OSPred Tool: A Digital Health Aid for Rapid Predictive Analysis of Correlations Between Early End Points and Overall Survival in Non-Small-Cell Lung Cancer Clinical Trials.

Purpose: Overall survival (OS) is the gold standard end point for establishing clinical benefits in phase III oncology trials. However, these trials are associated with low success rates, largely driven by failure to meet the primary end point. Surrogate end points such as progression-free survival (PFS) are increasingly being used as indicators of biologic drug activity and to inform early go/no-go decisions in oncology drug development.

Correlation Between Early Endpoints and Overall Survival in Non-Small-Cell Lung Cancer: A Trial-Level Meta-Analysis.

Early endpoints, such as progression-free survival (PFS), are increasingly used as surrogates for overall survival (OS) to accelerate approval of novel oncology agents. Compiling trial-level data from randomized controlled trials (RCTs) could help to develop a predictive framework to ascertain correlation trends between treatment effects for early and late endpoints. Through trial-level correlation and random-effects meta-regression analysis, we assessed the relationship between hazard ratio (HR) OS and (1) HR PFS and (2) odds ratio (OR) PFS at 4 and 6 months, stratified according to the mechanism of action of the investigational product.

Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study.

Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day.

Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors.

Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors.

Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib.

Effects of the Src inhibitor saracatinib (AZD0530) on renal function in healthy subjects.

Background: Saracatinib (AZD0530), a potent Src inhibitor, is a subject of current evaluation as an anticancer therapy. Increased plasma creatinine levels have previously been observed after saracatinib administration in healthy subjects and this study was undertaken to characterize the underlying mechanism of this increase.

Subjects And Methods: 56 healthy male subjects were assigned to either single- (n=28; randomised to placebo or saracatinib 500 mg) or multiple-dose oral treatment (n=28; randomised to placebo or saracatinib 125 mg for 14 days).

Epidermal growth factor receptor expression analysis in chemotherapy-naive patients with advanced non-small-cell lung cancer treated with gefitinib or placebo in combination with platinum-based chemotherapy.

Purpose: Two large, randomized, placebo-controlled trials (IRESSA NSCLC Trial Assessing Combination Therapy; INTACT 1 and 2) in non-small-cell lung cancer (NSCLC) failed to show survival benefit for gefitinib (IRESSA) in combination with first-line platinum-based chemotherapy. Epidermal growth factor receptor (EGFR) staining was assessed retrospectively in relation to survival response to gefitinib in combination with chemotherapy.

Methods: Tumor biopsies obtained prior to start of therapy were assessed by immunohistochemistry for EGFR using the Dako EGFR pharmDx assay (Dako, Denmark).

A phase II trial of gefitinib in patients with non-metastatic hormone-refractory prostate cancer.

Objective: To investigate, in a phase II trial, the use of the epidermal growth factor receptor (EGFR) inhibitor gefitinib as monotherapy in patients with non-metastatic hormone refractory prostate cancer (HRPC), as current treatment options for this disease are limited, and agents which target the EGFR should be assessed because EGFR is highly expressed in prostate cancer and associated with a poor prognosis.

Patients And Methods: Patients with histologically or cytologically confirmed cancer of the prostate with no evidence of metastatic disease were enrolled into this open-label, multicentre study of monotherapy with gefitinib 500 mg/day. The primary endpoint of the study was biochemical response, defined as a >/=50% decrease in serum prostate-specific antigen (PSA) level.

Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

Purpose: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib.

Patients And Methods: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC.