Phase 1/2 study of epacadostat in combination with durvalumab in patients with metastatic solid tumors.

BACKGROUND: Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS: The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS: The most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained. CONCLUSIONS: Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect. CLINICAL TRIAL INFORMATION: A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).

Phase 1 study of epacadostat in combination with atezolizumab for patients with previously treated advanced nonsmall cell lung cancer.

Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). Here we report results from the open-label, dose-escalation, Phase 1b ECHO-110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum-based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose-limiting toxicities (DLTs). Twenty-nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty-three patients (79%) had treatment-related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment-related AEs. No fatal treatment-related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD-L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD-L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited.

Results from oral gavage carcinogenicity studies of ruxolitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats.

Ruxolitinib is a selective and potent inhibitor of Janus kinase (JAK) 1 and JAK2. It is approved for the treatment of patients with intermediate or high-risk myelofibrosis, or those with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. To investigate its carcinogenic potential, ruxolitinib was administered by oral gavage once daily to Tg.rasH2 mice for 6 months at doses of 15, 45 or 125 mg/kg/day, and to Sprague-Dawley (Crl:CD) rats for 2 years at 10, 20 or 60 mg/kg/day. Ruxolitinib had no effect on survival, and did not increase the incidence of any neoplastic findings in either species. Exposure (AUC) was similar to or exceeded that associated with therapeutic use. Lymphoid depletion and a decrease in extramedullary hematopoiesis in the spleen occurred in rats, which were attributed to the pharmacologic activity of ruxolitinib. In Tg.rasH2 mice, increased inflammation in the nasal cavity was observed. Dose-dependent decreases in a number of spontaneous neoplastic/preneoplastic lesions were observed in rats, including mammary tumors in females, adrenal pheochromocytomas in males, hepatocellular adenomas/carcinomas in males, and hepatic basophilic (males and females) and eosinophilic (males) foci. Peribiliary fibrosis was also decreased. Clear cell foci in the liver were increased in females. Based on the results of these studies, ruxolitinib is not considered to be carcinogenic.

Natural history of preoperative subcentimeter pulmonary nodules in patients with resectable pancreatic adenocarcinoma: a retrospective cohort study.

OBJECTIVE: To determine the detection rate, radiologic characteristics, and natural history of incidental subcentimeter pulmonary nodules (SCPN) among patients with resectable pancreatic adenocarcinoma and to clarify whether further preoperative evaluation should be considered. BACKGROUND: The clinical significance of SCPN detected by routine preoperative abdominal imaging in patients with pancreatic adenocarcinoma is unknown. METHODS: Patients who underwent resection for pancreatic adenocarcinoma between 2000 and 2010 were queried from a prospectively maintained database at a single institution. Pre- and postoperative computed tomographic (CT) imaging was independently reviewed and the presence and radiologic features of SCPNs were analyzed for associations with overall survival (OS). RESULTS: Of the 463 patients who met inclusion criteria, 329 (71%) had reviewable preoperative imaging. Preoperative SCPNs were described in 59 patients (18%), and 41 patients had follow-up imaging available for review. Only increasing age (67.1 vs 63.5 years; P = 0.005) was associated with the presence of SCPN. Six patients (1.8%) had new or enlarging nodules after surgery, of whom 5 (1.5%) had confirmed metastatic adenocarcinoma. There was no difference in OS between patients with or without preoperative SCPN (16.1 vs 19.1 months; P = 0.201). No radiographic criterion of SCPN (including number, size, laterality, calcification, or contour) was associated with OS. CONCLUSIONS: Neither the presence of preoperative SCPN nor nodule characteristics was associated with OS among patients who underwent pancreaticoduodenectomy (PD) for pancreatic cancer. These data do not support routine additional workup of preoperative SCPN in patients with resectable pancreatic adenocarcinoma.

Chemotherapy Response Rates Among Patients With Endometrial Cancer Who Have Elevated Serum Platelets.

