Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation.

BACKGROUND: In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL). METHODS: In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m2 intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes. RESULTS: Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12). CONCLUSIONS: Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC.

Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer.

Background: Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents. Methods: WISTERIA was a prospective, parallel two-group, open-label, dose-finding, phase I clinical trial. Eligible patients had histologically confirmed oral, laryngeal, or hypopharyngeal squamous cell carcinoma, ECOG performance status 0/1, and aged ≥18-to-≤70 years. Primary outcomes were adverse events and defining recommended dose and schedule of AZD1775 in combination with cisplatin in pre-operative (Group A), or with cisplatin/radiotherapy in post-operative (Group B) patients. Dose determination was guided by a modified time-to-event continual reassessment method (mTITE-CRM). Results: Between 30-Oct-2017 and 15-Jul-2019, nine patients were registered: Three into Group A and six into Group B. WISTERIA was closed early due to poor recruitment. Five dose-limiting toxicities (DLTs) were reported in four Group B patients. Seven serious adverse events were reported in four patients: One in Group A, and three in Group B. Three were related to treatment. No treatment-related deaths were reported. Conclusions: WISTERIA did not complete its primary objectives due to poor recruitment and toxicities reported in Group B. However, use of the novel mTITE-CRM improved flexibility in reducing accrual suspension periods and should be considered for future trials in complex patient populations. Clinical Trial Registration: ISRCTN76291951.

The impact of inter-cycle treatment delays on overall survival in patients with advanced-stage ovarian cancer.

INTRODUCTION: Chemotherapy forms the cornerstone of systemic treatment for advanced ovarian cancer, extending overall survival; however, drug-related toxicity can lead to treatment delays, potentially diminishing treatment efficacy. This study evaluated the impact of treatment delays on all-cause mortality of patients with ovarian cancer, to better inform decisions on patient management. METHODS: This retrospective, population-based cohort study included 1517 women with advanced-stage ovarian cancer, receiving first-line adjuvant or neoadjuvant chemotherapy in 2014 and 2015. The frequency of inter-cycle delays >7 days was calculated using drug administration dates. Kaplan-Meier estimates were used to compare 2-year overall survival (OS) between patients who were delayed and those treated to schedule. Cox proportional hazards regression was used to investigate the impact of treatment delay on all-cause mortality. Inverse probability of treatment weighting propensity scores were used to adjust for confounding variables. RESULTS: Delays >7 days occurred in 35.3% of patients. Two-year OS probability was 62.7% in patients who experienced treatment delays >7 days (95% CI, 58.7-66.9) compared to 69.1% in those treated to schedule (95% CI, 66.2-72.0). Delays were not significantly associated with all-cause mortality when adjusted for confounders (HR 1.00 95% CI, 0.83-1.20, P = .9). CONCLUSIONS: Delays to chemotherapy treatment were not significantly associated with worsened survival in patients with advanced-stage ovarian cancer. These results can inform clinical decision making that prioritize toxicity management and quality of life for those treated with chemotherapy.

The impact of inter-cycle treatment delays on 5-year all-cause mortality in early-stage breast cancer: A retrospective cohort study.

BACKGROUND: Inter-cycle delays to chemotherapy are often required to manage drug toxicity. The impact of delays on mortality is poorly characterised. This retrospective cohort study examined the association of treatment delay with all-cause mortality in early-stage breast cancer. METHODS: This real-world analytical study included adult women with stage 2 or 3 breast cancer receiving first-line (neo-)adjuvant chemotherapy between 01/01/2014 and 31/12/2015 in England. Inter-cycle delays > 7 days during the treatment period were calculated, and the association of treatment delay with 5-year all-cause mortality was investigated. Survival was compared between patients experiencing treatment delay and those completing treatment to schedule using landmark methodology and Kaplan-Meier (KM) estimator. Cox proportional hazards regression was used to investigate the impact of delay on survival, using inverse probability of treatment weighting to adjust for confounding variables. RESULTS: 8567 patients were included. 17 % (1448) experienced inter-cycle delay > 7 days during the treatment period. 1120 (13 %) women had died at the end of the 5-year follow up period. Median follow-up time was 5.5 years. Survival probability was significantly lower in patients experiencing treatment delay by KM estimator analysis (p < 0.0001). Cox proportional hazards regression demonstrated a significant positive association between delay and 5-year all-cause mortality (HR 1.33 95 % CI 1.12-1.61, p < 0.001). CONCLUSIONS: This is the largest study of its kind demonstrating an association between treatment delay and all-cause mortality. These findings support interventions to improve toxicity management allowing completion of chemotherapy to schedule where patients experience treatment delay due to treatment-related toxicity or hospital capacity pressures.

Use of heart failure medical therapy before and after a cancer diagnosis: A longitudinal study.

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.

Eftilagimod Alpha (Soluble LAG3 Protein) Combined with Pembrolizumab as Second-Line Therapy for Patients with Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability. PATIENTS AND METHODS: In this multinational phase II trial using Simon's two-stage design, patients who were PD-L(1)-naïve with R/M HNSCC who had failed first-line platinum-based therapy, unselected for PD-L1, received intravenous pembrolizumab (200 mg, once every 2 weeks) combined with subcutaneous efti (30 mg once every 2 weeks for 24 weeks and once every 3 weeks thereafter). The primary endpoint was objective response rate per RECIST 1.1 modified for immune-based therapy by investigator assessment. Additional endpoints included duration of response, progression-free survival, overall survival, and tolerability. Pharmacodynamic effects (absolute lymphocyte count) and Th1 cytokine biomarkers (IFNγ/CXCL10)] were evaluated in liquid biopsies. RESULTS: Between March 2019 and January 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 combined positive score <20. With a median follow-up of 38.8 months, the objective response rate was 29.7%, including 13.5% complete responders. The median duration of response was not reached. Rapid and sustained absolute lymphocyte count increase was observed in patients who had an objective response. Th1 biomarkers increased sustainably after first treatment. No unexpected safety signals were observed. CONCLUSIONS: Efti plus pembrolizumab was safe and showed encouraging antitumor activity and pharmacodynamic effects in patients with second-line head and neck squamous cell carcinoma (HNSCC), thus supporting further evaluation of this combination in earlier treatment lines.

The performance of a Bayesian value-based sequential clinical trial design in the presence of an equivocal cost-effectiveness signal: evidence from the HERO trial.

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.

Correlation of high-resolution computed tomography and immunological bronchoalveolar lavage in interstitial lung disease at the onset of inflammatory rheumatic diseases: implications for diagnosis and therapeutic strategies.

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.

Psychometric Properties of the Parental Stress Scale in Swedish Parents of Children with and without Neurodevelopmental Conditions.

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.

A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

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.

Effect of statin treatment on the risk of cancer in patients with heart failure: A target trial emulation study.

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.

CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

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.

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.

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.

Parent Training Tailored to Parents With ADHD: Development of the Improving Parenting Skills Adult ADHD (IPSA) Program.

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.

Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK.

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.

Is internet-based parent training for everyone? Predictors and moderators of outcomes in group vs. internet-based parent training for children with disruptive behavior problems.

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.

[Is JAK inhibition an option in the treatment of interstitial lung disease in rheumatoid arthritis?] / Ist JAK-Hemmung eine Option in der Behandlung der interstitiellen Lungenerkrankung bei einer rheumatoiden Arthritis?

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.

Reach and predictors of effects during nation-wide dissemination of the universal parenting program All Children in Focus.

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.

Personalising monitoring for chemotherapy patients through predicting deterioration in renal and hepatic function.

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.