Efficacy of immune checkpoint inhibitors in alveolar soft-part sarcoma: results from a retrospective worldwide registry.

BACKGROUND: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS. MATERIALS AND METHODS: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome. RESULTS: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively. CONCLUSIONS: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options.

Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study.

BACKGROUND: Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. PATIENTS AND METHODS: Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. RESULTS: Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. CONCLUSIONS: Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W.

Alteration of plasma alanine, glutamate, and glycine Level: A potentiate manic episode of bipolar disorder.

INTRODUCTION: The amino acids that function as co-agonists at the N-methyl-D-aspartate (NMDA) receptor have been investigated in bipolar disorder (BD). However, studies comparing amino acid levels in the plasma of BD patients with healthy controls have yielded inconsistent results. We, therefore, conducted a study in Hospital Universiti Sains Malaysia to determine the plasma levels of glutamate, glycine, and alanine in BD patients and compared them with the healthy controls. MATERIALS AND METHODS: An overnight fast of 10-hour plasma levels of glutamate, glycine, alanine, and tryptophan were measured in 83 bipolar patients, and were compared to a group of 82 healthy controls. RESULTS: The mean (SD) age of bipolar patients was 40.9 (12.1), while the mean (SD) age for control groups was 35.6 (7.7) years. The median (25th, 75th percentile) of glutamate and alanine levels in bipolar patients was 111.0 (65.0,176.0) and 530.0 (446.0,629.0), respectively, while the mean (SD) of glycine level in bipolar patients was 304.0 (98.1). Significant higher glutamate, glycine, and alanine levels were found in bipolar disorder patients in the manic episode as compared to the healthy controls. CONCLUSION: Although the exact relationship between peripheral NMDA receptor co-agonist levels in the pathogenesis of BD is not well understood, these findings should be explored and may enlighten some new paths for BD therapy which could reward the patients also clinicians.

Bridging the communication gap between radiographers and patients to improve chest radiography image acquisition: A multilingual solution in the COVID-19 pandemic.

INTRODUCTION: A chest X-ray (CXR), taken in full inspiration, is important to ensure pathology in the lungs will not be missed. To achieve this, effective communication on breathing instructions for patients is crucial. During the COVID-19 pandemic, radiographers in Sengkang General Hospital (SKH) were challenged when performing CXR for the patients whose native language is not English. Most of these patients were foreign workers living in the same dormitory which had formed the largest COVID-19 cluster in Singapore. These dormitory residents found it difficult to understand and adhere to breathing instructions, resulting in a suboptimal degree of inspiration when the CXRs were taken. This may ultimately affect the diagnostic value of the radiographs. This paper aims to share and evaluate how radiographers tackled this issue and continued to acquire fully-inspired CXR for the dormitory residents despite the language barrier. METHODS: Using a combination of online survey and retrospective analysis of the rejection rates of CXR done over the period of early April to early June, a team of radiographers evaluated the effectiveness of using audio recordings in managing the issue of not achieving a fully inspired CXR for patients due to language barrier. RESULTS: The rejection rate for CXR due to suboptimal inspiration decreased from 26% to 9% upon implementation of the audio recordings. 92.3% of the CXRs taken within this period also fulfilled the criteria of a fully-inspired CXR, as evidenced by having at least 9 posterior ribs seen above the right hemi-diaphragm. Survey results found a fairly balanced number of radiographers who agreed and disagreed that a fully-inspired CXR was achieved for most of their patients after utilisation of translation manuals and audio recordings. CONCLUSION: After the implementation of audio recordings, the decrease in rejection rate of CXR and an audit which demonstrated that CXR quality was upheld had proven that the radiographers successfully achieved fully-inspired CXR for suspected COVID-19 patients. This confirmed that using pre-recorded audio instructions was an efficient intervention albeit being a one-way communication, leads to more accurate imaging results, aligning with existing literature on communication experiences between radiographers and patients. Moreover, the decreased rejection rate of CXRs had increased department efficiency consequently reducing departmental expenses in the long run. IMPLICATIONS OF PRACTICE: Given that we have an ageing population and the vast majority of the elderly converse in their various dialects, positive feedback from radiographers presented opportunities to expand the translation manual and audio recordings to include local dialects. These can be seamlessly integrated in CXR and other procedures in the hospital setting. To ensure that the translations are culturally sensitive, attention should be paid to the translation process of instructions into other languages and local dialects by enlisting the help of native speakers.

