Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma
- Conditions
- Glioblastoma or Malignant Glioma
- Interventions
- Drug: AMG 596Drug: AMG 404
- Registration Number
- NCT03296696
- Lead Sponsor
- Amgen
- Brief Summary
This is a Phase 1/1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 monotherapy or in combination with AMG 404 in Subjects with Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII).
This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive glioblastoma or malignant glioma. This study will enroll 2 groups of subjects according to disease stage, recurrent disease (Group 1) and maintenance treatment after SoC in newly diagnosed disease (Group 2).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 30
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose exploration AMG 596 Dose exploration of the intervention, AMG 596 alone or in combination with AMG 404 Dose exploration AMG 404 Dose exploration of the intervention, AMG 596 alone or in combination with AMG 404 Dose expansion AMG 596 Dose expansion of the intervention, AMG 596 alone or in combination with AMG 404 Dose expansion AMG 404 Dose expansion of the intervention, AMG 596 alone or in combination with AMG 404
- Primary Outcome Measures
Name Time Method Number of Participants With Dose-Limiting Toxicities (DLTs) Up to 28 days A DLT was any of the following occurring and regarded by the investigator as related to AMG 596. Hematological DLTs: absolute neutrophil count (ANC) \<0.5×10\^9/L for ≥7 days, febrile neutropenia with ANC\<0.5×10\^9/L and fever ≥38.5°C, platelets\<50×10\^9/L\>7 days or clinically significant bleeding. Non-hematological DLTs: any grade 4 non-hematological toxicity, any grade ≥3 non-hematological toxicity if nausea and vomiting, grade 3 non-hematologic toxicity lasting \>3 days despite treatment, grade 3 fatigue wasn't classified as DLT, grade 3 acute kidney injury, grade 3 seizure, ataxia, encephalopathy, other grade 3 neurologic-related adverse events lasting \>3 days despite treatment, neurologic-related adverse event leading to treatment interruption needing\>1 week to resolve to grade≤1, any grade 3 endocrinopathy that can't be controlled by hormonal replacement. Toxicity grading was graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
Number of Participants With Treatment Emergent Adverse Events (TEAEs) First dose of study drug until 37 days after last dose or end of study, whichever is earlier. Duration with median (min, max) in months: 3.32 (1.28, 29.31) An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant. A TEAE was any AE that begun or worsened after the initial dose of investigational product. Any clinically significant changes in vital signs, physical examinations, and clinical laboratory tests that begun or worsened after the initial dose of investigational product were recorded as TEAEs.
Number of Participants With Treatment-Related Adverse Events (AEs) First dose of study drug until 37 days after last dose or end of study, whichever is earlier. Duration with median (min, max) in months: 3.32 (1.28, 29.31) A treatment-related AE was defined as any untoward medical occurrence in a clinical trial participant that was considered related to the investigational product. Any clinically significant changes in vital signs, physical examinations, and clinical laboratory tests that were considered related to the investigational product were recorded as treatment-related AEs.
- Secondary Outcome Measures
Name Time Method Average Steady-state Concentration (Css) of Serum AMG 596 Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end Area Under the Concentration-time Curve (AUC) for Serum AMG 596 Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end There were insufficient evaluable samples collected for the determination of AUC.
Clearance for Serum AMG 596 Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end Clearance (CL) is calculated based on dose and AUC.
Apparent Volume of Distribution at Steady-State for Serum AMG 596 Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end The formula for volume of distribution is dose/concentration. For this study, the dose is measured in mcg/day and concentration is measure as ng/mL resulting in units of mcg/day/(ng/mL) for volume of distribution.
Terminal Half-life (t1/2) Associated With Lambda z (λz) for Serum AMG 596 Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end Number of Participants With an Objective Response (OR) Per Modified Response Assessment in Neuro-Oncology Criteria (RANO) Criteria With AMG 596 Monotherapy Baseline up to 12 Months Objective response was defined as the number of participants with complete response (CR) or partial response (PR) per modified RANO criteria. CR per modified RANO: disappearance of all enhancing disease, no new lesions, stable or improved T2-weighted fluid-attenuated inversion recovery (T2/FLAIR), no more than physiological steroids, clinically stable or improved, disappearance confirmed with follow-up scans after ≥4 weeks. PR per modified RANO: ≥50% decrease in the sum of perpendicular diameters of enhancing disease from baseline, stable or improved T2/FLAIR, stable or decreased steroid dose, clinically stable or improved, decrease confirmed with follow up scan after ≥ 4 weeks.
Time to Response With AMG 596 Monotherapy Up to 12 months Time to response was calculated as the number of months from the date of first administration of AMG 596 to the date of confirmation of first objective response per magnetic resonance imaging (MRI) scan. If a participant did not respond, time to response was censored at the date of the last evaluable response assessment.
Response Duration With AMG 596 Monotherapy Up to 30 months Response duration was analysed as the number of months between the first tumor response assessment of an OR (PR or CR) which is subsequently confirmed to the time of the first tumor response assessment of progressive disease or death if due to disease progression.
Time to Progression (TTP) With AMG 596 Monotherapy Up to 12 Months The TTP was calculated as the time from the date of first dose of AMG 596 until the date of diagnosis of progression of tumor. Participants who did not have progression were censored at the last radiological non-missing evaluable tumor assessment date.
Progression-free Survival (PFS) With AMG 596 Monotherapy Up to 12 months The PFS was calculated as the time from the date of first dose of AMG 596 until the date of diagnosis of progression of tumor, or date of death, whichever was earlier.
Trial Locations
- Locations (10)
University of California Los Angeles
🇺🇸Los Angeles, California, United States
Vrije Universiteit Medisch Centrum
🇳🇱Amsterdam, Netherlands
Universitaetsklinikum Wuerzburg
🇩🇪Würzburg, Germany
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden
🇩🇪Dresden, Germany
Royal North SHore Hospital
🇦🇺St Leonards, New South Wales, Australia
Gustave Roussy
🇫🇷Villejuif, France
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Universitatsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Cataluña, Spain