OBJECTIVE: This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer. METHODS: From 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 × 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. χ² Test and Student t test were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival. RESULTS: There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46-5.38; P < 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26-3.98; P < 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56-1.88, P = 0.93). CONCLUSIONS: Patients with endometrial cancer who have an elevated serum platelet count greater than 400 × 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range.

Comparison of brain structural variables, neuropsychological factors, and treatment outcome in early-onset versus late-onset late-life depression.

OBJECTIVE: To compare differences in gray matter volumes, white matter and subcortical gray matter hyperintensities, neuropsychological factors, and treatment outcome between early- and late-onset late-life depressed (LLD) subjects. METHODS: We conducted a prospective, nonrandomized, controlled trial at the outpatient clinics at Washington University and Duke University on 126 subjects, aged 60 years or older, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received neuropsychological testing and magnetic resonance imaging. Subjects were excluded for cognitive impairment or severe medical disorders. After 12 weeks of sertraline treatment, subjects' MADRS scores over time and neuropsychological factors were studied. RESULTS: Left anterior cingulate thickness was significantly smaller in the late-onset depressed group than in the early-onset LLD subjects. The late-onset group also had more hyperintensities than the early-onset LLD subjects. No differences were found in neuropsychological factor scores or treatment outcome between early-onset and late-onset LLD subjects. CONCLUSION: Age at onset of depressive symptoms in LLD subjects are associated with differences in cortical thickness and white matter and subcortical gray matter hyperintensities, but age at onset did not affect neuropsychological factors or treatment outcome.

Postradiation damage to the pelvic girdle in cervical cancer patients: is intensity-modulated radiation therapy safer than conventional radiation?

OBJECTIVES: Intensity-modulated radiation therapy (IMRT) is frequently utilized in the treatment of cervical cancer. Our study compared instances of pelvic fractures, osteonecrosis, and osteomyelitis posttreatment with conventional radiation therapy (RT) versus IMRT in patients with cervical carcinomas. METHODS: Eighty-three patients primarily treated with IMRT were case matched with 83 historical control subjects treated with conventional RT. Pretreatment and posttreatment computed tomography scans were reviewed. Logistic regression analysis was utilized to examine the effects of treatment type (conventional RT vs IMRT) on the occurrence of posttreatment pelvic bony structure complications while adjusting for confounders. RESULTS: In the IMRT group, 3 (4%) of 83 patients developed posttreatment sacral fractures (median follow-up, 51 months). In the conventional RT group, there were 14 pelvic girdle complications (17%): 9 fractures, 2 cases of osteonecrosis, and 3 cases of osteomyelitis (median follow-up, 43.5 months; odds ratio, 4.49 for conventional vs IMRT groups, P = 0.01; 95% confidence interval, 1.4-14.1). In addition, there were 4 cases of posttreatment osteoporosis in the conventional RT group. All patients with complications in the IMRT group and 11 of 13 in the conventional RT group were symptomatic. CONCLUSIONS: Intensity-modulated radiation therapy is associated with a lower risk for pelvic girdle complications than conventional RT.

Intestinal perforation in gynecologic oncology: do all patients benefit from surgical management?

OBJECTIVE: To identify those patients with gynecologic cancers and intestinal perforation in whom conservative management may be appropriate. METHODS: A retrospective review was performed of all gynecologic oncology patients with intestinal perforation at our institution between 1995 and 2011. The Kaplan-Meier method and Cox proportional hazards models were used to analyze factors influencing survival. RESULTS: Forty-three patients met the study criteria. The mean age was 59 years (range: 38-82 years). A large number of patients had peritoneal carcinomatosis and history of bowel obstruction. Surgery was performed in 28 patients, and 15 were managed conservatively. Overall mortality at 1, 3, 6, and 12 months was 26%, 40%, 47%, and 59%, respectively. Only cancer burden at the time of perforation was independently predictive of mortality. Patients with peritoneal carcinomatosis, distant metastasis, or both were at 42 times higher risk of death than those with no evidence of disease (95% CI: 3.28-639.83), and at 7 times higher risk of death than those with microscopic/localized disease (95% CI: 1.77-29.94). When adjusted for the extent of disease spread, management approach (conservative vs. surgical) was not a significant predictor of survival (p≥0.05). The length of hospital stay (19 days vs. 7 days) and the complication rate (75% vs. 26.7%) were significantly higher in the surgical group than in the non-surgical group (p<0.05). CONCLUSIONS: Patients who develop intestinal perforation in the setting of widely metastatic disease have a particularly poor prognosis. Aggressive surgical management is unlikely to benefit such patients and further impairs their quality of life.

