ABSTRACT
PURPOSE: Eftilagimod alpha (efti), a soluble LAG-3 protein, activates antigen-presenting cells (APC) and downstream T-cells. TACTI-002 (Part C) evaluated whether combining efti with pembrolizumab led to strong anti-tumor responses in 2nd line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients, while demonstrating good tolerability. METHODS: In this multinational phase 2 trial using Simon's 2-stage design, R/M HNSCC PD-L(1)-naïve patients who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, Q3W) combined with subcutaneous efti (30 mg Q2W for 24 weeks and Q3W thereafter). The primary endpoint was objective response rate (ORR) per iRECIST by investigator assessment. Additional endpoints included duration of response (DoR), progression free survival (PFS), overall survival (OS) and tolerability. Pharmacodynamic effects (absolute lymphocyte count [ALC] and Th1 cytokine biomarkers [IFN-gamma/CXCL-10]) were evaluated in liquid biopsies. RESULTS: Between Mar 2019 - Jan 2021, 39 patients were enrolled; 37 were evaluated for response. All patients received prior chemotherapy and 40.5% were pretreated with cetuximab. 53.1% of patients had PD-L1 CPS <20. With a median follow up of 38.8 months, ORR was 29.7%, including 13.5% complete responders. Median DoR was not reached. Rapid and sustained ALC increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed. CONCLUSION: Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in 2nd line HNSCC patients, thus supporting further evaluation of this combination in earlier treatment lines.
ABSTRACT
BACKGROUND: There is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations - including the costs of the trial - might inform the design and conduct of adaptive clinical trials. METHODS: We apply a recently published Bayesian model of a value-based sequential clinical trial to data from the 'Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis' (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design's operating characteristics with those of a conventional fixed length design. RESULTS: In contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure. CONCLUSION: Evidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.
Subject(s)
Bayes Theorem , Cost-Benefit Analysis , Osteoarthritis , Research Design , Humans , Cost-Benefit Analysis/methods , Cost-Benefit Analysis/statistics & numerical data , Osteoarthritis/economics , Osteoarthritis/drug therapy , Osteoarthritis/therapy , Hydroxychloroquine/therapeutic use , Hydroxychloroquine/economics , Clinical Trials as Topic/methods , Clinical Trials as Topic/economics , Clinical Trials as Topic/statistics & numerical data , Sample SizeABSTRACT
OBJECTIVES: Inflammatory rheumatic diseases (IRD) are often associated with interstitial lung disease (ILD). The aim of the present study was to establish a correlation between the findings on HRCT and the immunological bronchoalveolar lavage (BAL). METHODS: The study included 74 patients with newly diagnosed IRD and evidence of ILD on HRCT with the following pattern: ground-glass opacities (GGO), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). Patients with other HRCT pattern were excluded. No patient received any immunosuppressive therapy. In addition to HRCT, immunological BAL was performed and the American Thoracic Society clinical practice guideline were used to define BAL patterns (lymphocytic cellular pattern, neutrophilic cellular pattern, eosinophilic cellular pattern and unspecified pattern). RESULTS: The main HRCT patterns were NSIP (47.3%), GGO (33.8%), and UIP (18.9%). BAL patterns showed the following distribution: 41.9% lymphocytic cellular pattern, 23.0% neutrophilic cellular pattern, 18.9% eosinophilic cellular pattern, and 16.2% unspecific cellular pattern. Placing these data in the context of the HRCT findings, the lymphocytic cellular BAL pattern (48%) was most commonly BAL pattern associated with GGO pattern in HRCT, whereas neutrophilic and lymphocytic cellular BAL patterns were the dominant feature in NSIP and UIP. CONCLUSION: In patients with new-onset IRD and ILD, inflammatory pulmonary changes are predominate, reflected by GGO on HRCT and a mainly lymphocytic cell profile in the immunological BAL. In NSIP or UIP on HRCT, the percentages of lymphocytes and neutrophils were higher in BAL fluid, representing a fibrotic component in addition to the inflammation. Consequently, patients with evidence of GGO on HRCT should primarily be treated with anti-inflammatory/immunosuppressive therapy, whereas in patients with NSIP and UIP a combination of anti-inflammatory and anti-fibrotic agents would be the appropriate treatment.
