Heterocycles display an intrinsic reactivity which enables rich, versatile and productive transformations. Taking into account their ubiquitous presence in natural products and drugs, the development ...of new, fast and efficient preparative protocols for these structures remains an urgent task in Organic Synthesis. Multicomponent reactions using heterocyclic chemistry offer new possibilities to exploit this exclusive reactivity. Recent results show relevant examples of such transformations. Several approaches which allow the construction of complex heterocyclic compounds from simple starting materials using this principle have been analyzed.
Big plays from small heterocycles! The use of simple heterocycles as substrates in multicomponent reactions enable the straightforward syntheses of complex structures (see scheme) and opens interesting possibilities for the study of new reactivity pathways.
Summary Background Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to ...increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. Methods The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT01771458. Findings Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus 2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30). Interpretation The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. Funding Institut Curie.
SummaryBackgroundPre-clinical and clinical evidence suggests that simultaneous blockade of VEGF receptor-2 (VEGFR-2) and PD-1 or PD-L1 enhances antigen-specific T-cell migration, antitumour activity, ...and has favourable toxicity. In this study, we aimed to assess the safety and preliminary antitumour activity of ramucirumab (an IgG1 VEGFR-2 antagonist) combined with pembrolizumab (an IgG4 PD-1 antagonist) in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, or urothelial carcinoma. MethodsWe did a multicohort, non-randomised, open-label, phase 1a/b trial at 16 academic medical centres, hospitals, and clinics in the USA, France, Germany, Spain, and the UK. We enrolled adult patients aged 18 years or older with histologically confirmed gastric or gastro-oesophageal junction adenocarcinoma (cohorts A and B), non-small-cell lung cancer (cohort C), or urothelial carcinoma (cohort D), whose disease had progressed on one or two lines of previous therapy (for those with gastric or gastro-oesophageal junction adenocarcinoma) or one to three lines of previous therapy (for those with non-small-cell lung cancer and urothelial carcinoma) that included platinum (for all tumour types) or fluoropyrimidine or both (for gastric or gastro-oesophageal junction adenocarcinoma). Eligibility criteria included presence of measurable disease and an Eastern Cooperative Oncology Group performance status of 0–1. Patients with previously untreated gastric or gastro-oesophageal junction adenocarcinoma and non-small-cell lung cancer were also enrolled (in two additional separate cohorts); the results for these cohorts will be reported separately. The first 21-day treatment cycle was a dose-limiting toxicity observation period (phase 1a; safety run-in), followed by a phase 1b cohort expansion stage. Pembrolizumab 200 mg was administered intravenously on day 1, and intravenous ramucirumab was administered at 8 mg/kg on days 1 and 8 for cohort A or at 10 mg/kg on day 1 for cohorts B, C, and D, every 3 weeks, until disease progression or other discontinuation criteria were met. The primary endpoint was the safety and tolerability of ramucirumab in combination with pembrolizumab assessed by the incidence of adverse events in both phase 1a and 1b and as dose-limiting toxicities during phase 1a. The safety and activity analysis set included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02443324, and is no longer enrolling patients. FindingsBetween July 30, 2015 and June 24, 2016, we enrolled and treated 92 patients (41 with gastric or gastro-oesophageal junction adenocarcinoma, 27 with non-small-cell lung cancer, and 24 with urothelial carcinoma). Median follow-up was 32·8 months (IQR 28·1–33·6). During the first cycle of treatment (phase 1a safety run-in; n=11), one patient with gastro-oesophageal junction adenocarcinoma who received the 8 mg/kg dose of ramucirumab had grade 3 abdominal pain, colitis, hepatitis, interstitial lung disease, and jaundice, and grade 4 cholestasis, and died on treatment on day 40; the death was deemed related to progressive disease. No additional dose-limiting toxicities occurred and the decision was made to maintain the full planned doses of ramucirumab and pembrolizumab in phase 1b (n=81). Treatment-related adverse events occurred in 75 (82%) of 92 patients, the most common of which was fatigue (in 33 patients 36%), predominantly of grade 1 or 2 severity. 22 patients (24%) had one or more treatment-related adverse events of grade 3 or worse, most commonly hypertension (six patients; 7%) and colitis (five patients; 5%). Serious adverse events occurred in 53 (58%) of 92 patients, and were deemed related to treatment in 22 (24%) patients. The most common treatment-related serious adverse events were abdominal pain in patients with gastric or gastro-oesophageal junction adenocarcinoma (in three 7% of 41 patients); asthenia and myocardial infarction in patients with non-small-cell lung cancer (two 7% of 27 patients), and colitis in patients with urothelial carcinoma (two 8% of 24 patients). Six (7%) of 92 patients discontinued treatment because of treatment-related adverse events, and one death (from pulmonary sepsis in a patient with gastric or gastro-oesophageal junction adenocarcinoma) was deemed related to treatment. The number of patients achieving an objective response was three (7%; 95% CI 1·5–19·9) of 41 in the gastric or gastro-oesophageal junction adenocarcinoma cohort, eight (30%; 13·8–50·2) of 27 in the non-small-cell lung cancer cohort, and three (13%, 2·7–32·4) in the urothelial carcinoma cohort. InterpretationRamucirumab in combination with pembrolizumab showed a manageable safety profile with favourable antitumour activity in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma, non-small-cell lung cancer, and urothelial carcinoma. Our results contribute to the growing evidence that supports dual inhibition of the VEGF–VEGFR2 and PD-1–PD-L1 pathways. This combination could be further explored with or without chemotherapy, especially for patients with tumours for which single-agent checkpoint inhibitors have shown no additional benefit over chemotherapy. FundingEli Lilly and Company, and Merck and Co.
Abstract Context Demographic, personal, clinical, and behavioral factors predicting chemotherapy-induced nausea and vomiting (CINV) have been assessed in the past, but inconsistencies exist in the ...literature, studies have methodological shortcomings, and many risk factors have been examined in cross-sectional studies and univariate analyses. Objectives To evaluate the predictive power of personal and treatment-related characteristics in the development of CINV, using a large and prospectively evaluated sample of a heterogeneous group of cancer patients receiving routine chemotherapy. Methods This was a multicountry, multisite prospective study over three cycles of chemotherapy. Adult patients from eight European countries about to receive highly and moderately emetogenic chemotherapy were recruited. Clinicians completed a case report form at or before the initial chemotherapy treatment, recording patient demographic and baseline clinical characteristics. Participants completed a daily patient diary for six days per chemotherapy cycle describing their CINV experience. Baseline patient data also included a history of nausea/vomiting (yes/no), patient expectation of nausea (0–100 mm visual analogue scale VAS), prechemotherapy anxiety (0–100 mm VAS), and prechemotherapy nausea (0–100 mm VAS) measured during the 24-hour period before chemotherapy initiation. Results There were 991 evaluable patients with complete Cycle 1 data, 888 for Cycle 2 data, and 769 for Cycle 3 data. A complex picture of predictor variables was shown, with different contribution of variables to the acute, delayed, and overall phases of CINV. Key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and no CINV complete response in an earlier cycle (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway. Conclusion The results of this study provide clarity for the relative contribution of a set of characteristics in the development of CINV. Following evidence-based clinical antiemetic guidelines is of paramount importance, alongside treating patients with increased risk for CINV more aggressively, which both could lead to more optimal CINV management. These data can assist clinicians in making decisions about the antiemetic management of their patients.
