Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study.

Purpose: This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers.

Patients And Methods: Eligible patients (n = 36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles.

Adjuvant Olaparib for Patients with - or -Mutated Breast Cancer.

Background: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with or germline mutation-associated early breast cancer.

Methods: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with or germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy.

Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in -Amplified Gastric Cancer.

Purpose: Some gastric cancers harbor gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options.

Biomarker-driven phase 2 umbrella trial study for patients with recurrent small cell lung cancer failing platinum-based chemotherapy.

Background: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study.

Methods: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes.

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis.

Combination of Docetaxel Plus Savolitinib in Refractory Cancer Patients: A Report on Phase I Trial.

MET amplification is a frequently observed genomic aberration in solid tumors. We conducted a phase I trial to evaluate dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) for the combination therapy. The following dose levels were tested in this single-arm phase I study: docetaxel as an intravenous infusion over 1 hour at 60 mg/m once every 3 weeks of a 21-day schedule plus savolitinib (level 1, 200 mg qd; level 2, 400 mg qd; level 3, 600 mg qd; level 4800 mg qd).

Defining actionable mutations for oncology therapeutic development.

Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.

The Challenges of Precision Oncology Drug Development and Implementation.

The drivers of precision medicine are clear: for patients (and physicians)--more options, durable clinical benefit, reduced exposure to non-effective drugs and potential to leverage current scientific and technological advances; for the pharmaceutical industry--the potential to tackle core challenges in discovering and developing better and more efficacious medicines, to reduce rates of attrition in drug development and to reduce development costs; for healthcare systems and payers--improved efficiency through the provision of effective care and avoiding ineffective treatments. Oncology has been at the vanguard, the improvements gained in patient survival notable. However, the increasing number of molecular subgroups requires an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments.

Precision medicine in oncology drug development: a pharma perspective.

A rapid expansion in precision medicine founded on the potential for durable clinical benefit through matching a drug to a predictive marker used to select patients has driven the development of targeted drugs with accompanied companion diagnostics for patient selection. Oncology has been at the forefront, with the improvements in patient survival notable. Increasing numbers of molecular subgroups require an equally increasing number (and new generation) of highly selective agents targeting inevitably lower incidence molecular segments, posing significant challenges for drug development.

Patient-centric trials for therapeutic development in precision oncology.

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease.

The impact of germline mutations on targeted therapy.

Targeted therapies provide clinical benefit and improved therapeutic index. They have a growing prominence in patient management and focus in drug development. Their development is fuelled by our deepening knowledge of complex disease phenotypes and the need for improvement in new therapeutic efficacy.

Neuromedin U stimulates contraction of human long saphenous vein and gastrointestinal smooth muscle in vitro.

The neuropeptide Neuromedin U (NMU) stimulates smooth muscle contraction, and modulates local blood flow and adrenocortical function via two endogenous receptors, NMU1 and NMU2. Although its amino-acid sequence is highly conserved across species, the physiological effects of NMU are variable between species and little is known of its effects on human tissues. We have examined the contractile effects of NMU-25 on human smooth muscles of the gastrointestinal (GI) tract (ascending colon, gallbladder) and long saphenous vein (LSV) using in vitro organ bath bioassays.

Expression of angiogenic VEGF-A (soluble isoforms 121, 165) and lymphangiogenic VEGF-C in colorectal cancers with micro-satellite instability.

Background And Objectives: Colorectal cancers (CRC) with high-level micro-satellite instability (MSI-H) show reduced metastatic potential and better prognosis compared to stage-matched stable (MSS) cancers. Angiogenesis/lymphangiogenesis, central to tumour growth and spread, is mediated by vascular endothelial growth factor (VEGF) cytokines, but little is known of their relationship to MSI.

Methods: In this study, 67 sporadic CRC with identified MSI status, and 8 samples of normal colon were analysed for VEGF-A soluble isoforms (VEGF-121/VEGF-165) and VEGF-C gene transcription (by RT-PCR and scanning densitometry), and blood vessel density (BVD; measuring angiogenesis) and VEGF-C protein expression (measuring lymphangiogenesis).

Advanced qRT-PCR technology allows detection of the cholecystokinin 1 receptor (CCK1R) expression in human pancreas.

Objectives: To help clarify the controversy over the detection of expression of the cholecystokinin 1 receptor (CCK1R; CCKAR) in human pancreas.

Methods: Applied qRT-PCR to detect CCK1R expression using the SYBR green/Smart Cycler II and the QZyme oligonucleotide/ABI PRISM 7500 systems to detect CCK1R expressed message in highly purified cDNAs from human pancreas and other tissues. Samples of normal pancreas were obtained at operation (pancreaticoduodenectomy; Whipple's procedure) and used to ascertain the expression of CCK1R in human tissue and investigate donor individual variability in expression levels by semi-quantitative RT-PCR and scanning densitometry.

Use of a needleless injection system for digital ring block anesthesia.

Digital ring block anesthesia, which is frequently used before surgery for ingrown toenails, is often extremely uncomfortable for patients and can be the most distressing aspect of the procedure. The authors used a novel needleless injection device to induce digital anesthesia before surgery and compared it in terms of patient discomfort and preference with use of a standard needle and syringe for injection in individuals undergoing simultaneous bilateral nail procedures. Use of the needleless device significantly reduced the pain associated with this procedure and was preferred over use of a standard needle and syringe by all individuals.