Subject(s)
Bronchoalveolar Lavage Fluid , Lung Diseases, Interstitial , Rheumatic Diseases , Tomography, X-Ray Computed , Humans , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/diagnosis , Female , Male , Tomography, X-Ray Computed/methods , Middle Aged , Rheumatic Diseases/diagnostic imaging , Rheumatic Diseases/immunology , Aged , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Adult , Bronchoalveolar Lavage/methodsABSTRACT
AIMS: We aim to evaluate change in the use of prognostic guideline-directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non-cancer controls, including renin-angiotensin-system inhibitors (RASIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). METHODS AND RESULTS: We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12 months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non-cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR = 1.51, 95% CI = 1.35-1.68; beta-blockers: OR = 1.22, 95% CI = 1.08-1.37; MRAs: OR = 1.31, 95% CI = 1.08-1.59) and poor persistence (RASIs: OR = 2.04, 95% CI = 1.75-2.37; beta-blockers: OR = 1.35, 95% CI = 1.12-1.63; MRAs: OR = 1.49, 95% CI = 1.16-1.93), and higher risks for dose down-titration for RASIs (OR = 1.69, 95% CI = 1.40-2.04) and beta-blockers (OR = 1.31, 95% CI = 1.05-1.62). Cancer diagnosis was not associated with treatment initiation or dose up-titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. CONCLUSIONS: Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.
ABSTRACT
Background: Parents of children with neurodevelopmental conditions (NDC) are at risk of experiencing elevated levels of parental stress. Access to robust instruments to assess parental stress is important in both clinical and research contexts. Objective: We aimed to evaluate the psychometric properties of a Swedish version of the Parental Stress Scale (PSS), completed by parents of 3- to 17-year-old children, with and without NDCs. Method: Main analyses were conducted on data from three independent samples: a community sample (n=1018), a treatment-seeking sample of parents of children with various disabilities (n=653), and a sample of parents of children with Attention-Deficit/Hyperactivity Disorder (ADHD) who themselves reported varying ADHD symptom severities (n=562). Additional analyses were enabled by the use of data from a complementary test-retest sample (n=337). Results: The internal consistency of the PSS was good (Cronbach's alpha, α=.87) and its test-retest reliability moderate (ICC=.66). The scale correlated in the expected direction with related constructs (r=.50-.56 in the community sample). An exploratory factor analysis found its internal structure to reflect two aspects of parental stress: Lack of Parental Rewards and Role Satisfaction (factor 1, α=.90) and Parental Stressors and Distress (factor 2, α=.85). The treatment-seeking parents of children with disabilities reported higher parental stress than community reference parents (p<.001; Cohen's d=1.17). Moreover, we found that parents with high ADHD symptom severity reported higher parental stress than parents with low ADHD symptom severity (p<.001; d=0.39). Conclusion: In summary, we found evidence in support of the reliability and validity of the PSS, which overall was judged to be useful as a measure of parental stress in a Swedish context. In addition, our results underline the importance of considering parental stress and related needs in assessments and intervention planning involving families of children with NDCs.
ABSTRACT
PURPOSE: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF. METHODS: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database-UK (2000 to 2019) with a clone-censor-weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3-6 years, and >6 years after initiation. The study outcomes were any incident cancer and site-specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10-year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping. RESULTS: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94-1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3-6 years: RR, 0.94; 95% CI, 0.70-1.33. >6 years: RR, 0.97; 95% CI, 0.79-1.26). No significant risk difference was observed on any site-specific cancer diagnoses. CONCLUSIONS: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF.
