Open-Label, Multicenter, Phase I Study to Assess Safety and Tolerability of Adavosertib Plus Durvalumab in Patients with Advanced Solid Tumors.

Background: Adavosertib (AZD1775) is a small-molecule Wee1 inhibitor. Durvalumab is a PD-L1 inhibitor.

Objective: The safety, tolerability, pharmacokinetics, and preliminary antitumor activity of adavosertib plus durvalumab were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).

Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial.

Background: Adavosertib is a first-in-class, selective small-molecule inhibitor of Wee1. Olaparib is an inhibitor of poly(ADP-ribose) polymerase (PARP). Preclinical data suggest that adavosertib enhances the antitumor effect of PARP inhibitors.

Multidisciplinary Delphi Consensus on Safety of Combining Transarterial Radioembolization with Yttrium-90 Microspheres with Systemic Anticancer Agents for the Treatment of Liver Malignancy.

Purpose: To provide guidance, via multidisciplinary consensus statements, on the safety interactions between systemic anticancer agents (such as radiosensitizing chemotherapy, immunotherapy, targeted therapy, and peptide receptor radionuclide therapy) and transarterial radioembolization (TARE) with yttrium-90 (Y)-labeled microspheres in the treatment of primary and metastatic liver malignancies.

Materials And Methods: A literature search identified 59 references that informed 26 statements on the safety of Y TARE combined with systemic therapies. Modified Delphi method was used to develop consensus on statements through online anonymous surveys of the 12 panel members representing the fields of interventional radiology, medical oncology, surgical oncology, hepatology, and pharmacy, focusing on hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC), neuroendocrine tumors, metastatic breast cancer, and intrahepatic cholangiocarcinoma.

"The students keep me hopeful": Teacher hope during the COVID-19 pandemic.

This study examined teacher enactment of hope, specifically willpower, waypower, and agency in the shadow of the COVID-19 glare. Participants of this mixed methods study were K-12 public school classroom teachers (n = 233) in a Western US state. Quantitative survey results indicated teachers maintained moderate to high levels of hope.

A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors.

Background: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.

Objective: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles.

Patients And Methods: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease.

A phase Ib study of adavosertib, a selective Wee1 inhibitor, in patients with locally advanced or metastatic solid tumors.

Adavosertib selectively inhibits Wee1, which regulates intra-S and G2/M cell-cycle checkpoints. This study investigated dosing schedules for adavosertib monotherapy, determining the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients with advanced solid tumors.Patients received oral adavosertib qd or bid on a 5/9 schedule (5 days on treatment, 9 days off) in 14-day cycles, or qd on one of two 5/2 schedules (weekly, or for 2 of 3 weeks) in 21-day cycles.

A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies.

Background: This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers.

Methods: Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle.

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours.

Background: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours.

Methods: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses.

A real-world retrospective study of the use of Ki-67 testing and treatment patterns in patients with HR+, HER2- early breast cancer in the United States.

Background: The National Comprehensive Cancer Network recommends that patients with hormone receptor-positive early breast cancer be considered for adjuvant endocrine therapy (ET) after primary treatment like surgical excision. Adjuvant chemotherapy (CT) use primarily depends on risk of recurrence. Biomarkers such as Ki-67 potentially have most value in patients with intermediate risk factors, such as involvement of 1-3 positive nodes.

Discordance in Tumor Mutation Burden from Blood and Tissue Affects Association with Response to Immune Checkpoint Inhibition in Real-World Settings.

Background: Tumor mutation burden (TMB), a biomarker for immune checkpoint inhibitor (CPI) response, is reported by both blood- and tissue-based next-generation sequencing (NGS) vendors. However, the agreement between TMB from blood (bTMB) and tissue (tTMB) in real-world settings, both in absolute value and association with CPI response, is not known.

Materials And Methods: This study utilizes Sarah Cannon's precision medicine platform, Genospace, to harmonize clinico-genomic data from 17 206 patients with cancer with NGS results from September 2015 to August 2021.

Tumor-Specific and Tumor-Agnostic Molecular Signatures Associated With Response to Immune Checkpoint Inhibitors.

Purpose: Next-generation sequencing (NGS) testing is being incorporated into routine standard of care for patients with cancer. Immune checkpoint inhibitors (CPIs) are approved for use in both tumor-specific and tumor-agnostic indications. We sought to determine tumor type-specific or tumor-agnostic correlations between mutations detected by NGS and response to CPIs.

