Neoplasms
Conditions
Keywords
Human Immunoglobulin Gamma-1 (IgG1), Monoclonal Antibody (MAb), Epidermal Growth Factor Receptor (EGFR), Advanced Solid Tumors
Brief summary
This study is to establish the safety and pharmacokinetic (PK) profile of IMC-11F8, administered either: (1) in a 3-week cycle; or (2) in a 2-week cycle to Japanese participants with advanced solid tumors who have not responded to standard therapy or for whom no standard therapy is available.
Detailed description
This single center, open-label, single-arm, Phase 1 study will enroll 18 participants at a maximum. The actual size will vary depending on the dose-limiting toxicities (DLTs) observed and the resultant sizes of the cohorts. Participants will receive IMC-11F8 administered intravenously, once every 2 weeks or on Days 1 and 8 every 3 weeks for 6 weeks (1 cycle). All infusions can be administered within ± 1 day of the scheduled administration date. After 1 cycle of treatment, participants who have an objective response or stable disease may continue to receive IMC-11F8 at the same dose and schedule until disease progression or other withdrawal criteria are met. A minimum of 3 participants will be enrolled in each cohort. Dose escalation in successive cohorts will occur once all participants complete 1 cycle of therapy. Participants will be enrolled sequentially into each cohort. A completed participant will be either a participant who completes the initial 6-week treatment period (Cycle 1) or a participant who discontinues therapy for an IMC-11F8-related toxicity during Cycle 1. Participants who do not complete the first 6 weeks of treatment for reasons other than an IMC-11F8-related toxicity will be replaced. Toxicity data for each cohort will be reviewed prior to dose escalation. Upon completion of all required safety evaluations during the initial 6 weeks, the next cohort of new participants will be treated at the next higher dose level using a dose escalation scheme.
Interventions
BIOLOGICALIMC-11F8
600 milligrams (mg) intravenously, Days 1 and 8 every 3 weeks
Sponsors
Parexel
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Solid tumor participant who has been histopathologically or cytologically documented * Advanced primary or recurrent solid tumors participant who has not responded to standard therapy or for whom no standard therapy is available * The participant has measurable or nonmeasurable lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0 guidelines * The participant has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 at study entry * The participant is able to provide written informed consent * The participant is age 20 years or older * The participant has a life expectancy of \> 3 months * The participant has adequate hematologic function * The participant has adequate renal function * The participant agrees to use adequate contraception for the duration of study participation and for at least 12 weeks after the last dose of study therapy * The participant has adequate recovery from recent surgery, chemotherapy, and radiation therapy (including palliative radiation therapy). At least 28 days (6 weeks for nitrosoureas or mitomycin C) must have elapsed from major surgery, prior chemotherapy, prior treatment with an investigational agent or device, or prior radiation therapy. For treatment with nonapproved monoclonal antibodies, a minimum of 8 weeks must have elapsed * The participant is willing to comply with study procedures until the End-of-Therapy visit
Exclusion criteria
* The participant has received chemotherapy or therapeutic radiotherapy within 28 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, or the participant has ongoing side effects ≥Grade 2 due to agents administered more than 28 days earlier (except alopecia) * The participant has documented and/or symptomatic brain or leptomeningeal metastases (participants who are clinically stable \[no symptoms during the 4 weeks prior to enrollment\] with an assessment that no further treatment \[radiation, surgical excision, or administration of steroids\] is required are permitted to enter the study) * The participant has an uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection requiring systemic antibiotic treatment * Congestive heart failure (Class III or IV per the New York Heart Association heart disease classification guidelines) * The participant has participated in clinical studies of nonapproved experimental agents or procedures within 4 weeks prior to first dose of study therapy, or within 8 weeks prior to first dose of study therapy for nonapproved monoclonal antibodies * The participant has received any previous treatment with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR). Previous treatment with EGFR tyrosine kinase inhibitors (TKI), approved or nonapproved, is allowed. There must be a time interval of at least 4 weeks between the last EGFR TKI dose and the first dose of IMC-11F8 * The participant has acute or subacute intestinal occlusion/obstruction * The participant has a history of inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis) requiring medical intervention in the 3 years prior to study entry * The participant has acute pulmonary disorder, interstitial pneumonia, pulmonary fibrosis, or history thereof * The participant has a known allergy to any of the treatment components, or to monoclonal antibodies or other therapeutic proteins such as fresh frozen plasma, human serum albumin, cytokines, or interleukins. In the event that there is suspicion that the participant may have allergies, the participant should be excluded * The participant, if female, is pregnant (confirmed by urine or serum pregnancy test) or lactating * The participant has known alcohol or drug dependency * The participant is hepatitis B virus (HBV) antigen, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody positive * The participant is assessed as inadequate for the study by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK: Vss of Necitumumab After Multiple Doses | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | Vss is that amount of plasma in which the study drug needs to be dissolved to attain a steady state drug concentration. Data did not allow calculation of Vss for participants in Cohorts 1 and 3. |
| Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | Baseline up to 24 weeks plus 30 days post last dose of study drug | Data presented are the number of participants who experienced 1 or more TEAEs or SAEs regardless of causality. An adverse event was considered as TEAE if it occurred any time after the administration of the first dose of study drug or up to 30 days after the last dose of study treatment or if it occurred prior to the first dose and worsened while on treatment. A summary of SAEs and other non-SAEs regardless of causality is located in the Reported Adverse Events module. |
| Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Necitumumab After a Single Dose | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 hours (h) after end of infusion. Cohort 2: predose, immediately after infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | — |
| PK: Cmax of Necitumumab After Multiple Doses | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | Cmax at steady state (after the last dose of the initial 6-week treatment cycle). |
| PK: Minimum Concentration (Cmin) of Necitumumab After a Single Dose | Cycle 1; Cohorts 1, 2 and 3: prior to second infusion | Cmin is defined as the minimum concentration the drug achieved after administration of first infusion and prior to the administration of second infusion. |
| PK: Cmin of Necitumumab After Multiple Doses | Cycle 1; Cohorts 1and 3: prior to fourth infusion. Cohort 2: prior to third infusion | Cmin was calculated prior to the last dose of the initial 6-week treatment cycle. |
| PK: Area Under the Concentration-Time Curve From Time 0 to Last Time Point [AUC (0-tlast)] of Necitumumab After a Single Dose | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | — |
| PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of Necitumumab After a Single Dose | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for all the remaining participants. |
| PK: Area Under the Concentration-Time Curve From Time 0 to 336 h Postdose [AUC(0-336)] of Necitumumab After Multiple Doses | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | Steady state AUC(0-336) values are reported. |
| PK: Half-Life (t½) of Necitumumab After a Single Dose | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | The t½ is defined as the time taken for study drug in blood to decrease to half of its concentration. |
| PK: t½ of Necitumumab After Multiple Doses | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | The t½ is defined as the time taken for study drug in blood to decrease to half of its concentration. |
| PK: Clearance (CL) of Necitumumab After a Single Dose | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | CL is defined as the volume of plasma that is cleared of study drug per unit time. CL was not analyzed for participants in Cohorts 1 and 3 as CL is derived from AUC(0-∞). AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for the remaining participants. |
| PK: CL of Necitumumab After Multiple Doses | Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | CL is defined as the volume of plasma that is cleared of study drug per unit time. Data did not allow calculation of CL for participants in Cohorts 1 and 3. |
| PK: Steady-State Volume of Distribution (Vss) of Necitumumab After Single Dose | Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion | Vss is that amount of plasma in which the study drug needs to be dissolved to attain a steady state drug concentration. Vss was not analyzed for participants in Cohorts 1 and 3 as Vss is derived from AUC (0-∞). AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for the remaining participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | For Cohorts 1, 2 and 3: Prior to first infusions of Cycles 1, 2, and 4 and at the 30-day follow-up visit (+7 days) after the last dose of study drug | Treatment-emergent samples were defined as samples which showed at least 4-fold difference (2 dilution increase) at post-baseline in IK titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20). |
Countries
Japan
Participant flow
Pre-assignment details