Immunotherapy in soft-tissue sarcoma.

Soft-tissue sarcoma (sts) is a rare mesenchymal malignancy that accounts for less than 1% of all adult tumours. Despite the successful advancement of localized therapies such as surgery and radiotherapy, these tumours can, for many, recur-often with metastatic disease. In the advanced setting, the role of systemic therapies is modest and is associated with poor survival. With the discovery of immunotherapies in other tumour types such as melanoma and lung cancer, interest has been renewed in exploring immunotherapy in sts. The biology of some stss makes them ripe for immunotherapy intervention; for example, some stss might have chromosomal translocations resulting in pathognomonic fusion products that have been shown to express cancer/testis antigens. Here, we present a targeted review of the published data and ongoing clinical trials for immunotherapies in patients with sarcoma, which comprise immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines.

Preliminary dengue vector surveillance in the Sunda Islands, Indonesia: Interchange of breeding habitat preferences of Aedes aegypti and Aedes albopictus.

Ovitrap surveillance was conducted to determine the infestation patterns of dengue vectors in fourteen study sites across eight provinces located in the Sunda Islands, Indonesia. High ovitrap indices up to 70% and 90% were obtained from indoor and outdoor areas, respectively. Mean numbers of Ae. aegypti and Ae. albopictus larvae ranged from 0.13 to 14.50 and 0.10 to 18.60, respectively. Mixed infestation (<10%) and interchange of breeding habitat preferences of Ae. albopictus and Ae. aegypti were also observed in the present study.

Monitoring Insecticide Resistance Profiles of Aedes aegypti (Diptera: Culicidae) in the Sunda Islands of Indonesia Based on Diagnostic Doses of Larvicides.

This study was conducted to monitor the susceptibility status of Aedes aegypti (Linnaeus) larvae in the Sunda Islands of Indonesia against various organophosphates and organochlorines. Larval bioassay was performed in accordance with the World Health Organization standard protocol. Field-collected and reference strains of Ae. aegypti larvae were tested against diagnostic doses of eight larvicides belonging to organophosphates and organochlorines, namely bromophos (0.050 mg/liter), chlopyrifos (0.002 mg/liter), fenitrothion (0.020 mg/liter), fenthion (0.025 mg/liter), malathion (0.125 mg/liter), temephos (0.012 mg/liter), DDT (0.012 mg/liter), and dieldrin (0.025 mg/liter). Mortality rates of larvae were recorded at 24-h posttreatment. This study showed that Ae. aegypti larvae from Padang, Samarinda, Manggarai Barat, and South Central Timor were susceptible to both fenitrothion and dieldrin (mortality rates ≥ 98%). About 6 out of 10 field strains of Ae. aegypti larvae were resistant (<80% mortality rates) against fenthion, whereas Ae. aegypti larvae from Kuningan, Samarinda, Sumba, and South Central Timor exhibited some degrees of resistance (mortality rates 80-98%). All field-collected Ae. aegypti larvae were resistant against diagnostic doses of chlorpyrifos, malathion, temephos, and DDT with mortality rates ranging from 0 to 74.67%. Continued insecticide susceptibility studies are essential to identify the efficacy of insecticides for an improved dengue vector control and to delay the development of insecticide resistance.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials.

BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. RESULTS: A total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95-5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). CONCLUSIONS: In our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

A rationale for universal tranexamic acid in major joint arthroplasty: overall efficacy and impact of risk factors for transfusion.