Next-Generation Sequencing of Patients With Breast Cancer in Community Oncology Clinics.

Purpose: Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results.

Methods: We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019.

Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study.

Purpose: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer.

Patients And Methods: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin.

A Phase 1b Trial of Prexasertib in Combination with Standard-of-Care Agents in Advanced or Metastatic Cancer.

Background: The checkpoint kinase 1 (CHK1) inhibitor prexasertib exhibited modest monotherapy antitumor activity in prior trials, suggesting that combination with chemotherapy or other targeted agents may be needed to maximize efficacy.

Objectives: The aim of this study was to determine the recommended phase II dose and schedule of prexasertib in combination with either cisplatin, cetuximab, pemetrexed, or 5-fluorouracil in patients with advanced and/or metastatic cancer, and to summarize preliminary antitumor activity of these combinations.

Patients And Methods: This phase Ib, nonrandomized, open-label study comprised dose-escalation phase(s) with multiple sub-arms evaluating different prexasertib-drug combinations: Part A, prexasertib + cisplatin (n = 63); Part B, prexasertib + cetuximab (n = 41); Part C, prexasertib + pemetrexed (n = 3); Part D, prexasertib + 5-fluorouracil (n =8).

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Laboratory Reference Ranges and Testing Intervals Work Group.

Purpose: In clinical research, eligibility criteria promote patient safety and optimize the evidence generated from clinical trials. However, overly stringent eligibility criteria, including laboratory requirements, may limit enrollment, resulting in delayed trial completion and potentially limiting applicability of trial results to a general practice population.

Experimental Design: Starting in 2018, a working group consisting of experts in direct patient care, the FDA, industry, and patient advocacy developed recommendations to guide the optimal use of laboratory reference ranges and testing intervals in clinical trial eligibility criteria and study procedures.

Preclinical Evaluation and Phase Ib Study of Prexasertib, a CHK1 Inhibitor, and Samotolisib (LY3023414), a Dual PI3K/mTOR Inhibitor.

Purpose: Prexasertib, a checkpoint kinase 1 inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib + samotolisib, a PI3K/mTOR inhibitor.

Patients And Methods: Prexasertib + samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient-derived xenograft (PDX) mouse models.

Negative-pressure wound therapy compared with standard dressings following surgical treatment of major trauma to the lower limb: the WHiST RCT.

Background: Major trauma is the leading cause of death in people aged < 45 years. Patients with major trauma usually have lower-limb fractures. Surgery to fix the fractures is complicated and the risk of infection may be as high as 27%.

Molecular Profiling in Drug Development: Paving a Way Forward.

As researchers learn more about tumor biology and the molecular mechanisms involved in tumorigenesis, metastasis, and tumor evolution, clinical trials are growing more complex and patient selection for clinical trials is becoming more specific. Rather than exploit certain phenotypic characteristics of tumor cells (e.g.

Effect of physio-chemical seed treatments on opium poppy downy mildews caused by Peronospora meconopsidis and P. somniferi.

Downy mildew of opium poppy is the single biggest disease constraint afflicting the Australian poppy industry. Within the pathosystem, the transmission of infections via infested seed is of major concern. Both downy mildew pathogens of poppy; Peronospora meconopsidis and P.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial.

Background: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC).

Methods: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity.

Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors.

Purpose We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study. Experimental Design Patients with advanced solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off ("21/7"); (2) intermittent cobimetinib and 21/7 pictilisib ("intermittent"); or (3) both agents once-daily for 7-days-on 7-days-off ("7/7"). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively.

Detection of Two Peronospora spp., Responsible for Downy Mildew, in Opium Poppy Seed.

Downy mildew is a serious threat to opium poppy production globally. In recent years, two pathogen species, Peronospora somniferi and Peronospora meconopsidis, which induce distinct symptoms, have been confirmed in Australia. In order to manage the spread of these pathogens, identifying the sources of inoculum is essential.

Evaluation of Prexasertib, a Checkpoint Kinase 1 Inhibitor, in a Phase Ib Study of Patients with Squamous Cell Carcinoma.

Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. Patients were given prexasertib 105 mg/m as a 1-hour infusion on day 1 of a 14-day cycle.

Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort.

Objective: This phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance.