Single-agent gemcitabine versus cisplatin-etoposide: Early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer

Background This randomised study was designed to determine the response rate, survival and toxicity of single-agent gemcitabine and cisplatin-etoposide in chemo-naïve patients with locally advanced or metastatic non-small-cell lung cancer. Patients and methods Gemcitabine 1,000 mg/m2 was given as a 30 min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small-cell lung cancer, measurable disease, Zubrod PS 0-2; no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. Results 146 patients were enrolled, 71 patients on gemcitabine and 75 patients on cisplatin-etoposide. Patient characteristics were well matched across both arms. Sixty-six gemcitabine patients and 72 cisplatin-etoposide patients were evaluable. Partial responses were seen in 12 gemcitabine patients (18.2%; 95% CI: 9.8-30) and 11 cisplatin-etoposide patients (15.3%; 95% CI: 7.9-25.7). Early indications show no statistical differences between the two treatments with respect to time to disease progression or survival. Haematological and laboratory toxicity were moderate and manageable. However, hospitalisation because of neutropenic fever was required for 6 (8%) cisplatin-etoposide patients but not for any gemcitabine patients. Non-haematological toxicity was more pronounced with significant differences in nausea and vomiting (grade 3 and 4: 11% gemcitabine vs. 29% cisplatin-etoposide; despite the allowance for 5-HT3 antiemetics during the first cycle of cisplatin-etoposide), and alopecia (grade 3 and 4: 3% gemcitabine vs. 62% cisplatin-etoposide). Conclusions In this randomised study, single-agent gemcitabine was at least as active but better tolerated than the combination cisplatin-etoposid

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial

BackgroundAlmost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.MethodsWe did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847.FindingsBetween March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6-8·7]) than in the supportive care group (3·2 months [2·8-4·1]; hazard ratio [HR] 0·48 [95% CI 0·33-0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33-0·72]; p=0·0002). Grade 3-4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection.InterpretationSwitch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma.FundingDutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies.Pathogenesis and treatment of chronic pulmonary disease

Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2–16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5–7.1) versus 1.9 months (95% CI 1.4–3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16–5.43). Corresponding median OS was 10.6 months (95% CI: 7.0–8.6) versus 4.7 months (95% CI: 3.2–8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46–9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p &lt; 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice.</p

Incorporation of group 14 elements into siloxane-bridged paracyclophanes cyclo-[p,p´-Me2SiC6H4EMe2C6H4SiMe2O]2 (E = C, Si, Ge, Sn)§

The bis(arylene silanes) p,p\u27-HMe2SiC6H4EMe2C6H4SiMe2H (E = C (10), Si (11), Ge (12), Sn(13)) were prepared by the in situ Grignard reaction of p,p\u27-BrC6H4CMe2C6H4Br, Mg turnings, and HSiMe2Cl (for 10) and the Grignard reaction using p-HMe2SiC6H4Br, Mg turnings, and Me2ECl2 (E = Si for 11, Ge for 12, Sn for 13). The oxidation of 10-13 using Pearlman\u27s catalyst, Pd(OH)2/C, in aqueous THF provided the bis(arylene silanols) p,p\u27-HOMe2SiC6H4EMe2C6H4SiMe2OH (E = C (14), Si (15), Ge (16), Sn(17)). The HCl-catalyzed condensation of 14-17 in highly diluted solutions of acetone/water afforded the siloxane-bridged paracyclophanes cyclo-[p,p\u27-Me2SiC6H4EMe2C6H4SiMe2O]2 (6-9) that incorporate the group 14 elements E = C, Si, Ge, and Sn. Compounds 6-17 were investigated by multinuclear solution and solid-state NMR spectroscopy and 6 and 9 also by X-ray crystallography.<br /