Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.

BACKGROUND: Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. METHODS: We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. FINDINGS: Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. INTERPRETATION: Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. FUNDING: Eisai Inc.

Methylnaltrexone for opioid-induced constipation in advanced illness.

BACKGROUND: Constipation is a distressing side effect of opioid treatment. As a quaternary amine, methylnaltrexone, a mu-opioid-receptor antagonist, has restricted ability to cross the blood-brain barrier. We investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness. METHODS: A total of 133 patients who had received opioids for 2 or more weeks and who had received stable doses of opioids and laxatives for 3 or more days without relief of opioid-induced constipation were randomly assigned to receive subcutaneous methylnaltrexone (at a dose of 0.15 mg per kilogram of body weight) or placebo every other day for 2 weeks. Coprimary outcomes were laxation (defecation) within 4 hours after the first dose of the study drug and laxation within 4 hours after two or more of the first four doses. Patients who completed this phase were eligible to enter a 3-month, open-label extension trial. RESULTS: In the methylnaltrexone group, 48% of patients had laxation within 4 hours after the first study dose, as compared with 15% in the placebo group, and 52% had laxation without the use of a rescue laxative within 4 hours after two or more of the first four doses, as compared with 8% in the placebo group (P<0.001 for both comparisons). The response rate remained consistent throughout the extension trial. The median time to laxation was significantly shorter in the methylnaltrexone group than in the placebo group. Evidence of withdrawal mediated by central nervous system opioid receptors or changes in pain scores was not observed. Abdominal pain and flatulence were the most common adverse events. CONCLUSIONS: Subcutaneous methylnaltrexone rapidly induced laxation in patients with advanced illness and opioid-induced constipation. Treatment did not appear to affect central analgesia or precipitate opioid withdrawal. (Clinical Trials.gov number, NCT00402038 [ClinicalTrials.gov].).

Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults.

BACKGROUND: The current goal of human immunodeficiency virus type 1 (HIV-1) therapy is to maximally suppress viral replication. Securing this goal requires new drugs and treatment classes. The chemokine receptor CCR5 provides an entry portal for HIV-1, and PRO 140 is a humanized monoclonal antibody that binds to CCR5 and potently inhibits CCR5-tropic (R5) HIV-1 in vitro. METHODS: A randomized, double-blind, placebo-controlled, dose-escalating study was conducted in 39 individuals with HIV-1 RNA levels or =5000 copies/mL, CD4(+) cell counts > or =250 cells/microL, no antiretroviral therapy for 3 months, and only R5 HIV-1 detectable. Cohorts were randomized 3:10 to receive placebo or doses of PRO 140 of 0.5, 2, or 5 mg/kg. Subjects were monitored for 58 days for safety, antiviral effects, and serum concentrations of PRO 140. RESULTS: PRO 140 was generally well tolerated and demonstrated potent, rapid, prolonged, and dose-dependent antiviral activity. Mean reductions in HIV-1 RNA level of 0.58 log(10), 1.20 log(10) (P= .0002) and 1.83 log(10) (P= .0001) were observed for the 0.5-, 2-, and 5-mg/kg dose groups, respectively. Reductions in mean viral load of > or =10-fold were observed within 4 days and persisted for 2-3 weeks after treatment. CONCLUSIONS: This trial established clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity after a single dose. TRIAL REGISTRATION: ISRCTN Register: ISRCTN45537485 .