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AZD1152 was generally well tolerated with neutropenia being the most frequently reported AE and DLT. Exposure to AZD1152-hQPA, the active drug of AZD1152, was linear.

A B S T R A C T PurposeTo compare gefitinib with placebo in chemotherapy naïve patients with advanced non-small-cell lung cancer (NSCLC) and poor performance status. Patients and MethodsNSCLC patients (chemotherapy naïve, WHO performance status 2 or 3; unfit for chemotherapy; stage IIIB/IV) were randomly assigned to gefitinib (250 mg/d) plus best supportive care (BSC; n ϭ 100) or placebo plus BSC (n ϭ 101). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and safety. Correlation of gefitinib efficacy with EGFR gene copy number (fluorescent in situ hybridization [FISH]) was explored. ResultsHazard ratios (HRs; gefitinib:placebo) were 0.82 (95% CI, 0.60 to 1.12; P ϭ .217) for PFS and 0.84 (95% CI, 0.62 to 1.15; P ϭ .272) for OS. As expected for this patient population, OS for both arms was poor, at about 3 months. ORRs were 6.0% (gefitinib) and 1.0% (placebo). QOL and PSI rates were 21.1% and 28.3% (gefitinib) and 20.0% and 28.3% (placebo), respectively. In EGFR FISH-positive patients (n ϭ 32), HRs were 0.29 (95% CI, 0.11 to 0.73) for PFS and 0.44 (95% CI, 0.17 to 1.12) for OS. No unexpected adverse events occurred. ConclusionThere was no statistically significant difference in PFS, OS, and ORRs after treatment with gefitinib or placebo, in the overall population; improvements in QOL and symptoms were similar in both groups. Tolerability profile of gefitinib was consistent with previous studies. PFS was statistically significantly improved for gefitinib-treated patients with EGFR FISH-positive tumors.

The purpose of this study was to determine the maximum-tolerated dose (MTD), pharmacokinetics and safety profile for two different dosing regimens of barasertib, a selective inhibitor of Aurora B Kinase. In this Phase I trial, patients with advanced solid malignancies were treated with escalating doses of barasertib, administered as either a 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Thirty-five patients were treated. The MTDs were 150 mg as a 48-h continuous infusion and 220 mg administered as two 2-h infusions (110 mg/day, days 1, 2, 15 and 16), with neutropenia the dose-limiting toxicity (DLT) of each schedule. Common Terminology Criteria of Adverse Events (CTCAE) grade ≥ 3 neutropenia (with or without fever) occurred in 34% of patients overall. Other adverse events, many of hematologic or gastrointestinal etiology, were of mild or moderate intensity. No objective tumor responses were observed, although stable disease was observed in 23% of patients. Systemic exposure to barasertib-hQPA, the more active moiety to which barasertib is converted, was observed by 1 and 6 h into the 2-h and continuous infusion, respectively, and exhibited linear pharmacokinetics. In summary, barasertib was generally well tolerated, with neutropenia the most frequent and dose-limiting toxicity, irrespective of schedule. Future development of barasertib will depend on better definition of its therapeutic index.

BackgroundE7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046.MethodsThis first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment.ResultsNo dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses.ConclusionsIn this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting.Trial registration numberNCT02540291.

SummaryThis follow‐up extension of a randomised phase II study assessed differences in long‐term outcomes between bortezomib‐thalidomide‐dexamethasone (VTD) and VTD‐cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m2; days 1, 4, 8, 11), thalidomide (100 mg; days 1–21), and dexamethasone (40 mg; days 1–4, 9–12), with/without cyclophosphamide (400 mg/m2; days 1, 8), for four 21‐day cycles before stem‐cell mobilisation/transplantation. After a median follow‐up of 64·8 months, median time‐to‐next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76–2·09; P = 0·370]. Five‐year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD‐negative versus MRD‐positive patients with bone marrow‐confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long‐term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

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The purpose of this study is to assess patient, tumour and treatment related factors on quality of life (QoL) outcomes of patients who received definitive or postoperative radiotherapy +/- chemotherapy for head and neck (H&N) cancer. In this cross-sectional study, 110 H&N cancer patients were evaluated in follow-up visit and were asked to fill out the European Organisation for Research and Treatment of Cancer QoL Core Questionnaire (QLQ-C-30) and H&N Module (QLQ-H&N35). Patients were also graded for their late side effects using EORTC/RTOG scoring system. The QLQ C-30 and QLQ-H&N35 mean scores were compared using ANOVA analysis for these variables: age, gender, occupation, educational status, social security status, place of residence, tumour localization, clinical stage, comorbidity, Karnofsky performance score, treatment modality and side effects. Median follow-up was 29 (4-155) months. Tumour localization was significant factor affecting physical (P = 0.03), social (P = 0.01), cognitive (P = 0.002) functioning. Treatment modality had significant impact on the physical (P = 0.02) and cognitive scores (P = 0.008). Global QoL was affected significantly by disease stage (P = 0.01) and occupation (P = 0.01). The QLQ-H&N35 scores were found significantly higher in patients with moderate/severe late morbidity. Tumour localization and the treatment modality are the most important factors affecting the QoL of H&N cancer patients treated definitively.