SummaryBackgroundDesmoid tumours are locally aggressive tumours associated with substantial morbidity. No systemic treatments are approved for this disease, with methotrexate–vinblastine the only ...chemotherapy regimen assessed in a clinical trial setting to date. VEGF overexpression is a common feature in aggressive desmoid tumours. Pazopanib is an oral antiangiogenic agent targeting VEGF receptors 1, 2, and 3, platelet-derived growth factor receptor-like protein (PDGFR) α and β, and c-KIT tyrosine kinases. We aimed to assess antitumour activity and safety of targeted therapy or combination chemotherapy in progressive desmoid tumours. MethodsDESMOPAZ was a non-comparative, randomised, open-label, phase 2 trial conducted at 12 centres from the French Sarcoma Group. We enrolled adults (≥18 years) with progressive desmoid tumours, normal organ function and centrally documented progressive disease according to Response Evaluation Criteria in Solid Tumors version 1.1 based on two imaging assessments obtained within less than a 6-month interval. Participants were randomly assigned (2:1) to oral pazopanib 800 mg per day for up to 1 year or to an intravenous regimen combining vinblastine (5 mg/m 2 per dose) and methotrexate (30 mg/m 2 per dose), administered weekly for 6 months and then every other week for 6 months. Randomisation was stratified according to inclusion centre and tumour location. The primary endpoint was the proportion of patients who had not progressed at 6 months in the first 43 patients who had received one complete or two incomplete cycles of pazopanib. This endpoint was also assessed as a prespecified exploratory endpoint in all patients who had received one complete or two incomplete cycles of methotrexate–vinblastane. Safety analyses were done for all patients who received at least one dose of allocated treatment. This trial was registered with ClinicalTrials.gov, number NCT01876082. FindingsFrom Dec 4, 2012, to Aug 18, 2017, 72 patients were enrolled and randomly assigned (n=48 in the pazopanib group; n=24 in the methotrexate–vinblastine group). Median follow-up was 23·4 months (IQR 17·1–25·5). 46 patients in the pazopanib group and 20 patients in the methotrexate–vinblastine group were assessable for activity. In the first 43 patients assessable for the primary endpoint in the pazopanib group, the proportion of patients who had not progressed at 6 months was 83·7% (95% CI 69·3–93·2). The proportion of patients treated with methotrexate–vinblastine who had not progressed at 6 months was 45·0% (95% CI 23·1–68·5). The most common grade 3 or 4 adverse events in the pazopanib group were hypertension (n=10, 21%) and diarrhoea (n=7, 15%) and in the methotrexate–vinblastine group were neutropenia (n=10, 45%) and liver transaminitis (n=4, 18%). 11 patients (23%) had at least one serious adverse event related to study treatment in the pazopanib group, as did and six patients (27%) in the methotrexate–vinblastine group. InterpretationPazopanib has clinical activity in patients with progressive desmoid tumours and could be a valid treatment option in this rare and disabling disease. FundingGlaxoSmithKline and Novartis.
Summary Background Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this ...agent's efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. Methods In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov , NCT01900743. Findings From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9–2·3) with regorafenib versus 1·7 months (0·9–1·8) with placebo (HR 0·89 95% CI 0·48–1·64 p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5–5·0) with regorafenib versus 1·8 (1·0–2·8) months with placebo (HR 0·46 95% CI 0·46–0·80 p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4–11·6) with regorafenib versus 1·0 (0·8–1·4) with placebo (HR 0·10 95% CI 0·03–0·35 p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0–7·8) with regorafenib versus 1·0 (0·9–1·9) with placebo (HR 0·46 95% CI 0·25–0·81 p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 19% events in the 89 patients in the regorafenib group vs two 2% events in the 92 patients in the placebo group), hand and foot skin reaction (14 15% vs no events) and asthenia (12 13% vs six 6%). One treatment-related death occurred in the regorafenib group due to liver failure. Interpretation Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. Funding Bayer HealthCare.
Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies ...is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3(+) TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3(+) TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56(bright) (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST.
The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma.
Thirty patients were entered onto the ...study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles.
The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities.
Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.
The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of ...gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3' untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation.
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