A Study of MEDI-575 in Subjects With Recurrent Glioblastoma Multiforme

Best overall response rate is calculated based upon the disease assessments recorded during the study visits using RANO criteria. Best overall response includes complete response (CR), CR with confirmation, partial response (PR), PR with confirmation, stable disease and progressive disease. Confirmed responses are those that persist on repeat imaging studies at least 4 weeks after the initial documentation of response.

Objective response rate (ORR) is defined as the proportion of participants with confirmed CR or confirmed PR using RANO criteria. Confirmed CR and PR are those that persist on repeat imaging study for at least 4 weeks after the initial documentation of the response. CR is defined as complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks, no new lesions, stable or improved nonenhancing (T2/FLAIR) lesions, patient is off corticosteroids and stable or improved clinically. PR is defined as 50% decrease compared with baseline in the measurement of all measurable enhancing lesions sustained for at least 4 weeks, no progression of nonmeasurable disease, no new lesions, stable or improved nonenhancing (T2/FLAIR) lesions, no increase in the corticosteroid dose and stable or improved clinically.

Time to response (TTR) is defined as the time from the study entry to the first documentation of confirmed CR or confirmed PR. Analysis was based on responses confirmed at a repeat assessment made at least 4 weeks after the initial response, with the TTR taken as the first time the response was observed, not the confirmation assessment. TTR was estimated using Kaplan-Meier method.

Duration of response is defined as the duration from the first documentation of objective disease response (ie, confirmed CR or confirmed PR) to the first documented disease progression. Duration of response was estimated using Kaplan-Meier method and evaluated only for the participants of subgroup with an objective response.

Time to progression (TTP) is defined as time from the start of treatment with MEDI-575 until the documentation of disease progression. Disease progression was defined by at least 25% increase in measurement of enhancing lesions compared with the smallest tumor measurement obtained during the study; or significant increase in T2/FLAIR nonenhancing lesion compared with baseline scan or best response; or any new lesion; or clear clinical deterioration; or failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease. TTP was estimated using Kaplan-Meier method.

PFS rate at 3 and 9 months is defined as proportion of participants who neither progressed nor died due to any cause, whichever occurred first after first dose at 3 months and 9 months, respectively. Progression was defined as at least 25% increase in measurement of enhancing lesions compared with the smallest tumor measurement obtained during the study; or significant increase in T2/FLAIR nonenhancing lesion compared with baseline scan or best response; or any new lesion; or clear clinical deterioration; or failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease. Proportion of participants with PFS at 3 and 9 months were estimated using Kaplan-Meier method.

PFS was measured from the start of treatment with MEDI-575 until the documentation of disease progression or death due to any cause, whichever occurred first. Progression was defined as at least 25% increase in measurement of enhancing lesions compared with the smallest tumor measurement obtained during the study; or significant increase in T2/FLAIR nonenhancing lesion compared with baseline scan or best response; or any new lesion; or clear clinical deterioration; or failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease. PFS was censored on the date of last tumor assessment documenting absence of tumor progression for participants who have no documented progression and were still alive prior to data cutoff, dropout, or the initiation of alternate anticancer treatment. Time to PFS was estimated using Kaplan-Meier method.

Overall survival is defined as the time from the start of treatment with MEDI-575 until death. For the participants who were alive at the end of study or lost to follow-up, Overall survival was censored on the last date when participants were known to be alive. The Overall survival was estimated using the Kaplan-Meier method.

MEDI-575 (study drug) blocks platelet-derived growth factor (PDGF) binding to PDGF receptor (PDGFR) alpha and inhibits signaling. The tissue samples which were collected prior to the study entry (archived tumor samples) were evaluated by immunohistochemistry staining for expression of PDGFR alpha signaling protein that are targets of MEDI-575. Expression of PDGFR alpha in tumor cells and tumor-associated stromal cells were evaluated for intensity and distribution of staining. The percentage of participants with positive PDGFR alpha staining in the tumor cells and tumor-associated stromal cells were reported.

An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Treatment-emergent AEs (TEAEs) are AEs occurring or worsening after the administration of study drug until 90 days after the last dose of study drug or until the participant began another anticancer therapy, which ever came first. A serious AE (SAE) is any AE that results in death, is immediately life threatening, require (or prolong) inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, or is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above. The TEAEs and SAEs were summarized using MedDRA version 15.1. Participants were counted only once for each event, regardless of number of events the participant had.

Eastern Cooperative Oncology Group (ECOG) performance status is a scale that measures how cancer affects the daily life of a participant on an ordinal scale from grade 0 (fully active ie, best) to 5 (dead ie, worst). Following are ECOG grades: 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair >50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead.

Laboratory evaluations of blood and urine samples were performed, including hematology (hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count with differential); serum chemistry (calcium, chloride, magnesium, potassium, sodium, aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma glutamyl transferase, lactic dehydrogenase, carbon dioxide/bicarbonate, blood urea nitrogen, uric acid, creatinine, total bilirubin, glucose, albumin, total protein, triglycerides, cholesterol, phosphorous); urinalysis (pH, protein, blood, glucose, ketones, bilirubin); and coagulation parameters. Abnormal laboratory finding that required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation, was reported as an AE. Number of participants with TEAEs related to laboratory evaluations were reported.

All 12-lead electrocardiograms (ECGs) performed during the study were obtained in triplicate (ie, 3 ECGs were obtained within a 5-minute time period) and analyzed. Number of participants with TEAEs related to ECG after the start of study drug administration were reported. Participants were counted only once for each system organ class and preferred term, regardless of how many events the participants had.

Vital sign assessments were conducted throughout the study and included body temperature, blood pressure (seated), pulse rate and respiratory rate. The TEAEs related to vital signs in participants were reported. Participants were counted only once for each system organ class and preferred term, regardless of how many events the participants had.