Subject(s)
Heart Failure , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Neoplasms , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Neoplasms/epidemiology , Research Design , Heart Failure/epidemiology , CognitionABSTRACT
BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.
ABSTRACT
BACKGROUND: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. METHODS: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. DISCUSSION: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. TRIAL REGISTRATION: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.
Subject(s)
Oropharyngeal Neoplasms , Papillomavirus Infections , Humans , Cisplatin/adverse effects , Quality of Life , Treatment Outcome , Oropharyngeal Neoplasms/therapy , Randomized Controlled Trials as Topic , Multicenter Studies as Topic , Clinical Trials, Phase III as TopicABSTRACT
BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.
Subject(s)
Morpholines , Neoplasms , Pyrimidines , Sulfonamides , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Indoles , Inflammation/drug therapy , Genomics , Ataxia Telangiectasia Mutated Proteins/geneticsABSTRACT
OBJECTIVE: To describe the development of the Improving Parenting Skills Adult ADHD (IPSA) parent training (PT) program, designed for parents with ADHD. METHOD: IPSA was developed using an iterative co-creation approach, involving parents with ADHD from the initial knowledge mobilization phase onwards. The program prototype was evaluated by 16 parents with ADHD, in an open trial of program feasibility. RESULTS: IPSA was deemed feasible in terms of acceptability and levels of active participation, with no evidence of unintended harm. All but one participant completed the program, attending on average 84% of sessions. Pre-to-post within-group comparisons of targeted skills and outcomes revealed changes in the expected direction regarding, for example, use of introduced parenting skills (Cohen's d = 1.3). CONCLUSION: The program prototype was found acceptable, accessible, and safe. Findings support the potential value of adapting PT protocols for parents with ADHD and warrant further evaluation of IPSA in a randomized controlled trial.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adult , Humans , Attention Deficit Disorder with Hyperactivity/therapy , Parenting , Parents/educationABSTRACT
Parent training is an effective treatment for disruptive behavior problems in children. However, as there is limited access to traditional face-to-face treatment, other delivery formats have been evaluated. This study aims to evaluate possible predictors and moderators of outcome, completion and engagement in parent training when delivered in group or through the internet. A recent randomized controlled non-inferiority trial (N = 161) demonstrated equal effectiveness of the parent training program Comet when delivered in group (gComet) and through the internet (iComet). Demographic, clinical and theory-driven variables were studied to find predictors and moderators of treatment effect, completion and engagement. Linear mixed effects models were used to determine predictors and moderators of change in disruptive behavior from baseline to the 3- and 12-month follow-up. Most variables did not have significant predictive or moderating effects. However, there were some variables that predicted or moderated outcomes that may have implications for practice (e.g., comorbid emotional problems, preferred treatment format, and ADHD). This trial can contribute to guiding clinical work with children with disruptive behavior and results indicate that parent training in both treatment formats can be offered regardless of a range of demographic and clinical factors. Taking patients' treatment preferences into account can increase treatment completion.
Subject(s)
Child Behavior Disorders , Problem Behavior , Child , Humans , Child Behavior Disorders/therapy , Child Behavior Disorders/psychology , Comorbidity , Parents/education , Problem Behavior/psychology , Treatment OutcomeABSTRACT
INTRODUCTION: Head and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck carcinoma (HNSCC) is platinum-based chemotherapy combined with the anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, cetuximab. However, most patients will have poor median overall survival (OS) of 6-9 months despite treatment. HNSCC tumours exhibit an immune landscape poised to respond to immunotherapeutic approaches, with most tumours expressing the immunosuppressive receptor programmed death-ligand 1 (PD-L1). We undertook the current study to determine the safety and efficacy of avelumab, a monoclonal antibody targeting the interaction between PD-L1 and its receptor on cytotoxic T-cells, in combination with cetuximab. METHODS AND ANALYSIS: This is a multi-centre, single-arm dose de-escalation phase II safety and efficacy study of avelumab combined with cetuximab; the study was to progress to a randomised phase II trial, however, the study will now complete after the safety run-in component. Up to 16 participants with histologically/cytologically recurrent/metastatic squamous cell carcinoma (including HNSCC) who have not received cetuximab previously will be recruited. All patients will receive 10 mg/kg avelumab and cetuximab (500, 400 or 300 mg/m2 depending on the cohort open at time of registration) on days 1 and 15 of 4-week cycles for up to 1 year, (avelumab not given cycle 1 day 1). A modified continual reassessment method will be used to determine dose de-escalation. The primary objective is to establish the safety of the combination and to determine the optimum dose of cetuximab. Secondary objectives include assessing evidence of antitumour activity by evaluating response rates and disease control rates at 6 and 12 months as well as progression-free and OS. ETHICS AND DISSEMINATION: Approval granted by City and East REC (18/LO/0021). Findings will be published in peer-reviewed journals and disseminated at conferences. TRIAL REGISTRATION NUMBER: NCT03494322.