Time to initiation of postoperative chemotherapy: an outcome measure for patients undergoing laparoscopic resection for rectal cancer.

BACKGROUND: Laparoscopic rectal cancer surgery has limited short-term benefits in comparison with open surgery. Long-term measures of recovery are needed. OBJECTIVE: The aim of this study was to assess the impact of surgical approach (laparoscopic vs open) for the treatment of rectal cancer on the time to postoperative chemotherapy. DESIGN: This study is a retrospective review of 150 patients who underwent low anterior resection and received postoperative chemotherapy between 2005 and 2011. SETTINGS: This study was conducted at a tertiary care hospital. PATIENTS: One hundred fifty patients who had stage II or III rectal cancer who underwent low anterior resection were selected. All patients received postoperative chemotherapy, the timing of which was at the discretion of the oncologist. MAIN OUTCOME MEASURES: Patient demographics, clinicopathologic variables, and time to postoperative chemotherapy were compared. Multivariate analysis was performed to identify variables affecting the time to postoperative chemotherapy. RESULTS: There were no differences in clinicopathologic variables between cohorts including age, BMI, sex, ASA score, diverting ileostomy, preoperative radiotherapy, or pathologic stage. Univariate analysis demonstrated differences in intraoperative blood loss (300 vs 448 mL, p < 0.01), length of stay (7.6 vs 8.9 days, p < 0.05), wound infection (12.0 vs 24.0%, p < 0.05), and tumor location (8.0 vs 6.9 cm, p < 0.05) for laparoscopic vs open patients. There were more complications in the open vs laparoscopic group (47 vs 24, p < 0.001); however, the percentage of patients experiencing complications in the open vs laparoscopic cohorts did not reach statistical significance (32.0 vs 18.7%, p = 0.09). A decrease in mean time to postoperative chemotherapy was found for patients undergoing laparoscopic vs open surgery (50.1 vs 75.2 days, p < 0.0001). Multivariate analysis demonstrated that the approach of surgery was an independent predictor of time to postoperative chemotherapy (p < 0.01). LIMITATIONS: This study was limited by its retrospective design and selection bias. CONCLUSIONS: In selected patients, patients undergoing laparoscopic rectal cancer surgery receive postoperative chemotherapy 25 days earlier than patients undergoing open surgery. Time to postoperative chemotherapy serves as an outcome measure for improved recovery in laparoscopic rectal cancer surgery.

Axillary ultrasound in patients with clinically node-negative breast cancer: which features are predictive of disease?

BACKGROUND: Axillary ultrasound is used in the evaluation of breast cancer patients to identify subclinical node-positive disease. The study aim was to identify whether certain radiologic characteristics correlate with cytology and final pathology. METHODS: We retrospectively reviewed ultrasound images of 110 women with clinically node-negative breast cancer and suspicious axillary ultrasound to identify specific anatomic characteristics previously shown to be more commonly associated with metastatic involvement. Results were compared with cytology and final pathology. We used descriptive statistics for data summary. RESULTS: Of the 110 patients, cytology was positive in 71 (68%) and final pathology was positive in 80 (73%). The most common indication for biopsy was lymph node cortex characterized by thickening or eccentric contour (N = 40). Loss of the fatty hilum was described in 17 patients, and 9 patients had lymph nodes with both abnormal cortical and hilar features. Of 43 patients with "suspicious" disease without specific criteria, the most common indication for biopsy was disparity in size of one or more lymph nodes compared with others. Maximum cortical thickness was greater in patients with positive cytology compared with those with negative cytology (7.6 versus 6.2 mm; P = 0.047). Ultrasound characteristics such as lymph node size, cortical morphology, contour, and hilar fat were not individually predictive of final cytology and pathology. CONCLUSIONS: Axillary ultrasound is a valuable tool that accurately predicted malignant axillary disease in 73% of patients with clinically node-negative breast cancer. Elaboration of standard criteria for nodal evaluation will improve usefulness of this imaging modality in preoperative staging of the axilla.

