Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. PATIENTS AND METHODS: Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. RESULTS: The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. CONCLUSIONS: Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.

Effect of tipranavir/ritonavir combination on the pharmacokinetics of tadalafil in healthy volunteers.

This study evaluated the effects of single-dose administration and steady-state concentrations of tipranavir 500 mg and ritonavir 200 mg (TPV/r) combination on the pharmacokinetics of tadalafil 10 mg (TAD) in an open-label study. Seventeen healthy male volunteers received sequential dosing of the studied product: TAD (day 1) alone in a single dose for 7 days followed by TAD (day 8) in a single dose with TPV/r (500/200 mg twice daily, days 8-18). Pharmacokinetic parameters were determined in a noncompartmental analysis. The geometric mean ratio and 90% confidence interval were used to evaluate drug interactions. The effect of a single dose of TAD on the pharmacokinetics of TPV/r resulted in a small decrease in exposure after either first-dose or steady-state TPV/r (geometric mean ratios [90% confidence interval]: area under the concentration-time curve, 0.85 [0.74-0.97]). In contrast, coadministration of TAD exposure was increased significantly (2.33 [2.02-2.69]) when administered with the first dose of TPV/r but not when TPV/r steady state was reached (1.01 [0.83-1.21]). Antiretroviral activity may not be reduced, but the dose of TAD should be reduced at the start of TPV/r therapy and then a full dose can be resumed after steady state is reached.

Hepatitis A vaccination of Argentinean infants: comparison of two vaccination schedules.

BACKGROUND: Early immunization to protect infants against hepatitis A (HA) is recommended in intermediate or high endemic areas of the world, but little is known of the effects of maternal antibodies on the immune response. We studied the immunogenicity and reactogenicity of an inactivated HA vaccine administered in two different schedules to 2-month-old infants in an intermediate/high endemic area in Argentina. METHODS: In this double-blind, randomized study 131 infants received either three doses (at 2, 4, 6 months of age [Group A]) or one dose (at 6 months of age [Group B]) of the pediatric inactivated HA vaccine, Avaxim 80, and a booster dose at 15-18 months. HAV antibodies were measured (ELISA) at 2, 7, 15-18 and 16-19 months of age. Immediate (30 min after injection) and solicited local and systemic reactions were recorded for 7 days after each injection. RESULTS: Of 107/131 subjects (81.6%) who completed the study and who provided final serum samples after booster dose, 94 (87.8%) were seropositive at enrolment (>20 mIU/mL) with geometric mean concentrations (GMC) of 2989 and 3637 mIU/mL in Groups A and B, respectively. One month post-booster GMCs were 8236 mIU/ml (95% CI; 6304, 10760) and 1687 mIU/ml (1148, 2479) in Groups A and B, respectively, with 100% seroprotection. CONCLUSIONS: The HA vaccine was well tolerated and induced immunological priming in both groups during the first year of life in spite of the presence of maternal antibodies. Post-booster GMCs achieved after one or three primary doses suggest a long-term protection against HA.

Immunogenicity and safety of low-dose intradermal rabies vaccination given during an Expanded Programme on immunization session in Viet Nam: results of a comparative randomized trial.

The World Health Organization recently recommended a rabies vaccine pre-exposure schedule using 3 intradermal (i.d.) injections of one-fifth the standard intramuscular (i.m.) dose of current cell culture vaccines as a cost-reducing alternative for developing countries. As a strategy to improve further the acceptability of childhood rabies immunization, we assessed, in a controlled, randomized trial performed in 240 Vietnamese infants, the possibility of associating i.d. administration of a one-fifth dose of purified Vero-cell rabies vaccine (PVRV) with routine Expanded Programme on Immunization vaccines given at 2, 3 and 4 months of age (diphtheria, tetanus, whole-cell pertussis and inactivated poliomyelitis combined vaccine, DTP-IPV). Safety and immunogenicity results were compared with a group of infants given 2 i.m. doses of PVRV (2, 4 months) in association with DTP-IPV (2, 3, 4 months). After i.d. injection, more infants experienced local reactions, particularly redness, but these reactions were generally mild and transient. The rate of systemic reactions was the same in both groups. Although the rabies antibody titres (rapid fluorescent focus inhibition test) were higher 1 month after the third vaccine dose in the i.m. group (30.6 IU/mL vs 12.0 IU/mL in the i.d. group), all infants in both groups had achieved WHO-acceptable protective antibody titres (> or = 0.5 IU/mL) at this time. There was no evidence for any interference between DTP-IPV and rabies vaccine, supporting the interest of a low-dose i.d. PVRV pre-exposure regimen in infants living in rabies-endemic developing countries.