Subject(s)
Antineoplastic Agents , Carcinoma, Squamous Cell , Head and Neck Neoplasms , Humans , Cetuximab/therapeutic use , Squamous Cell Carcinoma of Head and Neck/drug therapy , B7-H1 Antigen , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Carcinoma, Squamous Cell/drug therapy , Antibodies, Monoclonal , Head and Neck Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , United Kingdom , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Randomized Controlled Trials as Topic , Multicenter Studies as Topic , Clinical Trials, Phase II as TopicABSTRACT
A 69-year-old male patient with seropositive erosive rheumatoid arthritis (RA) presented to our clinic due to progressive dyspnea. High-resolution computed tomography (HRCT) and immunological bronchioalveolar lavage revealed ground-glass opacities and a lymphocytic alveolitis caused by interstitial lung disease (ILD) in RA. Considering previous forms of treatment, disease-modifying antirheumatic drug (DMARD) treatment was switched to tofacitinib. Tofacitinib treatment demonstrated a 33% reduction in ground-glass opacities by artificial intelligence-based quantification of pulmonary HRCT over the course of 6 months, which was associated with an improvement in dyspnea symptoms. In conclusion, tofacitinib represents an effective anti-inflammatory therapeutic option in the treatment of RA-ILD.
ABSTRACT
BACKGROUND: Parenting programs have the potential to improve population health, if widely disseminated. However, wide-scale dissemination is challenging. Also, more knowledge is needed of whether parenting programs are effective for the variability of families in the general population. METHODS: This study aimed to investigate who the universal parenting program All Children in Focus (ABC) reaches when offered in routine care in Sweden. A second aim was to investigate if the outcomes were predicted by factors related to family background, group leader experience, and homework completion. Questionnaires were collected before and after ABC from 1420 parents. Hierarchical regression analyses were performed to examine predictors of disruptive child behavior, parenting practices, and satisfaction. RESULTS: ABC was available in about 40% of Swedish municipalities and reached a fairly representative population sample, with the exception that fewer fathers than mothers participated. The examined predictors explained a small proportion of the variance in the outcomes (2.5, 3.5 and 14.7%, respectively). Still, the effect on disruptive child behavior was statistically significantly larger for parents born in Sweden, with higher education, and older children. The effect on parenting practices was also larger for parents born in Sweden, for mothers, and for those practicing homework more frequently. Most examined predictors showed no statistically significant association with child and parenting outcomes. Parents were generally satisfied with ABC and the significant predictors of satisfaction had little practical meaning. CONCLUSIONS: A fairly representative group of parents across Sweden were reached by ABC. Background variables, homework completion, and group leaders' experience explained a small proportion of variance in the outcomes. Meanwhile, the slightly lower intervention effects found for preschool children and parents born abroad calls for further investigation, since even small differences in effects can have an impact at a population level. The study also points to the importance of stressing homework completion and to increase the reach of universal parenting interventions to some underrepresented groups.
