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Supplementary Figure S1; Supplementary Appendix.

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. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing.Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours.Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.

We assessed the impact of the coronavirus disease 2019 (COVID-19) pandemic on the statistical analysis of time-to-event outcomes in late-phase oncology trials. Using a simulated case study that mimics a Phase III ongoing trial during the pandemic, we evaluated the impact of COVID-19-related deaths, time off-treatment and missed clinical visits due to the pandemic, on overall survival and/or progression-free survival in terms of test size (also referred to as Type 1 error rate or alpha level), power, and hazard ratio (HR) estimates. We found that COVID-19-related deaths would impact both size and power, and lead to biased HR estimates; the impact would be more severe if there was an imbalance in COVID-19-related deaths between the study arms. Approaches censoring COVID-19-related deaths may mitigate the impact on power and HR estimation, especially if study data cut-off was extended to recover censoring-related event loss. The impact of COVID-19-related time off-treatment would be modest for power, and moderate for size and HR estimation. Different rules of censoring cancer progression times result in a slight difference in the power for the analysis of progression-free survival. The simulations provided valuable information for determining whether clinical-trial modifications should be required for ongoing trials during the COVID-19 pandemic.

Clinical development is the scientific process of exploring and confirming the product attributes and therapeutic role of potential new medical treatments. This chapter provides an overview of the clinical development of a pharmaceutical product for medical use, introducing and discussing the principles of clinical development and application of those principles on both a programmatic and a study level. While the development process is continuous, beginning during the discovery of an innovative potential pharmaceutical product and ending with the replacement of the innovative pharmaceutical by a more effective or safer alternative treatment, the process follows an orderly path of evidence-based, goal-directed development. This chapter focuses on the clinical development and registration of an innovative pharmaceutical product in the treatment of patients or of an additional indication for an existing pharmaceutical product.

Background In clinical trials that assess novel therapeutic agents in patients with non-small-cell lung cancer (NSCLC), early endpoints (e.g. progression-free survival [PFS] and objective response rate) are often evaluated as indicators of biological drug activity, and are used as surrogate endpoints for overall survival (OS). Compiling trial-level data could help to develop a predictive framework to ascertain correlation trends between treatment effects for early (e.g. odds ratio [OR] for PFS at 6 months) and late endpoints (e.g. hazard ratio [HR] OS). Methods A dataset was compiled, which included 81 randomized, controlled trials (RCTs; Phase II–IV) of NSCLC (Stages I–IV), with 35 drugs and 156 observations. The dataset was collected from multiple source databases, including Citeline, TrialTrove, clinicaltrials.gov, and PubMed. We applied random-effects meta-analysis to correlate a variety of treatment effects for early endpoints with HR OS. We performed meta-regression analyses across different data-strata, stratified by the mechanism of action (MoA) of the investigational product (programmed death protein-1/programmed death-ligand 1 [PD-1/PD-L1], epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor, and DNA damage response). Results Low (Spearman’s rho 0.3– 1, indicate benefit with the investigational product. Conclusions Using a comprehensive summary data set in the NSCLC space, we observed low-to-moderate correlations between treatment effects for early endpoints and HR OS across RCTs of agents with different MoAs, including trials of PD-1/PD-L1 checkpoint inhibitors. Exploration of additional endpoints, beyond RECIST, is required to identify other early indicators of efficacy that might predict HR OS. By incorporating additional trial-level parameters and building composite biomarkers using machine intelligence methods, in collaboration with innovative trial design efforts, we envisage to improve the prediction of HR OS from early endpoints.

We would like to thank the authors of the letter (Bartlett et al. 2020) for sharing their concerns regarding reporting treatment effect under nonproportional hazards (NPH), and we respect their pos...

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. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.

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. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.

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. RESULTS Fifty-eight men were enrolled across 10 centres in the USA; none of the 40 evaluable patients had a PSA response. Gefitinib was generally well tolerated, with diarrhoea being the most common treatment- related adverse event, in 71% of patients. There was treatment-related grade 3 diarrhoea in 5% of patients, with no grade 4 adverse events or deaths during the course of the study. CONCLUSIONS Gefitinib has no single-agent activity in non-metastatic HRPC, as assessed by decreases in serum PSA level. This phase II study also confirmed the well-established favourable tolerability profile of gefitinib monotherapy.

PurposeMost 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 MethodsWe 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.ResultsEGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype.ConclusionEGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

3520 Background: Agents that specifically inhibit the invasive phenotype of cancers are urgently required. AZD0530 is a potent, orally administered inhibitor of Src that has been shown preclinically to prevent phosphorylation of downstream mediators of motility and invasion, paxillin (Pax) and focal adhesion kinase (FAK), with inhibition of metastasis in vivo. Although Src activation is associated with poor prognosis, inhibition of Src activity in human cancers has never been demonstrated. Methods: Patients with cancer received AZD0530 in dose cohorts of 50 mg to 250 mg daily in this 2-part Phase I study. Paired tumor biopsies were acquired for investigation of Src inhibition. Part A defined MTD, toxicity profile and PK. Part B expanded the 50 mg, 125 mg and 175 mg cohorts to characterize changes in phosphorylation of the Src substrates Pax and FAK by evaluating intensity and localization of staining by IHC. Biopsy samples were assigned as pre- or post-AZD0530 treatment by an independent pathology panel blinded to treatment status, and tested for 80% concordance at a 10% alpha. Markers of bone turnover were collected. Results: There were 81 patients evaluable for safety assessment. The median number of prior therapies was 5 (1–27). Part A: DLTs occurred in 3 patients at 250 mg (leukopenia; septic shock (grd5) with renal failure; asthenia) and in 2 patients at 200 mg (febrile neutropenia; dyspnea). Part B confirmed the 50, 125 and 175 mg doses to be tolerable. The mean duration of AZD0530 treatment was 44 days (6–217); 11 patients were treated for longer than 3 months. The pathology panel found consistent modulation of phosphorylation and/or cellular localization of tumor Pax (P=0.067) and FAK (P=0.002) consequent to AZD0530 therapy. There was a dose response trend for reductions in Pax phosphorylation. Bone biomarker and PK data will be presented. Conclusion: For the first time, biomarkers have confirmed inhibition of Src in human cancers. AZD0530 is well tolerated at doses that demonstrate significant inhibition of Src activity. The trend for dose response changes in biomarkers of Src inhibition indicates that the MTD should be taken forward in further development. AZD0530 has a potential role in the prevention of metastases and invasion. No significant financial relationships to disclose.

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.Tumor biopsies obtained prior to start of therapy were assessed by immunohistochemistry for EGFR using the Dako EGFR pharmDx assay (Dako, Denmark). Analyses were stratified by trial and performed independently for patients randomized to placebo and gefitinib as well as for both treatment groups combined. A restricted backwards elimination Cox regression analysis was conducted to identify independent EGFR factors that were statistically significant (P0.10), and these were also tested for treatment interaction to assess if they served as predictive factors.Analyses found two statistically significant EGFR-based prognostic factors representing growth pattern and percent membrane staining in patients treated with gefitinib (P = 0.0023), placebo (P = 0.0128), and both combined (P0.0001). The prognostic effect was independent of other known prognostic factors. There was no predictive effect of either the growth pattern or membrane staining variable.While some previous studies indicate that higher EGFR expression correlates with poor survival, our analyses provide statistically significant evidence that the combination of EGFR expression and growth pattern is a strong prognostic indicator for improved survival within this setting. The effects of membrane staining and growth pattern are still significant when adjusting for mutation.