The purpose of this Phase 1 study is to determine if AMG 211 given as a continous intravenous (IV) infusion is safe and tolerable in adult participants that have advanced gastrointestinal adenocarcinoma. The study will be conducted in multiple sites and test increasing doses of AMG 211. The safety of participants will be monitored by intensive assessment of vital signs, electrocardiograms, physical examinations, and laboratory tests. Efficacy will be assessed by the usual imaging procedures and their interpretation.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
45
continuous intravenous infusion (cIV) infusion in cycles from 7 to 28 days
Research Site
Hamburg, Germany
Research Site
München, Germany
Research Site
Ulm, Germany
Research Site
Amsterdam, Netherlands
Research Site
Groningen, Netherlands
Number of Participants With Dose-Limiting Toxicities (DLTs)
A DLT was defined as any of the following occurring during the first 28 days of treatment and regarded by the investigator and/or sponsor as related to AMG 211. Hematological DLTs: absolute neutrophil count (ANC) \< 0.5 × 10⁹ cells/L for ≥ 7 days; febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) with ANC \< 0.5 × 10⁹ cells/L and fever ≥ 38.5°C; platelets \< 25 × 10⁹ cells/L ≥ 7 days. Non-hematological DLTs: any AMG 211-related ≥ grade 3 non-hematological toxicity, excluding nausea and vomiting not refractory to anti-emetics, flare-up of pain due to potential increase in tumor volume, cytokine release syndrome manageable with symptomatic treatment and/or infusion interruption of up to 2 days. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used to assess toxicities/adverse events.
Time frame: 28 days
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence, which does not necessarily have a causal relationship with study treatment. A serious adverse event (SAE) was defined as an event that: was fatal or life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/borth defect; or other significant medical event. A TEAE was defined as any AE starting on or after the first dose of study drug and up to and including 30 days after the end of last dose of study drug. The severity of each adverse event was graded using CTCAE version 4.03 criteria (1=mild, 2=moderate, 3=severe, 4=life-threatining, 5=death). 'Any TEAE' includes both serious and non-serious TEAEs.
Time frame: From first dose of study drug through end of treatment + 30 days (median time frame was 75.5 days).
Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Levels of AMG 211 in plasma samples collected during this study were analyzed using an electrochemiluminiscence assay. The lower limit of quantification (LLOQ) of the assay was 0.10 ng/mL.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Area under the serum concentration-time curve (AUC) from time 0 to the last quantifiable concentration was estimated using the linear trapezoidal method.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days
Area under the serum concentration-time curve (AUC) from time 0 to the last quantifiable concentration was estimated using the linear trapezoidal method.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Area under the serum concentration-time curve from time 0 to infinity was estimated using the linear trapezoidal method
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days
Area under the serum concentration-time curve from time 0 to infinity was estimated using the linear trapezoidal method
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/λz, where λz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days
Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/λz, where λz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Css was calculated as the average concentration between achievement of plateau and the end of infusion.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion
Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days
Css was calculated as the average concentration between achievement of plateau and the end of infusion.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Serum clearance (CL) calculated as CL = (actual dose)/(serum concentrations at steady-state \[Css\] x 24).
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days
Serum clearance (CL) calculated as CL = (actual dose)/(serum concentrations at steady-state \[Css\] x 24).
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Volume of distribution at steady-state calculated as (CL x t1/2,z)/0.693.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days
Volume of distribution at steady-state calculated as (CL x t1/2,z)/0.693.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Number of Participants With Anti-AMG 211 Antibody Formation
Blood samples collected during the study were tested for anti-AMG 211 binding antibodies using an electrochemiluminescence-based bridging immunoassay. The number of participants with anti-AMG 211 antibody formation includes participants with a negative or no result at baseline and a positive antibody binding result postbaseline.
Time frame: Predose and 24 hours after the end of infusion during each treatment cycle, until 4 weeks after the last dose. Median time frame was 75.5 days.
Number of Participants With an Overall Objective Response
Disease response was assessed by radiological imaging using standardized contrast-enhanced magnetic imaging (MRI) or computed tomography (CT), and evaluated according to the modified Immune-Related Response Criteria (irRC). Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline.
Time frame: Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days.
Duration of Response
Duration of response was defined as the number of days between the date of the first tumor assessment indicating an objective response through to the subsequent date of progression as classified by modified irRC or death due to any cause. Analyzed in participants with an overall objective response. Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline.
Time frame: Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days.
Time to Response
Time to response was defined as the number of days from the first administration of AMG 211 to the first objective assessment of response as per modified irRC. Analyzed in participants with an overall objective response. Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline.
Time frame: Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days.
Time to Tumor Progression in Participants Treated at the Maximum Tolerated Dose (MTD)
Disease was assessed by radiological imaging using standardized contrast-enhanced MRI or CT, and evaluated according to the modified irRC. Immune-related progressed disease (irPD) was defined as an increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment.
Time frame: From first dose of AMG 211 until tumor progression, assessed through the end of study (up to 4 weeks after the last dose). The median time frame was 75.5 days.
Progression Free Survival (PFS) at 6 Months in Participants Treated at the MTD
PFS was defined as the percentage of participants who were progression-free at 6 months. Immune-related progressed disease (irPD) was defined as an increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment.
Time frame: 6 months