Bootstrapping GEE models for fMRI regional connectivity.

An Alzheimer's fMRI study has motivated us to evaluate inter-regional correlations during rest between groups. We apply generalized estimating equation (GEE) models to test for differences in regional correlations across groups. Both the GEE marginal model and GEE transition model are evaluated and compared to the standard pooling Fisher-z approach using simulation studies. Standard errors of all methods are estimated both theoretically (model-based) and empirically (bootstrap). Of all the methods, we find that the transition models have the best statistical properties. Overall, the model-based standard errors and bootstrap standard errors perform about the same. We also demonstrate the methods with a functional connectivity study in a healthy cognitively normal population of ApoE4+ participants and ApoE4- participants who are recruited from the Adult Children's Study conducted at the Washington University Knight Alzheimer's Disease Research Center.

A Phase 1/2 Study of the Oral Janus Kinase 1 Inhibitors INCB052793 and Itacitinib Alone or in Combination With Standard Therapies for Advanced Hematologic Malignancies.

BACKGROUND: The Janus kinase (JAK)/signal transducers and activators of transcription pathway has been implicated in the pathogenesis and progression of various hematologic malignancies. JAK1-regulated cytokines stimulate proliferation and growth of malignant cells and resistance to certain therapies. PATIENTS AND METHODS: This phase 1/2 study evaluated 2 oral, novel JAK1 inhibitors (INCB052793 and itacitinib) in advanced hematologic malignancies. Phase 1a assessed dose escalation and expansion of INCB052793 monotherapy. Phase 1b evaluated INCB052793 plus standard therapy in relapsed/refractory multiple myeloma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). Phase 2 evaluated INCB052793 or itacitinib plus azacitidine in DNA methyltransferase inhibitor (DNMTi)-refractory AML or MDS. Primary endpoints included safety and tolerability for phase 1, and objective response rate for phase 2. RESULTS: Fifty-eight patients were enrolled, all received study treatment and discontinued either treatment or participation in the study. The most common reasons for treatment discontinuation were progressive disease (35.4% and 50.0%) and adverse events (22.9% and 20.0%) for INCB052793 and itacitinib plus azacitidine, respectively. In phase 1, 12 of 39 patients (31%) achieved an objective response; 35 mg once daily was selected as the phase 2 dose. Two patients with DNMTi-refractory disease had an objective response in phase 2. The study was terminated for lack of efficacy. CONCLUSION: Inhibition of JAK1 with INCB052793 (monotherapy or combination therapy) or itacitinib plus azacitidine did not demonstrate clinically meaningful responses in these patients with hematopoietic malignancies.

Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib.

Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) and an approximate 2-fold increase in maximal exposure (Cmax ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC0-∞ ) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.

Surface-Modified Sewage Sludge-Derived Carbonaceous Catalyst as a Persulfate Activator for Phenol Degradation.

In this study, a catalytic persulfate oxidation process comprising sodium persulfate (PS) and modified sewage sludge-derived carbonaceous catalysts was tested for the degradation of phenol. Sludge-based biochar was modified by high-temperature treatment combined with hydrochloric acid oxidation. The surface properties of carbonaceous catalysts before and after modification were characterized by elemental analysis, N2 isothermal adsorption-desorption, scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. The effects of reaction parameters including catalyst dosage, PS/phenol molar ratio, initial pH and reaction temperature on the degradation rate of phenol were investigated. The kinetics of phenol transformation was explored and the reaction rate appeared pseudo first-order kinetics. In SS-600-HCl/PS system, 91% phenol could be efficiently degraded under certain reaction conditions ([phenol]0 = 100 mg/L, catalyst dosage = 0.8 g/L, PS/phenol molar ratio = 3/1, pH = 7, 25 °C) in 180 min. Thus, the results showed that the modified sewage sludge-derived carbonaceous catalyst had a better ability to activate PS for phenol degradation.