BACKGROUND: Tranexamic acid (TXA) therapy is effective in reducing postoperative red blood cell (RBC) transfusion in total joint arthroplasty (TJA), yet uncertainty persists regarding comparative efficacy and safety among specific patient subgroups. We assessed the impact of a universal TXA protocol on RBC transfusion, postoperative hemoglobin (Hb), and adverse outcomes to determine whether TXA is safe and effective in TJA, both overall and in clinically relevant subgroups. STUDY DESIGN AND METHODS: A retrospective observational study was performed on patients undergoing TJA at our institution spanning 1 year before and after the implementation of a universal protocol to administer intravenous (IV) TXA. The primary outcome was percentage of patients transfused, and secondary outcomes were perioperative Hb and occurrence of adverse events (death, myocardial infarction, stroke, seizure, pulmonary embolism, deep vein thrombosis, and acute kidney injury ). Outcomes were compared in pre- and post-protocol groups with χ2 analysis. Logistic regression compared risk of transfusion in pre- and post-protocol subgroups of patients with differing risk for transfusion (anemia, body mass index [BMI], and sex). RESULTS: No differences were found in baseline patient characteristics across pre- and post-protocol groups (n = 1084 and 912, respectively). TXA use increased from 32.3% to 92.2% while transfusion rates decreased from 10.3% to 4.8% (p < 0.001). Postoperative Day 3 Hb increased from 95.8 to 101.4 g/L (p < 0.001). Logistic regression demonstrated reduced transfusion in post-protocol subgroups regardless of sex, anemia, or BMI (p < 0.001). No increase in adverse events was observed (p = 0.8451). CONCLUSIONS: Universal TXA was associated with a reduction of RBC transfusion, overall and in clinically relevant subgroups, strengthening the rationale for universal therapy.

Preliminary dengue vector surveillance in the Sunda Islands, Indonesia: Interchange of breeding habitat preferences of Aedes aegypti and Aedes albopictus

@#Ovitrap surveillance was conducted to determine the infestation patterns of dengue vectors in fourteen study sites across eight provinces located in the Sunda Islands, Indonesia. High ovitrap indices up to 70% and 90% were obtained from indoor and outdoor areas, respectively. Mean numbers of Ae. aegypti and Ae. albopictus larvae ranged from 0.13 to 14.50 and 0.10 to 18.60, respectively. Mixed infestation (<10%) and interchange of breeding habitat preferences of Ae. albopictus and Ae. aegypti were also observed in the present study.

Potential biomarkers of tissue hypoxia during acute hemodilutional anemia in cardiac surgery: A prospective study to assess tissue hypoxia as a mechanism of organ injury.

PURPOSE: Hemodilutional anemia is associated with acute kidney injury (AKI) and mortality in patients undergoing cardiac surgery by mechanisms that may include tissue hypoxia. Our hypothesis was to assess if changes in the potential hypoxic biomarkers, including methemoglobin and erythropoietin, correlated with a decrease in hemoglobin (Hb) concentration following hemodilution on cardiopulmonary bypass (CPB). METHODS: Arterial blood samples were taken from patients (n = 64) undergoing heart surgery and CPB at baseline, during CPB, following CPB, and in the intensive care unit (ICU). Potential hypoxic biomarkers were measured, including methemoglobin, plasma Hb, and erythropoietin. Data were analyzed by repeated measures one-way analysis of variance on ranks and linear regression. RESULTS: Hemoglobin levels decreased following CPB and methemoglobin increased in the ICU (P < 0.001 for both). No correlation was observed between the change in Hb and methemoglobin (P = 0.23). By contrast, reduced Hb on CPB correlated with increased lactate, reduced pH, and increased erythropoietin levels following CPB (P ≤ 0.004 for all). Increased plasma Hb (P < 0.001) also correlated with plasma erythropoietin levels (P < 0.001). CONCLUSION: These data support the hypothesis that erythropoietin rather than methemoglobin is a potential biomarker of anemia-induced tissue hypoxia. The observed relationships between decreased Hb during CPB and the increase in lactate, reduced pH, and increase in erythropoietin levels suggest that early changes in plasma erythropoietin may be a pragmatic early biomarker of anemia-induced renal hypoxia. Further study is required to determine if anemia-induced increases in erythropoietin may predict AKI in patients undergoing cardiac surgery. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01883713). Registered 21 June 2013.

Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database.

Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication.

Pregnancy-induced hypertension and neonatal outcomes: a systematic review and meta-analysis.

