piperidines and regorafenib

The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.

Topics: Anilides; Crizotinib; Humans; Imatinib Mesylate; Imidazoles; Indoles; Neoplasms; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Pyridines; Pyrroles; Quinazolines; Receptor Protein-Tyrosine Kinases; Sorafenib; Sunitinib

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Axitinib; Fatigue; Humans; Imidazoles; Indazoles; Indoles; Kidney; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib

Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.. IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0-1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1-21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1-21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.. Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7-13·6). Median overall survival was 8·87 months (95% CI 7·00-10·61) with atezolizumab plus cobimetinib, 7·10 months (6·05-10·05) with atezolizumab, and 8·51 months (6·41-10·71) with regorafenib; the hazard ratio was 1·00 (95% CI 0·73-1·38; p=0·99) for the combination versus regorafenib and 1·19 (0·83-1·71; p=0·34) for atezolizumab versus regorafenib. Grade 3-4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3-4 adverse events in the combination group were diarrhoea (20 [11%] of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).. IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.. F Hoffmann-La Roche Ltd/Genentech Inc.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Middle Aged; Phenylurea Compounds; Piperidines; Prognosis; Pyridines; Salvage Therapy; Survival Rate

Topics: Antibodies, Monoclonal, Humanized; Azetidines; B7-H1 Antigen; Colorectal Neoplasms; Humans; Phenylurea Compounds; Piperidines; Pyridines

To clarify the effects of cylcin E1 expression on HCC tumor progression, we studied the expression of cyclin E1 and inhibitory efficacy of regorafenib and sorafenib in HCC cells, and investigated a potential therapy that combines regorafenib treatment with cyclin E1 inhibition.. Western blotting for caspase-3 and Hoechst 33225 staining was used to measure the expression level of apoptosis-related proteins under drug treatment.. Our results showed that enhanced expression of cyclin E1 after transfection compromised apoptosis in HCC cells induced by regorafenib or sorafenib. Conversely, down-regulation of cyclin E1 gene expression or inhibition of cyclin E1 by the cyclin-dependent kinase (CDK) inhibitors dinaciclib (DIN) or flavopiridol sensitized HCC cells to regorafenib and sorafenib by inducing apoptosis. The expression of Mcl-1, which is modulated by STAT3, plays a key role in regulating the therapeutic effects of CDK inhibitors. Xenograft experiments conducted to test the efficacy of regorafenib combined with DIN showed dramatic tumor inhibitory effects due to induction of apoptosis. Our results suggested that the level of cyclin E1 expression in HCCs may be used as a pharmacodynamic biomarker to assess the antitumor effects of regorafenib or sorafenib.. Combining regorafenib and CDK inhibitors may enhance the clinical efficiency of the treatment of HCCs.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cyclic N-Oxides; Cyclin E; Drug Synergism; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Indolizines; Liver Neoplasms; Male; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Oncogene Proteins; Phenylurea Compounds; Piperidines; Prognosis; Pyridines; Pyridinium Compounds; Sorafenib; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards. The method was validated based on FDA recommendations, including assessment of extraction yield (74-104%), matrix effects, analytical recovery (94-104%) with low variability (<15%). The method is sensitive (lower limits of quantification within 1 to 200 ng/mL), accurate (intra- and inter-assay bias: -0.3% to +12.7%, and -3.2% to +6.3%, respectively) and precise (intra- and inter-assay CVs within 0.7-7.3% and 2.5-8.0%, respectively) over the clinically relevant concentration range (upper limits of quantification 500 to 100,000 ng/mL). This method is applied in our laboratory for both clinical research programs and routine therapeutic drug monitoring service of PKIs.

Topics: Administration, Oral; Antineoplastic Agents; Azetidines; Child; Chromatography, High Pressure Liquid; Humans; Imidazoles; Indazoles; Indoles; Limit of Detection; Linear Models; Oximes; Phenylurea Compounds; Piperidines; Pyridines; Pyridones; Pyrimidines; Pyrimidinones; Reproducibility of Results; Sulfonamides; Tandem Mass Spectrometry; Vemurafenib