 16 participants |
Secondary
Maximum Concentration (Cmax) of IMC-11F8 at Study Day 1 of Cycle 1
Time frame: Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose
Population: All enrolled participants who received any quantity of study drug and had pharmacokinetic (PK) data available to calculate Cmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Maximum Concentration (Cmax) of IMC-11F8 at Study Day 1 of Cycle 1 | 344 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 46 |
Secondary
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) or Death
The number of participants who experienced AEs, SAEs or death during the study and within 30 days of last dose. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: First dose to end of treatment and 30-day post treatment follow-up up to 31 months
Population: All enrolled participants who received any quantity of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) or Death | AEs | 44 participants |
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) or Death | SAEs | 16 participants |
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) or Death | Deaths | 3 participants |
Secondary
Overall Survival (OS)
OS was defined as the duration from the date of first dose to the date of death from any cause. OS was estimated by the Kaplan-Meier method. Participants who were alive at the time of the data inclusion cutoff or lost to follow-up, OS was censored at the last contact.
Time frame: First dose to date of death from any cause up to 30 months
Population: All enrolled participants who received any quantity of study drug. Participants censored =14.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Overall Survival (OS) | 22.5 months |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause. Progressive disease (PD) was determined using RECIST v1.0 criteria. PD was defined as ≥20% increase in the sum of LD of target lesions, taking as reference the smallest sum of the LD recorded since treatment started or the appearance of new lesions and/or unequivocal progression of existing nontarget lesions. PFS was estimated by the Kaplan-Meier method. Participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last tumor assessment prior to the earliest of the following events: 2 or more missed visits, additional cancer treatment or the end of the follow-up period.
Time frame: First dose to measured PD or death up to 30 months
Population: All enrolled participants who received any quantity of study drug. Participants censored =13.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Progression-Free Survival (PFS) | 10.0 months |
Secondary
Serum Anti-IMC-11F8 Antibody Assessment (Immunogenicity)
A participant was considered to have an anti-IMC-11F8 response if there were 2 consecutive positive samples or if the final sample tested is positive. Participants with a baseline sample positive for anti-IMC-11F8 antibodies were considered unevaluable for immunogenicity. A sample was considered positive for IMC-11F8 antibodies if it exhibited a post-baseline treatment emergent antibody level that exceeded the upper 95% confidence interval of the mean determined from the normal anti-IMC 11F8 level found in healthy treatment-naïve individuals.
Time frame: Baseline up to last day of treatment plus 45 days after last treatment (127 weeks)
Population: All participants who received any amount of study drug and were IMC-11F8 antibody negative at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Serum Anti-IMC-11F8 Antibody Assessment (Immunogenicity) | 4 participants |
Secondary
t1/2 at Study Day 1 of Cycles 2 Through 6
Time frame: Day 1 Cycles 2 through 6 predose and 1 hour post dose
Population: Zero participants were analyzed, t1/2 results were not collected.
Secondary
Volume of Distribution (Vss) of IMC-11F8 at Study Day 1 of Cycle 1
Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug at steady-state.
Time frame: Cycle 1 Day 1 predose, immediately after infusion, and 1, 2, 4, 24, 72, 96, 144, 168 and 236 hours postdose
Population: All enrolled participants who received any quantity of study drug and had PK data available to calculate Vss.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-11F8 (Necitumumab) + mFOLFOX-6 | Volume of Distribution (Vss) of IMC-11F8 at Study Day 1 of Cycle 1 | 3660 milliliters (mL) | Geometric Coefficient of Variation 32 |
Secondary
Vss at Study Day 1 of Cycles 2 Through 6
Time frame: Day 1 Cycles 2 through 6 predose and 1 hour postdose
Population: Zero participants were analyzed, Vss results were not collected.