The study had 3 cohorts and dose escalation in successive cohorts was to occur once all the participants completed 1 cycle of therapy. A completed participant was either a participant who completed the initial 6-week treatment period (Cycle 1) or a participant who discontinued therapy for an IMC-11F8 (Necitumumab) related toxicity during Cycle 1.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Necitumumab Necitumumab 600 mg administered intravenously on Days 1 and 8 every 3 weeks of a 6-week cycle. After Cycle 1, participants showing objective response or stable disease were to receive necitumumab at same dose and schedule until disease progression or other withdrawal criteria were met. | 3 |
| Cohort 2: Necitumumab Necitumumab 800 mg administered intravenously every 2 weeks of a 6-week cycle. After Cycle 1, participants showing objective response or stable disease were to receive necitumumab at same dose and schedule until disease progression or other withdrawal criteria were met. | 6 |
| Cohort 3: Necitumumab Necitumumab 800 mg administered intravenously on Days 1 and 8 every 3 weeks of a 6-week cycle. After Cycle 1, participants showing objective response or stable disease were to receive necitumumab at same dose and schedule until disease progression or other withdrawal criteria were met. | 6 |
| Total | 15 |
Baseline characteristics
| Characteristic | Cohort 1: Necitumumab | Cohort 2: Necitumumab | Cohort 3: Necitumumab | Total |
|---|---|---|---|---|
| Age, Continuous | 57.2 years FULL_RANGE 20.02 | 64.5 years FULL_RANGE 4.51 | 56.7 years FULL_RANGE 9.5 | 61.2 years FULL_RANGE 10.72 |
| Eastern Cooperative Oncology Group performance status (ECOG PS) 0 = Fully Active | 1 participants | 1 participants | 4 participants | 6 participants |
| Eastern Cooperative Oncology Group performance status (ECOG PS) 1 = Ambulatory, Restricted Work Activity | 2 participants | 5 participants | 2 participants | 9 participants |
| Gender Female | 1 Participants | 3 Participants | 4 Participants | 8 Participants |
| Gender Male | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Japanese | 3 participants | 6 participants | 6 participants | 15 participants |
| Region of Enrollment Japan | 3 participants | 6 participants | 6 participants | 15 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 1 / 3 | 0 / 6 | 1 / 6 |
Outcome results
Primary
Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)
Data presented are the number of participants who experienced 1 or more TEAEs or SAEs regardless of causality. An adverse event was considered as TEAE if it occurred any time after the administration of the first dose of study drug or up to 30 days after the last dose of study treatment or if it occurred prior to the first dose and worsened while on treatment. A summary of SAEs and other non-SAEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline up to 24 weeks plus 30 days post last dose of study drug
Population: All participants who received any quantity of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Necitumumab | Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | TEAEs | 3 participants |
| Cohort 1: Necitumumab | Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Cohort 2: Necitumumab | Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | TEAEs | 6 participants |
| Cohort 2: Necitumumab | Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Cohort 3: Necitumumab | Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | TEAEs | 6 participants |
| Cohort 3: Necitumumab | Number of Participants With 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | SAEs | 1 participants |
Primary
Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Necitumumab After a Single Dose
Time frame: Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 hours (h) after end of infusion. Cohort 2: predose, immediately after infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received single dose of study drug and had Cmax values for Day 1 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Necitumumab After a Single Dose | 306 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 29 |
| Cohort 2: Necitumumab | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Necitumumab After a Single Dose | 417 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 46 |
| Cohort 3: Necitumumab | Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of Necitumumab After a Single Dose | 352 micrograms per milliliter (µg/mL) | Geometric Coefficient of Variation 20 |
Primary
PK: Area Under the Concentration-Time Curve From Time 0 to 336 h Postdose [AUC(0-336)] of Necitumumab After Multiple Doses
Steady state AUC(0-336) values are reported.
Time frame: Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All the participants who received multiple doses of study drug and had AUC(0-336) values for Day 29 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to 336 h Postdose [AUC(0-336)] of Necitumumab After Multiple Doses | 56300 µg*h/mL | Geometric Coefficient of Variation 21 |
| Cohort 2: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to 336 h Postdose [AUC(0-336)] of Necitumumab After Multiple Doses | 81400 µg*h/mL | Geometric Coefficient of Variation 19 |
| Cohort 3: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to 336 h Postdose [AUC(0-336)] of Necitumumab After Multiple Doses | 105000 µg*h/mL | Geometric Coefficient of Variation 12 |
Primary
PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of Necitumumab After a Single Dose
AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for all the remaining participants.
Time frame: Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received single dose of study drug and had evaluable AUC(0-∞) values for Day~1 of Cycle 1. No participant of Cohorts 1 and 3 were analyzed for AUC(0-∞) on Day 1 of Cycle 1, due to fraction of data outside tlast \>30%
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to Infinity [AUC(0-∞)] of Necitumumab After a Single Dose | 66700 µg*h/mL | Geometric Coefficient of Variation 21 |
Primary
PK: Area Under the Concentration-Time Curve From Time 0 to Last Time Point [AUC (0-tlast)] of Necitumumab After a Single Dose
Time frame: Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received single dose of study drug and had evaluable AUC(0-∞) values for Day 1 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to Last Time Point [AUC (0-tlast)] of Necitumumab After a Single Dose | 23100 micrograms*hour/milliliter (µg*h/mL) | Geometric Coefficient of Variation 16 |
| Cohort 2: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to Last Time Point [AUC (0-tlast)] of Necitumumab After a Single Dose | 50100 micrograms*hour/milliliter (µg*h/mL) | Geometric Coefficient of Variation 24 |
| Cohort 3: Necitumumab | PK: Area Under the Concentration-Time Curve From Time 0 to Last Time Point [AUC (0-tlast)] of Necitumumab After a Single Dose | 31300 micrograms*hour/milliliter (µg*h/mL) | Geometric Coefficient of Variation 17 |
Primary
PK: Clearance (CL) of Necitumumab After a Single Dose
CL is defined as the volume of plasma that is cleared of study drug per unit time. CL was not analyzed for participants in Cohorts 1 and 3 as CL is derived from AUC(0-∞). AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for the remaining participants.
Time frame: Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All the participants who received single dose of study drug and had CL values for Day 1 of Cycle 1. No participant of Cohorts 1 and 3 were analyzed for CL on Day 1 of Cycle 1, due to fraction of data outside tlast \>30%
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Necitumumab | PK: Clearance (CL) of Necitumumab After a Single Dose | 12.0 milliliters per hour (mL/h) | Geometric Coefficient of Variation 21 |
Primary
PK: CL of Necitumumab After Multiple Doses
CL is defined as the volume of plasma that is cleared of study drug per unit time. Data did not allow calculation of CL for participants in Cohorts 1 and 3.
Time frame: Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All the participants who received multiple doses of study drug and had CL values for Day 29 of Cycle 1. CL of necitumumab was not assessed for participants in Cohorts 1 and 3, due to the irregular dosing regimen.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Necitumumab | PK: CL of Necitumumab After Multiple Doses | 9.83 mL/h | Geometric Coefficient of Variation 19 |
Primary
PK: Cmax of Necitumumab After Multiple Doses
Cmax at steady state (after the last dose of the initial 6-week treatment cycle).
Time frame: Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received multiple doses of study drug and had Cmax values for Day 29 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: Cmax of Necitumumab After Multiple Doses | 396 µg/mL | Geometric Coefficient of Variation 5 |
| Cohort 2: Necitumumab | PK: Cmax of Necitumumab After Multiple Doses | 523 µg/mL | Geometric Coefficient of Variation 17 |
| Cohort 3: Necitumumab | PK: Cmax of Necitumumab After Multiple Doses | 629 µg/mL | Geometric Coefficient of Variation 16 |
Primary
PK: Cmin of Necitumumab After Multiple Doses
Cmin was calculated prior to the last dose of the initial 6-week treatment cycle.
Time frame: Cycle 1; Cohorts 1and 3: prior to fourth infusion. Cohort 2: prior to third infusion
Population: All participants who received multiple doses of study drug and had Cmin serum concentrations prior to last dose of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: Cmin of Necitumumab After Multiple Doses | 108 µg/mL | Geometric Coefficient of Variation 23 |
| Cohort 2: Necitumumab | PK: Cmin of Necitumumab After Multiple Doses | 136 µg/mL | Geometric Coefficient of Variation 22 |
| Cohort 3: Necitumumab | PK: Cmin of Necitumumab After Multiple Doses | 220 µg/mL | Geometric Coefficient of Variation 16 |
Primary
PK: Half-Life (t½) of Necitumumab After a Single Dose
The t½ is defined as the time taken for study drug in blood to decrease to half of its concentration.
Time frame: Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received single dose of study drug and had t½ values for Day 1 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: Half-Life (t½) of Necitumumab After a Single Dose | 126 h | Geometric Coefficient of Variation 14 |
| Cohort 2: Necitumumab | PK: Half-Life (t½) of Necitumumab After a Single Dose | 207 h | Geometric Coefficient of Variation 31 |
| Cohort 3: Necitumumab | PK: Half-Life (t½) of Necitumumab After a Single Dose | 146 h | Geometric Coefficient of Variation 18 |
Primary
PK: Minimum Concentration (Cmin) of Necitumumab After a Single Dose
Cmin is defined as the minimum concentration the drug achieved after administration of first infusion and prior to the administration of second infusion.