An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants.

Parsaclisib, a selective, potent phosphatidylinositol 3-kinase delta inhibitor being developed for the treatment of cancer and autoimmune diseases, is primarily metabolized by cytochrome P450 (CYP) 3A4. This study assessed the pharmacokinetics (PK) and safety of parsaclisib alone or combined with itraconazole (potent CYP3A inhibitor) or rifampin (potent CYP3A4 inducer) in healthy participants. In this open-label, fixed-sequence study, cohort 1 received oral parsaclisib 10 mg once daily on days 1 and 8 and oral itraconazole 200 mg once daily on days 4-11; cohort 2 received oral parsaclisib 20 mg once daily on days 1 and 11 and oral rifampin 600 mg once daily on days 4-12. Parsaclisib plasma concentration was tested and PK parameters calculated by noncompartmental analysis. Geometric mean ratios (GMRs) and 2-sided 90% confidence intervals (CIs) were estimated by 2-factor analysis of variance. Thirty-six healthy participants were enrolled (18 per cohort). Parsaclisib maximum plasma drug concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) were increased by 21% and 107% with concomitant itraconazole versus parsaclisib alone (GMR, 1.21; 90%CI, 1.14-1.29; and 2.07; 90%CI, 1.97-2.17, respectively). Parsaclisib Cmax and AUC were reduced by 43% and 77%, respectively, with concomitant rifampin versus parsaclisib alone (GMR, 0.57; 90%CI, 0.53-0.60; and 0.23; 90%CI, 0.21-0.24, respectively). Headache was the most common adverse event, reported by 13.9% of participants (all in cohort 2). Single-dose parsaclisib alone or combined with itraconazole or rifampin appeared safe and well tolerated in healthy participants. Parsaclisib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors or inducers.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Itacitinib.

Itacitinib is a novel, selective, Janus kinase 1 inhibitor in development for treatment of graft-versus-host disease. The objective of this study was to assess pharmacokinetics and safety of 300-mg itacitinib dosed in participants with normal renal function (n = 10), severe renal impairment (n = 8), and end-stage renal disease (ESRD) on hemodialysis (n = 8). Serial plasma and urine samples (urine from normal and severe groups only) were collected before dosing until 72 hours after dosing. In the ESRD group, itacitinib was evaluated in 2 periods, when dosed before (period 1) and after (period 2) a hemodialysis session. Geometric mean ratios (90% confidence interval) in participants with severe renal impairment, ESRD period 1 and ESRD period 2 relative to participants with normal renal function were 1.65 (1.13-2.39), 0.71 (0.49-1.03), and 0.83 (0.57-1.20) for maximum plasma drug concentration and 2.23 (1.56-3.18), 0.81 (0.57-1.16), and 0.95 (0.66-1.35) for area under the plasma concentration-time curve from time zero to infinity. Itacitinib was well tolerated, and 3 grade 1 treatment-emergent adverse events were reported over the course of the study. Given the magnitude of exposure changes in participants with severe renal impairment or ESRD and the historic risk-benefit profile, no dose adjustment is recommended for itacitinib in patients with impaired renal function, although the final dosage recommendation will be based on cumulative pharmacokinetics and safety from this study and from the pivotal graft-versus-host disease trial. Additionally, itacitinib may be administered to patients undergoing dialysis regardless of the time of dialysis.

Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies.

PURPOSE: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). PATIENTS AND METHODS: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. RESULTS: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. CONCLUSIONS: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

Analysis of twin data using SAS.

SUMMARY: Twin studies are essential for assessing disease inheritance. Data generated from twin studies are traditionally analyzed using specialized computational programs. For many researchers, especially those who are new to twin studies, understanding and using those specialized computational programs can be a daunting task. Given that SAS (Statistical Analysis Software) is the most popular software for statistical analysis, we suggest that the use of SAS procedures for twin data may be a helpful alternative and demonstrate that we can obtain similar results from SAS to those produced by specialized computational programs. This numerical validation is practically useful, because a natural concern with general statistical software is whether it can deal with data that are generated from special study designs such as twin studies and if it can test a particular hypothesis. We concluded through our extensive simulation that SAS procedures can be used easily as a very convenient alternative to specialized programs for twin data analysis.

