Georgia Kollia

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab

PURPOSE Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

PURPOSE Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. PATIENTS AND METHODS Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. RESULTS Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. CONCLUSION Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

A Generalization of the Weibull Distribution with Application to the Analysis of Survival Data

Abstract The Weibull distribution, which is frequently used for modeling survival data, is embedded in a larger family obtained by introducing an additional shape parameter. This generalized family not only contains distributions with unimodal and bathtub hazard shapes, but also allows for a broader class of monotone hazard rates. Furthermore, the distributions in this family are analytically tractable and computationally manageable. The modeling and analysis of survival data using this family is discussed and illustrated in terms of a lifetime dataset and the results of a two-arm clinical trial.

Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab

PURPOSE Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts. PATIENTS AND METHODS A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation. RESULTS Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for ≥ 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible. CONCLUSION Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC.

Benefits and disadvantages of joint hypermobility among musicians.

BACKGROUND Joint hypermobility is considered to be both an advantage and a disadvantage. However, the degree of hypermobility in members of particular occupations requiring intense physical activity and the nature of the association between symptoms referable to specific joints and their hypermobility are unknown. METHODS We interviewed 660 musicians (300 women and 360 men) about work-related symptoms such as joint pain and swelling and examined them for joint hypermobility according to a standard protocol. We then determined the relation between the mobility of their fingers, thumbs, elbows, knees, and spine and any symptoms referable to these regions. RESULTS Five of the 96 musicians (5 percent) with hypermobility of the wrists, mostly instrumentalists who played the flute, violin, or piano, had pain and stiffness in this region, whereas 100 of the 564 musicians (18 percent) without such hypermobility had symptoms (P = 0.001). Hypermobility of the elbow was associated with symptoms in only 1 of 208 musicians (< 1 percent), whereas 7 of 452 (2 percent) without this hypermobility had symptoms (P = 0.45). Among the 132 musicians who had hypermobile knees, 6 (5 percent) had symptoms, whereas only 1 of 528 (< 1 percent) with normal knees had symptoms (P < 0.001). Of the 462 musicians who had normal mobility of the spine, 50 (11 percent) had symptoms involving the back, as compared with 46 of the 198 musicians (23 percent) who had hypermobility of the spine (P < 0.001). CONCLUSIONS Among musicians who play instruments requiring repetitive motion, hypermobility of joints such as the wrists and elbows may be an asset, whereas hypermobility of less frequently moved joints such as the knees and spine may be a liability.

Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538).

CRA9006^ Background: The monoclonal antibody nivolumab blocks PD-1, an inhibitory immune checkpoint receptor expressed by activated T cells. Pts with previously treated MEL or other tumors received nivolumab IV Q2W during dose escalation and/or cohort expansion in a phase I trial (Topalian et al., NEJM 2012;366:2443). METHODS Pts received ≤12 cycles (4 doses/cycle) of treatment until discontinuation criteria were met. Cohorts of MEL pts were expanded at 0.1, 0.3, 1, 3, and 10 mg/kg. We report overall survival data and long-term safety and response data from the MEL pts treated on this study. RESULTS 107 MEL pts received nivolumab as of July 2012. 103/107 pts (97%) were ECOG PS ≤1 and approximately 25% received ≥3 prior therapies. Median OS was 16.8 months across doses and 20.3 months at the 3 mg/kg dose selected for phase III trials. 44% and 40% of pts were alive at 2 and 3 yrs (Table). ORs were observed at all doses (highest at 3 mg/kg) (Table). Of 29 responders who initiated treatment ≥1 year prior to data analysis, 16 had responses lasting ≥1 year. Drug-related AEs (any grade) occurred in 82% of pts, with Gr 3-4 drug-related AEs in 21% of pts; the most common included lymphopenia (3%), fatigue, and increased lipase (2%). Gr 3-4 drug-related diarrhea (2%), endocrine disorders (2%), and hepatitis (1%) was observed. No Gr ≥3 drug-related pneumonitis was observed in the MEL cohort. CONCLUSIONS In this large cohort of pretreated MEL pts, nivolumab produced durable OS and responses with an acceptable safety profile. OS compares favorably with historical data. Data updated as of Feb 2013 will be reported. Phase III registration trials have been initiated. CLINICAL TRIAL INFORMATION NCT00730639. [Table: see text].

A Dose‐Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous Gatifloxacin in Healthy Adult Men

Study Objectives. To examine single‐ and multiple‐dose safety, tolerability and pharmacokinetics of gatifloxacin administered as daily 1‐hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic β‐cell function, and electrocardiogram (ECG).

Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise.

Study Objectives. To compare the effects of gatifloxacin and ciprofloxacin on glucose homeostasis, including glucose tolerance test (GTT), pancreatic β‐cell function, and insulin production and secretion in patients with noninsulin‐dependent (type 2) diabetes mellitus (NIDDM) maintained with diet and exercise; and to evaluate the pharmacokinetics, safety, and tolerability of gatifloxacin.

Interchangeability of 400-mg Intravenous and Oral Gatifloxacin in Healthy Adults

Study Objective. To evaluate the interchangeability of 400‐mg intravenous and oral doses of gatifloxacin.

An open-label study of aripiprazole: Pharmacokinetics, tolerability, and effectiveness in children and adolescents with conduct disorder

OBJECTIVES This study evaluated flexible-dose pharmacokinetics, safety, and effectiveness of aripiprazole in children and adolescents with conduct disorder (CD). METHODS This open-label, 15-day, three-center study with an optional 36-month extension enrolled a total of 23 patients: 12 children (6-12 years) and 11 adolescents (13-17 years) with CD and a score of 2-3 on the Rating of Aggression Against People and/or Property (RAAPP). Initially, the protocol used the following dosing: subjects <25 kg, 2 mg/day; subjects 25-50 kg, 5 mg/day; subjects >50-70 kg, 10 mg/day; and subjects >70 kg, 15 mg/day. Due to vomiting and sedation, this schedule was revised to: <25 kg, 1 mg/day; 25-50 kg, 2 mg/day; >50-70 kg, 5 mg/day; and >70 kg, 10 mg/day. RESULTS Aripiprazole pharmacokinetics were linear, and steady state appeared to be attained within 14 days. Both groups demonstrated improvements in RAAPP scores and Clinical Global Impressions-Severity (CGI-S) scores. Adverse events were similar to the known profile for aripiprazole in adults. CONCLUSION The pharmacokinetics of aripiprazole in children and adolescents are linear and comparable with those in adults. Aripiprazole was generally well-tolerated in patients with CD, particularly after protocol adjustments, with improvements in aggressive behavior.