Subject(s)
Parenting , Problem Behavior , Female , Child, Preschool , Child , Humans , Adolescent , Parents , Mothers , Child RearingABSTRACT
BACKGROUND: In those receiving chemotherapy, renal and hepatic dysfunction can increase the risk of toxicity and should therefore be monitored. We aimed to develop a machine learning model to identify those patients that need closer monitoring, enabling a safer and more efficient service. METHODS: We used retrospective data from a large academic hospital, for patients treated with chemotherapy for breast cancer, colorectal cancer and diffuse-large B-cell lymphoma, to train and validate a Multi-Layer Perceptrons (MLP) model to predict the outcomes of unacceptable rises in bilirubin or creatinine. To assess the performance of the model, validation was performed using patient data from a separate, independent hospital using the same variables. Using this dataset, we evaluated the sensitivity and specificity of the model. RESULTS: 1214 patients in total were identified. The training set had almost perfect sensitivity and specificity of >0.95; the area under the curve (AUC) was 0.99 (95% CI 0.98-1.00) for creatinine and 0.97 (95% CI: 0.95-0.99) for bilirubin. The validation set had good sensitivity (creatinine: 0.60, 95% CI: 0.55-0.64, bilirubin: 0.54, 95% CI: 0.52-0.56), and specificity (creatinine 0.98, 95% CI: 0.96-0.99, bilirubin 0.90, 95% CI: 0.87-0.94) and area under the curve (creatinine: 0.76, 95% CI: 0.70, 0.82, bilirubin 0.72, 95% CI: 0.68-0.76). CONCLUSIONS: We have demonstrated that a MLP model can be used to reduce the number of blood tests required for some patients at low risk of organ dysfunction, whilst improving safety for others at high risk.
Subject(s)
Bilirubin , Machine Learning , Humans , Retrospective Studies , Creatinine , Sensitivity and SpecificityABSTRACT
BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Colorectal Neoplasms , Enzyme Inhibitors , Lung Neoplasms , Humans , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Administration, Oral , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic useABSTRACT
BACKGROUND: Millions of children are victims of child abuse world-wide. Consequences include long-term health impacts and large societal costs. Parent training is promising to prevent abuse, but challenges with motivation and attrition must be overcome to reach parents in need. OBJECTIVE: To assess the effectiveness and acceptability of Safer Kids, a cognitive behavioral therapy-based parenting program delivered immediately after a report of child abuse. Safer Kids is used within the Child Welfare Services (CWS) in Sweden but has never been evaluated in an RCT. PARTICIPANTS AND SETTING: In total, 112 families with children 2-12 years referred to the Swedish CWS for physical or emotional child abuse participated. METHODS: Families were randomized to Safer Kids or intervention as usual (IAU). Data from parents, children and CWS were analyzed with multilevel and survival analyses. Primary outcomes were parent-rated child abuse potential and re-reports of abuse. Secondary outcomes were child abuse risk factors and treatment satisfaction. RESULTS: Data 4 and 7 months from baseline were available for 96 % of the families. All except one family (98 %) who started Safer Kids completed the program. Both groups improved from baseline to follow-ups on most effectiveness outcomes. The changes were not statistically different between groups. Parents and social workers were more satisfied with Safer Kids than IAU. CONCLUSIONS: Short manualized parenting programs can be a way to reach parents reported for child abuse with support. Safer Kids is a viable option to the CWS's standard interventions, as it was equally effective and slightly better accepted than IAU.
Subject(s)
Child Abuse , Parents , Child , Humans , Parents/psychology , Parenting/psychology , Risk Factors , Costs and Cost Analysis , Child Abuse/prevention & controlABSTRACT
INTRODUCTION: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. MATERIALS AND METHODS: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). RESULTS: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. CONCLUSION: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Neoplasms, Second Primary , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Proto-Oncogene Proteins c-met/genetics , Protein Kinase Inhibitors/adverse effects , Neoplasms, Second Primary/genetics , Exons , MutationABSTRACT
Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.