Background Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. Methods In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1-expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. Results The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). Conclusions Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436 .).
Background In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. Methods We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. Results The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. Conclusions Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893 .).
Background The National Lung Screening Trial (NLST) showed that screening with low-dose computed tomography (CT) as compared with chest radiography reduced lung-cancer mortality. We examined the cost-effectiveness of screening with low-dose CT in the NLST. Methods We estimated mean life-years, quality-adjusted life-years (QALYs), costs per person, and incremental cost-effectiveness ratios (ICERs) for three alternative strategies: screening with low-dose CT, screening with radiography, and no screening. Estimations of life-years were based on the number of observed deaths that occurred during the trial and the projected survival of persons who were alive at the end of the trial. Quality adjustments were derived from a subgroup of participants who were selected to complete quality-of-life surveys. Costs were based on utilization rates and Medicare reimbursements. We also performed analyses of subgroups defined according to age, sex, smoking history, and risk of lung cancer and performed sensitivity analyses based on several assumptions. Results As compared with no screening, screening with low-dose CT cost an additional $1,631 per person (95% confidence interval [CI], 1,557 to 1,709) and provided an additional 0.0316 life-years per person (95% CI, 0.0154 to 0.0478) and 0.0201 QALYs per person (95% CI, 0.0088 to 0.0314). The corresponding ICERs were $52,000 per life-year gained (95% CI, 34,000 to 106,000) and $81,000 per QALY gained (95% CI, 52,000 to 186,000). However, the ICERs varied widely in subgroup and sensitivity analyses. Conclusions We estimated that screening for lung cancer with low-dose CT would cost $81,000 per QALY gained, but we also determined that modest changes in our assumptions would greatly alter this figure. The determination of whether screening outside the trial will be cost-effective will depend on how screening is implemented. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385 .).
Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. Here, we determined high-resolution crystal structures of αβ-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane-pocket of β-tubulin and used their respective side chain to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. They further offer fundamental structural insights into the control mechanisms of microtubule dynamics.
The first total synthesis of the dimeric berberine alkaloid ilicifoline (ilicifoline B) is reported. Its carbon skeleton is constructed from ferulic acid, veratrole, and methanol. The synthesis reported herein employs starting materials solely derived from wood. The natural product is thus constructed entirely from renewable resources. The same strategy is applied to a formal total synthesis of morphinan alkaloids. The use of wood-derived building blocks (xylochemicals) instead of the conventional petrochemicals represents a sustainable alternative to classical synthetic approaches.
Purpose This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. Patients and methods Patients with advanced solid tumors refractory to all standard treatments were administered a single oral dose of DHP107 on a dose-escalating schedule (60-600 mg/m(2)) during the first chemotherapy cycle, and intravenous paclitaxel 175 mg/m(2) during subsequent cycles. Cohorts of 3 patients were treated at each dose level provided no DLTs were observed. The pharmacokinetics of paclitaxel and its metabolites were investigated for oral DHP107 and intravenous paclitaxel. Results Thirty-four patients were enrolled. Dose-limiting toxicities were not observed, even at the highest dose level (600 mg/m(2)). Further dose escalation was not performed because pharmacokinetics did not increase proportionally at doses above 250 mg/m(2). The coefficient of variance of AUClast DHP107 ranged from 11.8 % to 34.0 %, comparable to 24.4 % of intravenous paclitaxel 175 mg/m(2). There were no grade 4 toxicities, whereas grade 3 toxicities included diarrhea (12.1 %), neutropenia (6.1 %) and fatigue (3.0 %). While no objective responses were observed, 11 patients (33.3 %) showed stable disease. Conclusions DHP107 was safe and feasible in patients with advanced malignancies. As exposure of paclitaxel plateau among patients receiving more than 250 mg/m(2) of DHP107, the dose escalation of DHP107 may be limited to 250 mg/m(2) in further clinical trials.
In this study, a novel amphiphilic copolymer designed as N-octyl-N-phthalyl-3,6-O-(2-hydroxypropyl) chitosan (OPHPC) were synthesized and then conjugated with folic acid (FA-OPHPC) to produce a targeted drug carrier for tumor-specific drug delivery. OPHPC and FA-OPHPC were characterized by FT-IR, (1)H NMR, (13)C NMR and elemental analysis. Paclitaxel (PTX) loaded OPHPC micelles (PTX-OPHPC) with well-defined spherical shape and homogeneous distribution exhibited drug-loading rate ranging from 33.6% to 45.3% and entrapment efficiency from 50.5% to 82.8%. In the cellular uptake studies, PTX-OPHPC brought about a significantly higher amount of PTX accumulated in human breast adenocarcinoma cell line (MCF-7 cells) compared with Taxol. Moreover, the cellular uptake of PTX in PTX loaded FA-OPHPC micelles (PTX-FA-OPHPC) was 3.2-fold improved in comparison with that of PTX-OPHPC. The results revealed that OPHPC micelle might be a promising drug carrier for promoting PTX cellular uptake and FA-OPHPC micelle could be used as a potential tumor-targeted drug vector.
A 77-year-old male patient presented to our attention with violaceous nodular lesions on the skin of his hands and lower extremities. Clinical and histologic examination supported the diagnosis of Kaposi sarcoma. A first-line systemic chemotherapy based on liposomal doxorubicin at a dosage of 40 mg/m every 3 weeks for 5 cycles was carried out, resulting in partial resolution of skin lesions. However, 1 year later, a relapse of the disease in the lower limbs and a new lesion of the left eyelid were found, therefore the patient began a second-line therapy with 100 mg/m paclitaxel every 2 weeks. After 8 cycles of therapy, we observed a complete remission of eyelid tumor and a partial response of lower limbs lesions up to 6 months of follow up. In conclusion, eyelid Kaposi sarcoma was successfully treated with paclitaxel every 2 weeks, obtaining a complete response.
OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ-pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5-9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.
2-Methoxymethylpyrrolidine best performed, among several other proline derivatives, to control the enantioselective [3+3] annulation of beta-(hetero)aryl-alpha nitro-alpha,beta-enals with commercial 2,2-dimethyl-1,3-dioxan-5-one, a procedure which renders highly-oxygenated nitrocyclohexanes endowed with five new stereocenters. Use of this reaction allowed the development of a total synthesis of the antitumoral natural product (+) pancratistatin; it also converted our previous racemic route to tetrodotoxin into an enantioselective one.