A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC. METHODS: In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional. RESULTS: The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed. CONCLUSIONS: Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.

Potential negative ecological effects of corridors.

Despite many studies showing that landscape corridors increase dispersal and species richness for disparate taxa, concerns persist that corridors can have unintended negative effects. In particular, some of the same mechanisms that underlie positive effects of corridors on species of conservation interest may also increase the spread and impact of antagonistic species (e.g., predators and pathogens), foster negative effects of edges, increase invasion by exotic species, increase the spread of unwanted disturbances such as fire, or increase population synchrony and thus reduce persistence. We conducted a literature review and meta-analysis to evaluate the prevalence of each of these negative effects. We found no evidence that corridors increase unwanted disturbance or non-native species invasion; however, these have not been well-studied concerns (1 and 6 studies, respectively). Other effects of corridors were more often studied and yielded inconsistent results; mean effect sizes were indistinguishable from zero. The effect of edges on abundances of target species was as likely to be positive as negative. Corridors were as likely to have no effect on antagonists or population synchrony as they were to increase those negative effects. We found 3 deficiencies in the literature. First, despite studies on how corridors affect predators, there are few studies of related consequences for prey population size and persistence. Second, properly designed studies of negative corridor effects are needed in natural corridors at scales larger than those achievable in experimental systems. Third, studies are needed to test more targeted hypotheses about when corridor-mediated effects on invasive species or disturbance may be negative for species of management concern. Overall, we found no overarching support for concerns that construction and maintenance of habitat corridors may result in unintended negative consequences. Negative edge effects may be mitigated by widening corridors or softening edges between corridors and the matrix. Other negative effects are relatively small and manageable compared with the large positive effects of facilitating dispersal and increasing diversity of native species.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Corridors promote fire via connectivity and edge effects.

Landscape corridors, strips of habitat that connect otherwise isolated habitat patches, are commonly employed during management of fragmented landscapes. To date, most reported effects of corridors have been positive; however, there are long-standing concerns that corridors may have unintended consequences. Here, we address concerns over whether corridors promote propagation of disturbances such as fire. We collected data during prescribed fires in the world's largest and best replicated corridor experiment (Savannah River Site, South Carolina, USA), six -50-ha landscapes of open (shrubby/herbaceous) habitat within a pine plantation matrix, to test several mechanisms for how corridors might influence fire. Corridors altered patterns of fire temperature through a direct connectivity effect and an indirect edge effect. The connectivity effect was independent of fuel levels and was consistent with a hypothesized wind-driven "bellows effect." Edges, a consequence of corridor implementation, elevated leaf litter (fuel) input from matrix pine trees, which in turn increased fire temperatures. We found no evidence for corridors or edges impacting patterns of fire spread: plots across all landscape positions burned with similar probability. Impacts of edges and connectivity on fire temperature led to changes in vegetation: hotter-burning plots supported higher bunch grass cover during the field season after burning, suggesting implications for woody/herbaceous species coexistence. To our knowledge, this represents the first experimental evidence that corridors can modify landscape-scale patterns of fire intensity. Corridor impacts on fire should be carefully considered during landscape management, both in the context of how corridors connect or break distributions of fuels and the desired role of fire as a disturbance, which may range from a management tool to an agent to be suppressed. In our focal ecosystem, longleaf pine woodland, corridors might provide a previously unrecognized benefit during prescribed burning activities, by promoting fire intensity, which may assist in promoting plant biodiversity.

Phase Ib Study of PEGylated Recombinant Human Hyaluronidase and Gemcitabine in Patients with Advanced Pancreatic Cancer.

PURPOSE: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated. EXPERIMENTAL DESIGN: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated. RESULTS: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 µg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for "high"-HA patients (n = 6), and 3.5 and 5.7 months for "low"-HA patients (n = 11), respectively. CONCLUSIONS: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848-54. ©2016 AACR.

Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed.

PURPOSE: Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer. PATIENTS AND METHODS: In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation. RESULTS: In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%). CONCLUSION: Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.

Efficacy of osmotic-release oral system (OROS) methylphenidate for mothers with attention-deficit/hyperactivity disorder (ADHD): preliminary report of effects on ADHD symptoms and parenting.

OBJECTIVE: A preliminary study to examine the efficacy of osmotic-release oral system (OROS) methylphenidate for attention-deficit/hyperactivity disorder (ADHD) symptoms and parenting behaviors in mothers with ADHD who had children with ADHD. METHOD: Participants included 23 mother-child dyads in which both were diagnosed with DSM-IV ADHD. Mothers underwent a 5-week, double-blind titration (placebo, 36 mg/day, 54 mg/day, 72 mg/day, 90 mg/day) to an optimal dose of OROS methylphenidate, followed by random assignment to 2 weeks of placebo or their maximally effective dose. Primary outcome measures included maternal ADHD symptoms (Conners' Adult ADHD Rating Scale) and parenting (Alabama Parenting Questionnaire). Secondary outcomes included side effects ratings. Data were collected from December 2004 until August 2006. RESULTS: During Phase 1, mothers reported significant decreases in inattention (p < .001) and hyperactivity/impulsivity (p < .01) with increases in OROS methylphenidate dose. As dose increased, significant reductions in inconsistent discipline (p < .01) and corporal punishment use (p < .005) were also demonstrated. During Phase 2, small effects on inattention (d = 0.46) and hyperactivity/impulsivity (d = 0.38) were found for those randomly assigned to medication versus placebo. In addition, medium to large medication effects were found on maternal involvement (d = 0.52), poor monitoring/supervision (d = 0.70), and inconsistent discipline (d = 0.71), with small effects on corporal punishment (d = 0.42). During both phases, few adverse effects were noted. CONCLUSIONS: OROS methylphenidate was well tolerated and was associated with significant improvement in maternal ADHD symptoms and parenting. Variable effects on parenting suggest that behavioral interventions may be necessary to address impairments in parenting among adults with ADHD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00318981.

Rituximab-induced interstitial lung disease.

The aim of this study is to characterize rituximab-induced interstitial lung disease (R-ILD). The information on all reported cases of R-ILD was reviewed. This analysis focused on patient characteristics, underlying disease, rituximab dosing schedule, and R-ILD characteristic-like symptoms, diagnosis, treatment, and outcomes. Sixteen cases of R-ILD, including our two cases, have been reported in the literature. Commonalities include older age, clinical presentation, computerized tomography findings, pulmonary function tests, and biopsy findings. Therapy included corticosteroids and broad spectrum antibiotics. Prognosis has been variable. Patients who worsen despite corticosteroids have a poor outcome. The pathogenesis of R-ILD is largely unknown. Potential explanations for R-ILD may include the induction and release of cytotoxic substances. R-ILD is a rare but potentially fatal pulmonary toxicity due to rituximab. R-ILD should be considered in patients who present with dyspnea, fever, and cough, and there is no clear evidence of infection. Prompt diagnosis and treatment with corticosteroids is essential.