A Dose-escalation Study to Evaluate the Safety, Tolerability, and Antitumor Activity of MEDI-573 in Subjects With Advanced Solid Tumors

AEs were any unfavorable and unintended signs (including abnormal laboratory findings), symptoms, or diseases temporally associated with the use of MEDI-573, whether or not considered related to MEDI-573. A SAE was any AE that resulted in: death; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; was life-threatening; was a congenital anomaly/birth defect in the offspring of a study participant; or was an important medical event that may not have resulted in death, threatened life, or required hospitalization and that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes above. TEAEs were defined as AEs present at baseline that worsened in intensity after administration of MEDI-573, or events absent at baseline that emerged after administration of MEDI-573, up to 30 days after the last dose.

An abnormal laboratory finding that was judged by the investigator to be medically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-573, or events absent at baseline that emerged after administration of MEDI-573, for the period extending to 30 days after the last dose.

Vital signs and physical findings included parameters such as heart rate, blood pressure, temperature, and respiratory rate. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-573 or events absent at baseline that emerged after administration of MEDI-573, for the period extending to 30 days after the last dose.

The MTD was defined as the highest dose that can be safely administered to participants and was determined by the number of participants in each cohort with a dose-limiting toxicity (DLT). The number and proportion of participants in each dose cohort and the number of participants with a DLT was presented using the total number of participants in the MTD Evaluable Population as the denominator. 2 participants from Cohorts 0.5 and 5 mg/kg QWk (1 in each cohort) did not complete the DLT period and therefore not evaluable for MTD.

A DLT was defined as any grade greater than or equal to (>=) 3 treatment-related non-hematologic toxicity that occurred during the DLT assessment period with the following exceptions: Grade less than (<) 4 serum-high glucose (fasting) with duration of < 24 hours; Grade 3 fever (in the absence of neutropenia) defined as > 40.0 degree centigrade (°C) [greater than (>) 104.0°F] that resolved to normal or baseline within 24 hours of treatment and was not considered an SAE; or Grade 3 rigors/chills that responded to optimal therapy; any Grade >= 3 treatment-related hematologic toxicity that occurred during the DLT assessment period.

The OBED was defined as the dose at which all circulating insulin-like growth factor (IGF)-1 and IGF-2 ligand was sequestered by MEDI-573.

The Cmax was the maximum observed serum concentration of MEDI-573.

The tmax was defined as actual sampling time to reach the maximum observed serum concentration of MEDI-573.

The Ctrough was the lowest serum concentration of MEDI-573 within a dosing interval.

The Cmax/dose was the dose-normalized maximum serum concentration of MEDI-573.

Area under the serum concentration-time curve over the first dosing interval.

The AUCtau/dose was a measure of dose-normalized area under the serum concentration-time curve over the first dosing interval.

Two methods were used to assess the immunogenicity data: an ECL-based method and measurement of neutralizing ADA. The titer was calculated by multiplying the minimum assay dilution factor by the reciprocal of the highest dilution factor which yielded an ECL multiple equal to or greater than the screening assay cut-point factor.

The ORR was defined as the proportion of participants with confirmed complete response (CR) or partial response (PR) according to the RECIST criteria The CR was defined as disappearance of all target and nontarget lesions and no new lesions; and PR was definded as >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline [screening]) and no new lesions.

Progression-free survival (PFS) was defined as the duration from the start of treatment with MEDI-573 until the documentation of disease progression or death due to any cause, whichever occurred first.

Time to disease progression (TTP) was defined as the duration from the start of treatment with MEDI-573 until the documentation of disease progression.

Overall survival (OS) was defined as the time from the start of treatment with MEDI-573 until death.

Time to response was defined as the duration from the start of treatment with MEDI-573 to the first documentation of objective response (confirmed CR or PR) and was only assessed in participants who had achieved objective response.

Duration of response was defined as the duration from the first documentation of objective response (confirmed CR or PR) to the first documented disease progression.

The suppression profiles of both IGF-1 and IGF-2 post administration of MEDI-573 in relation to time course of antibody concentrations in serum were evaluated during treatment.