pyrimidinones and Small-Cell-Lung-Carcinoma

Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.. The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles.. 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. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle.. Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified).. Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors.. ClinicalTrials.gov identifier NCT02482311; registered June 2015.

Topics: Female; Humans; Lung Neoplasms; Ovarian Neoplasms; Pyrazoles; Pyrimidinones; Small Cell Lung Carcinoma; Triple Negative Breast Neoplasms

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.. The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients).. Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule.. To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Drug-Related Side Effects and Adverse Reactions; Female; Gene Amplification; Humans; Male; Middle Aged; Morpholines; Neoplasm Recurrence, Local; Platinum; Progression-Free Survival; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyrimidines; Pyrimidinones; Rapamycin-Insensitive Companion of mTOR Protein; Small Cell Lung Carcinoma; Tumor Suppressor Protein p53

Topics: Apoptosis; Benzoxazoles; Cell Line, Tumor; DNA Damage; Endoplasmic Reticulum Stress; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Pyrazoles; Pyrimidines; Pyrimidinones; Small Cell Lung Carcinoma; TOR Serine-Threonine Kinases

The monocarboxylate transporter-1 (MCT1) represents a novel target in rational anticancer drug design while AZD3965 was developed as an inhibitor of this transporter and is undergoing Phase I clinical trials ( http://www.clinicaltrials.gov/show/NCT01791595 ). We describe the optimisation of an immunofluorescence (IF) method for determination of MCT1 and MCT4 in circulating tumour cells (CTC) as potential prognostic and predictive biomarkers of AZD3965 in cancer patients.. Antibody selectivity was investigated by western blotting (WB) in K562 and MDAMB231 cell lines acting as positive controls for MCT1 and MCT4 respectively and by flow cytometry also employing the control cell lines. Ability to detect MCT1 and MCT4 in CTC as a 4(th) channel marker utilising the Veridex™ CellSearch system was conducted in both human volunteer blood spiked with control cells and in samples collected from small cell lung cancer (SCLC) patients.. Experimental conditions were established which yielded a 10-fold dynamic range (DR) for detection of MCT1 over MCT4 (antibody concentration 6.25 μg/mL; integration time 0.4 seconds) and a 5-fold DR of MCT4 over MCT 1 (8 μg/100 μL and 0.8 seconds). The IF method was sufficiently sensitive to detect both MCT1 and MCT4 in CTCs harvested from cancer patients.. The first IF method has been developed and optimised for detection of MCT 1 and MCT4 in cancer patient CTC.

Topics: Antineoplastic Agents; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Fluorescent Antibody Technique; Healthy Volunteers; Humans; Monocarboxylic Acid Transporters; Muscle Proteins; Neoplastic Cells, Circulating; Pyrimidinones; Small Cell Lung Carcinoma; Symporters; Thiophenes

The monocarboxylate transporter 1 (MCT1) inhibitor, AZD3965, is undergoing phase I evaluation in the United Kingdom. AZD3965 is proposed, via lactate transport modulation, to kill tumor cells reliant on glycolysis. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use.. AZD3965 sensitivity was determined for seven SCLC cell lines, in normoxia and hypoxia, and for a tumor xenograft model. Proof of mechanism was sought via changes in intracellular/tumor lactate. Expression of MCT1 and related transporter MCT4 was assessed by Western blot analysis. Drug resistance was investigated via MCT4 siRNAi and overexpression. The expression and clinical significance of MCT1 and MCT4 were explored in a tissue microarray (TMA) from 78 patients with SCLC.. AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intratumor lactate. In the TMA, high MCT1 expression was associated with worse prognosis (P = 0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors.. This study provides a rationale to test AZD3965 in patients with SCLC. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Inhibitory Concentration 50; Kaplan-Meier Estimate; Lactic Acid; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Monocarboxylic Acid Transporters; Multivariate Analysis; Muscle Proteins; Pyrimidinones; Small Cell Lung Carcinoma; Symporters; Thiophenes; Xenograft Model Antitumor Assays