GI Adenocarcinoma Clinical Trial
Official title:
A Phase 1 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 211 Administered as Continuous Intravenous Infusion in Subjects With Relapsed/Refractory Gastrointestinal Adenocarcinoma
| Verified date | February 2021 |
| Source | Amgen |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 45 |
| Est. completion date | January 9, 2018 |
| Est. primary completion date | November 6, 2017 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: - Informed consent provided - 18 years or older - Advanced relapsed/refracted gastrointestinal adenocarcinoma - At least 1 measurable tumor lesion - Tumor tissue available or is willing to undergo biopsy of a tumor lesion before the start of treatment - Adequate hematological, renal, and liver function - Body weight = 45 kg - Other inclusion criteria may apply Exclusion Criteria: - Malignancy other than gastrointestinal (GI) adenocarcinoma requiring current therapy - Evidence of uncontrolled systemic disease, active infection, Hepatitis B and/or C, human immunodeficiency virus (HIV), history of cardiac disease, history of significant central nervous system (CNS) disease, history of chronic autoimmune disease (with the exception of stable type 1 diabetes) - Major surgery within 28 days of study day 1 - Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment in another investigational device or drug study. Other investigational procedures while participating in this study are excluded. Exception to this criterion is the participation in the optional Imaging Study and all procedures related to this study. - Treatment with any chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for cancer within 14 days prior to study entry and not recovered from treatment - Unresolved toxicities from prior anti-tumor therapy - Males or Females of reproductive potential, and unwilling to practice an acceptable method of effective birth control while on study through 30 days after receiving the last dose of study drug - Females who are pregnant, planning to become pregnant, lactating/breastfeeding or who plan to breastfeed while on study through 30 days after receiving the last dose of study drug - Other exclusion criteria may apply |
| Country | Name | City | State |
|---|---|---|---|
| Germany | Research Site | Hamburg | |
| Germany | Research Site | München | |
| Germany | Research Site | Ulm | |
| Netherlands | Research Site | Amsterdam | |
| Netherlands | Research Site | Groningen |
| Lead Sponsor | Collaborator |
|---|---|
| Amgen | MedImmune LLC |
Germany, Netherlands,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 × 10? cells/L for = 7 days; febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) with ANC < 0.5 × 10? cells/L and fever = 38.5°C; platelets < 25 × 10? 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. | 28 days | |
| Primary | 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. | From first dose of study drug through end of treatment + 30 days (median time frame was 75.5 days). | |
| Secondary | 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. | 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. | |
| Secondary | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 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. | ||
| Secondary | 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. | 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. | |
| Secondary | 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. | 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. | |
| Secondary | 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 | 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. | |
| Secondary | 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 | 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. | |
| Secondary | 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)/?z, where ?z was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. | 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. | |
| Secondary | 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)/?z, where ?z was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. | 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. | |
| Secondary | 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. | 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 | |
| Secondary | 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. | 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. | |
| Secondary | 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). | 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. | |
| Secondary | 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). | 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. | |
| Secondary | 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. | 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. | |
| Secondary | 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. | 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. | |
| Secondary | 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. | 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. | |
| Secondary | 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. | 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. | |
| Secondary | 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. |
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. | |
| Secondary | 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. |
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. | |
| Secondary | 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. | 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. | |
| Secondary | 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. |
6 months |