Time frame: Cycle 1; Cohorts 1, 2 and 3: prior to second infusion
Population: All participants who received single dose of study drug and had Cmin serum concentrations analyzed prior to administration of second dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: Minimum Concentration (Cmin) of Necitumumab After a Single Dose | 86.0 µg/mL | Geometric Coefficient of Variation 10 |
| Cohort 2: Necitumumab | PK: Minimum Concentration (Cmin) of Necitumumab After a Single Dose | 72.9 µg/mL | Geometric Coefficient of Variation 24 |
| Cohort 3: Necitumumab | PK: Minimum Concentration (Cmin) of Necitumumab After a Single Dose | 127 µg/mL | Geometric Coefficient of Variation 18 |
Primary
PK: Steady-State Volume of Distribution (Vss) of Necitumumab After Single Dose
Vss is that amount of plasma in which the study drug needs to be dissolved to attain a steady state drug concentration. Vss was not analyzed for participants in Cohorts 1 and 3 as Vss is derived from AUC (0-∞). AUC(0-∞) was calculated only for participants in Cohort 2 as the percentage of AUC extrapolated beyond tlast was greater than 30% for the remaining participants.
Time frame: Cycle 1, Day 1; Cohorts 1 and 3: predose, immediately after end of infusion, 0.5, 1, 2, 6, 24, 96 and 168 h after end of infusion. Cohort 2: predose, immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received single dose of study drug and had Vss values for Day 1 of Cycle 1. Vss of necitumumab was not assessed for participants in Cohorts 1 and 3, due to the irregular dosing regimen.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Necitumumab | PK: Steady-State Volume of Distribution (Vss) of Necitumumab After Single Dose | 2780 milliliters (mL) | Geometric Coefficient of Variation 31 |
Primary
PK: t½ of Necitumumab After Multiple Doses
The t½ is defined as the time taken for study drug in blood to decrease to half of its concentration.
Time frame: Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All the participants who received multiple doses of study drug and had t½ values for Day 29 of Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Necitumumab | PK: t½ of Necitumumab After Multiple Doses | 190 h | Geometric Coefficient of Variation 36 |
| Cohort 2: Necitumumab | PK: t½ of Necitumumab After Multiple Doses | 233 h | Geometric Coefficient of Variation 18 |
| Cohort 3: Necitumumab | PK: t½ of Necitumumab After Multiple Doses | 286 h | Geometric Coefficient of Variation 18 |
Primary
PK: Vss of Necitumumab After Multiple Doses
Vss is that amount of plasma in which the study drug needs to be dissolved to attain a steady state drug concentration. Data did not allow calculation of Vss for participants in Cohorts 1 and 3.
Time frame: Cycle 1, Day 29; For Cohorts 1, 2 and 3: predose (prior to fourth infusion for Cohorts 1 and 3; prior to third infusion for Cohort 2), immediately after end of infusion, 0.5, 1, 2, 4, 8, 24, 48, 96, 168, 264 and 336 h after end of infusion
Population: All participants who received multiple doses of study drug and had Vss values for Day 29 of Cycle 1. Vss of necitumumab was not assessed for participants in Cohorts 1 and 3, due to the irregular dosing regimen.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: Necitumumab | PK: Vss of Necitumumab After Multiple Doses | 3370 mL | Geometric Coefficient of Variation 21 |
Secondary
Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies
Treatment-emergent samples were defined as samples which showed at least 4-fold difference (2 dilution increase) at post-baseline in IK titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
Time frame: For Cohorts 1, 2 and 3: Prior to first infusions of Cycles 1, 2, and 4 and at the 30-day follow-up visit (+7 days) after the last dose of study drug
Population: All participants who received any quantity of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Necitumumab | Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Positive for Anti-Necitumumab Antibodies | 0 participants |
| Cohort 1: Necitumumab | Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Negative for Anti-Necitumumab Antibodies | 3 participants |
| Cohort 2: Necitumumab | Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Positive for Anti-Necitumumab Antibodies | 0 participants |
| Cohort 2: Necitumumab | Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Negative for Anti-Necitumumab Antibodies | 6 participants |
| Cohort 3: Necitumumab | Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Positive for Anti-Necitumumab Antibodies | 0 participants |
| Cohort 3: Necitumumab | Immunogenicity (IK): Number of Participants With Treatment-Emergent Anti-IMC-11F8 Antibodies | Negative for Anti-Necitumumab Antibodies | 6 participants |