Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma

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)

Time frame: Up to 28 days

Population: The DLT Evaluable Analysis Set included all participants in the 7-day on/7-day off dosing groups who completed 100% of planned doses and all participants in the 28-day on/14-day off dosing groups who completed 90% of planned doses.

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.

Time frame: 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)

Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of AMG 596.

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.

Time frame: 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)

Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of AMG 596.

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.

Time frame: 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

Population: The pharmacokinetic (PK) analysis set contained all participants who received the investigational product and had available PK data for each timepoint.

There were insufficient evaluable samples collected for the determination of AUC.

Time frame: 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

Population: The pharmacokinetic (PK) analysis set contained all participants who received the investigational product and had available PK data for each timepoint. 0 participants had evaluable data for the determination of AUC, therefore 0 participants were analyzed for this endpoint.

Time frame: 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

Population: The pharmacokinetic (PK) analysis set contained all participants who received the investigational product and had available PK data for each timepoint.

Clearance (CL) is calculated based on dose and AUC.

Time frame: 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

Population: The pharmacokinetic (PK) analysis set contained all participants who received the investigational product and had available PK data for each timepoint.

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 frame: Baseline up to 12 Months

Population: The RANO Evaluable Analysis set included all participants that were enrolled and received at least one administration of AMG 596 and who had at least one measurable lesion identified by the Principal Investigator at baseline.

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.

Time frame: Up to 12 months

Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of AMG 596.

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 frame: Up to 30 months

Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of AMG 596. Only participants with OR were used for this analysis.

Time frame: 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

Population: The pharmacokinetic (PK) analysis set contained all participants who received the investigational product and had available PK data for each timepoint.

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.

Time frame: Up to 12 Months

Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of AMG 596

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.

Time frame: Up to 12 months

Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of AMG 596. Only participants with OR were used for this analysis.