Susceptibility-weighted imaging helps to discriminate pediatric multiple sclerosis from acute disseminated encephalomyelitis.

BACKGROUND: Susceptibility-weighted imaging is a relatively new magnetic resonance imaging sequence that can identify lesions of multiple sclerosis in adults. This study was designed to determine if susceptibility-weighted imaging is a useful discriminator between children who develop multiple sclerosis and children with monophasic acute disseminated encephalomyelitis. METHODS: Eighteen children who presented with acute central nervous system demyelination and had a brain magnetic resonance imaging study including susceptibility-weighted imaging within 6 months of the first clinical attack were studied. Final diagnosis was based on international consensus definitions. Brain lesions detected on the fluid-attenuated inversion recovery sequence were assessed for abnormal signal on susceptibility-weighted imaging. The burden of susceptibility abnormalities was then analyzed for differences between the multiple sclerosis and acute disseminated encephalomyelitis groups. RESULTS: Eight patients had a final diagnosis of acute disseminated encephalomyelitis and ten had multiple sclerosis. Twenty-two percent of fluid-attenuated inversion recovery lesions were identified on susceptibility-weighted imaging. The percentage of fluid-attenuated inversion recovery lesions identified on susceptibility-weighted imaging differed between the multiple sclerosis and acute disseminated encephalomyelitis groups (P = 0.04). The median percentage (minimum-maximum) of lesions identified on susceptibility-weighted imaging in the multiple sclerosis group was 0.22 (0-0.68) and in the acute disseminated encephalomyelitis group was 0.0 (0-0.17). CONCLUSION: Susceptibility-weighted imaging may be a useful technique in differentiating acute disseminated encephalomyelitis from multiple sclerosis at initial presentation.

Review of ongoing clinical trials in non-small-cell lung cancer: a status report for 2012 from the ClinicalTrials.gov Web site.

INTRODUCTION: Clinical research in non-small-cell lung cancer (NSCLC) is a rapidly evolving field. In an effort to identify the current trends in lung cancer clinical research, we reviewed ongoing clinical trials in NSCLC listed in the ClinicalTrials.gov registry in 2012, and we also compared this data to a similar survey conducted by us in 2009. METHODS: The Web site's advanced search function was used to search for the term "non-small cell lung cancer." The search was further refined by using the following options from the search page drop-down menu, "open studies" and "interventional." Studies with non-NSCLC tumor histologies and pediatric studies were excluded. RESULTS: Of the 477 trials included in the analysis, 105 (22.0%) were phase I, 223 phase II (46.8%), and 63 phase III trials (13.2%). When compared with data from 2009, university-sponsored trials decreased in number (45.4%-34.2%; p < 0.001) whereas industry-sponsored trials remained almost the same. There was a significant increase in trials conducted exclusively outside of the United States (35.9%-48.8%; p = 0.001). The number of studies with locations in China (61, 12.8%) was second only to that in the United States (244, 51.2%). Studies reporting biomarker analysis increased significantly from 37.5% to 49.1% in 2012 (p < 0.001). Biomarker-based patient selection also increased significantly from 7.9% to 25.8% (p < 0.001). Targeted therapies were evaluated in 70.6% of phase I/II and II trials, and the most common class of targeted agent studied was epidermal growth factor receptor tyrosine kinase inhibitors (38.0%). Prespecified accrual times were observed to increase when compared with data reported in 2009, especially among industry-sponsored studies. CONCLUSIONS: Our survey identified major changes in lung cancer clinical research since 2009. Almost half of all studies registered at the ClinicalTrials.gov Web site are being conducted outside the United States, and several novel molecularly targeted agents are being evaluated in the treatment of patients with NSCLC. More importantly, we identified a threefold increase in the number of studies that perform biomarker testing to determine patient selection over the last 3 years.