OBJECTIVE: Pregnancy-induced hypertension (PIH) is associated with preterm delivery but its independent impact on neonatal outcomes remains unclear. We sought to systematically review and meta-analyze clinical outcomes of preterm infants <37 weeks' gestation born to mothers with and without PIH. STUDY DESIGN: Medline, Embase, PsychINFO and CINAHL were searched from January 2000 to October 2016. Studies with low-moderate risk of bias reporting neonatal outcomes based on PIH as primary exposure variable were included. Data were extracted independently by two co-authors. RESULTS: PIH was associated with lower mortality (3 studies; adjusted odds ratio (aOR) 0.65; 95% confidence interval (CI) 0.54 to 0.79), lower severe retinopathy of prematurity (ROP) (2 studies; aOR 0.83; 0.72 to 0.96) and lower severe brain injury (2 studies; unadjusted OR (uOR) 0.57; 0.49 to 0.66). No association between PIH and short-term respiratory outcomes, bronchopulmonary dysplasia (BPD) or necrotizing enterocolitis (NEC) was identified. In subgroup analysis among infants <29 weeks' gestation, BPD odds were higher (3 studies; aOR 1.15; 1.06 to 1.26), whereas mortality lower (2 studies; aOR 0.73; 0.69 to 0.77). In subgroup analysis limited to severe PIH, odds of mortality (3 studies; uOR 2.36; 1.07 to 5.22) and invasive ventilation (3 studies; uOR 3.26; 1.11 to 9.61) were higher. In subgroup analysis limited to preeclampsia, odds of BPD (3 studies; uOR 1.21; 95% CI:1.03 to 1.43) and NEC were higher (3 studies; uOR 2.79; 95% CI:1.57 to 4.96). CONCLUSION: PIH was associated with reduced odds of mortality and ROP (all infants), but higher odds for BPD (<29 weeks' gestation). The paradoxical reduction in mortality may be due to survival bias and deserves further exploration in future studies.

Factors causing stress among first-year students attending a nursing college in KwaZulu-Natal, South Africa

Background. In South Africa (SA), there is a high failure rate of students in the first year of nursing and many drop out after this year, a precarious situation considering the shortage of professional nurses faced by the country. Academic success does not entirely comprise one's application of intellectual capacity. Other factors may affect academic success, which could lead to stress, in turn hindering students' academic potential.Objectives. To determine the stressors experienced by first-year nursing students who attended a college of nursing in SA and to ascertain the stress-relieving mechanisms used by these students.Methods. Student nurses (n=248) at a college of nursing in KwaZulu-Natal Province, SA, were required to complete a quantitative questionnaire. Data were collected between September and November 2013.Results. Long working hours, difficulty of academic work, poor study methods and family illness caused considerable stress. Family pressure to pay for necessities at home was also a factor that caused stress among the students. There was insufficient money to pay for textbooks for their studies. Stress-relieving mechanisms included playing with cell phones and socialising with friends. Lecturers, parents and fellow nursing students' friends were a source of support.Conclusion. First-year nursing students experience a variety of stressors not directly related to their studies. Stress- and time-management workshops would be beneficial to these students. We also suggest that institutional support units be created to assist students in adjusting to the tertiary environment

Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications.

Background Data on completeness of reporting of phase I cancer clinical trials in publications are lacking. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching primary publications published prior to November 1, 2016. Reporting in primary publications was compared with the ClinicalTrials.gov database using a 28-point score (2=complete; 1=partial; 0=no reporting) for 14 items related to study design, outcome measures and safety profile. Inconsistencies between primary publications and ClinicalTrials.gov were recorded. Linear regression was used to identify factors associated with incomplete reporting. Results After a review of 583 trials in ClinicalTrials.gov , 163 matching primary publications were identified. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were upgraded, downgraded or omitted in publications in 47% of trials. The overall median reporting score was 23/28 (interquartile range 21-25). Incompletely reported items in >25% publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Higher reporting scores were associated with phase I (vs phase I/II) trials (p<0.001), multicenter trials (p<0.001) and publication in journals with lower impact factor (p=0.004). Conclusions Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicalTrials.gov may provide more comprehensive data from new cancer drug trials.

A frontal external ventricular drain causing a third cranial nerve palsy.

This 47-year-old gentleman presented with acute hydrocephalus secondary to a colloid cyst. Bilateral external ventricular drains (EVDs) were inserted. The patient developed a third nerve palsy during post-operative period - cranial imaging demonstrated the tip of an EVD in this vicinity. The palsy recovered completely on slight withdrawal of the EVD.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. PATIENTS AND METHODS: In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. RESULTS: Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. CONCLUSION: Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.