Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors.

PURPOSE: In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin lymphomas (NHL). The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178. PATIENTS AND METHODS: Adult patients with treatment-refractory advanced solid tumors or NHL and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. RESULTS: Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months. CONCLUSIONS: JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. On the basis of safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.

Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents.

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10-5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.

Exercise to prevent shoulder problems after breast cancer surgery: the PROSPER RCT.

BACKGROUND: Upper limb problems are common after breast cancer treatment. OBJECTIVES: To investigate the clinical effectiveness and cost-effectiveness of a structured exercise programme compared with usual care on upper limb function, health-related outcomes and costs in women undergoing breast cancer surgery. DESIGN: This was a two-arm, pragmatic, randomised controlled trial with embedded qualitative research, process evaluation and parallel economic analysis; the unit of randomisation was the individual (allocated ratio 1 : 1). SETTING: Breast cancer centres, secondary care. PARTICIPANTS: Women aged ≥ 18 years who had been diagnosed with breast cancer and were at higher risk of developing shoulder problems. Women were screened to identify their risk status. INTERVENTIONS: All participants received usual-care information leaflets. Those randomised to exercise were referred to physiotherapy for an early, structured exercise programme (three to six face-to-face appointments that included strengthening, physical activity and behavioural change strategies). MAIN OUTCOME MEASURES: The primary outcome was upper limb function at 12 months as assessed using the Disabilities of Arm, Hand and Shoulder questionnaire. Secondary outcomes were function (Disabilities of Arm, Hand and Shoulder questionnaire subscales), pain, complications (e.g. wound-related complications, lymphoedema), health-related quality of life (e.g. EuroQol-5 Dimensions, five-level version; Short Form questionnaire-12 items), physical activity and health service resource use. The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit gained from an NHS and Personal Social Services perspective. Participants and physiotherapists were not blinded to group assignment, but data collectors were blinded. RESULTS: Between 2016 and 2017, we randomised 392 participants from 17 breast cancer centres across England: 196 (50%) to the usual-care group and 196 (50%) to the exercise group. Ten participants (10/392; 3%) were withdrawn at randomisation and 32 (8%) did not provide complete baseline data. A total of 175 participants (89%) from each treatment group provided baseline data. Participants' mean age was 58.1 years (standard deviation 12.1 years; range 28-88 years). Most participants had undergone axillary node clearance surgery (327/392; 83%) and 317 (81%) had received radiotherapy. Uptake of the exercise treatment was high, with 181 out of 196 (92%) participants attending at least one physiotherapy appointment. Compliance with exercise was good: 143 out of 196 (73%) participants completed three or more physiotherapy sessions. At 12 months, 274 out of 392 (70%) participants returned questionnaires. Improvement in arm function was greater in the exercise group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 16.3 (standard deviation 17.6)] than in the usual-care group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 23.7 (standard deviation 22.9)] at 12 months for intention-to-treat (adjusted mean difference Disabilities of Arm, Hand and Shoulder questionnaire score of -7.81, 95% confidence interval -12.44 to -3.17; p = 0.001) and complier-average causal effect analyses (adjusted mean difference -8.74, 95% confidence interval -13.71 to -3.77; p ≤ 0.001). At 12 months, pain scores were lower and physical health-related quality of life was higher in the exercise group than in the usual-care group (Short Form questionnaire-12 items, mean difference 4.39, 95% confidence interval 1.74 to 7.04; p = 0.001). We found no differences in the rate of adverse events or lymphoedema over 12 months. The qualitative findings suggested that women found the exercise programme beneficial and enjoyable. Exercise accrued lower costs (-£387, 95% CI -£2491 to £1718) and generated more quality-adjusted life years (0.029, 95% CI 0.001 to 0.056) than usual care over 12 months. The cost-effectiveness analysis indicated that exercise was more cost-effective and that the results were robust to sensitivity analyses. Exercise was relatively cheap to implement (£129 per participant) and associated with lower health-care costs than usual care and improved health-related quality of life. Benefits may accrue beyond the end of the trial. LIMITATIONS: Postal follow-up was lower than estimated; however, the study was adequately powered. No serious adverse events directly related to the intervention were reported. CONCLUSIONS: This trial provided robust evidence that referral for early, supported exercise after breast cancer surgery improved shoulder function in those at risk of shoulder problems and was associated with lower health-care costs than usual care and improved health-related quality of life. FUTURE WORK: Future work should focus on the implementation of exercise programmes in clinical practice for those at highest risk of shoulder problems. TRIAL REGISTRATION: This trial is registered as ISRCTN35358984. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 15. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Breast cancer is the most common cancer affecting women. Women now live longer because the detection and treatment of cancer has improved over the last 40 years. The side effects of breast cancer treatments can lead to complications, such as difficulties with arm movements, arm swelling (lymphoedema), pain and poor quality of life. These problems can last for many years after the cancer has been treated. Usual care after breast cancer surgery is to give patients an information leaflet explaining arm exercises that they can undertake after their operation. Offering exercise support from a physiotherapist may be a better way to help those at risk of developing shoulder problems after breast cancer treatment than providing a leaflet only. WHAT DID WE DO?: We compared two strategies to prevent shoulder problems in women having breast cancer treatment: information leaflets and an exercise programme. We invited women with a new diagnosis of breast cancer who were at higher risk of developing shoulder problems than other women with a new diagnosis of breast cancer. We recruited 392 women aged 28­88 years from 17 breast cancer units across England. Women were allocated to one of two groups by chance using a computer. Everyone was given information leaflets that explained what type of exercises to do after surgery. Half of the women (n = 196) were then invited to take part in an exercise programme, supported by a trained physiotherapist. These women followed a programme of shoulder mobility, stretching and strengthening exercises for up to 1 year. We measured changes in arm function, pain, arm swelling (lymphoedema) and physical and mental quality of life, and the cost of treatments during the whole first year of recovery, in everyone. We also spoke to the women and physiotherapists to find out whether or not these treatment strategies were acceptable to them. WHAT DID WE FIND OUT?: Women doing the exercise programme had better arm function, less pain and better quality of life than the women given an information leaflet only. Women said that the exercise programme helped with their recovery during cancer treatment. Exercise was cheap to deliver (£129 per person) and led to improved overall quality of life at 1 year after breast cancer surgery.

Exercise versus usual care after non-reconstructive breast cancer surgery (UK PROSPER): multicentre randomised controlled trial and economic evaluation.

OBJECTIVE: To evaluate whether a structured exercise programme improved functional and health related quality of life outcomes compared with usual care for women at high risk of upper limb disability after breast cancer surgery. DESIGN: Multicentre, pragmatic, superiority, randomised controlled trial with economic evaluation. SETTING: 17 UK National Health Service cancer centres. PARTICIPANTS: 392 women undergoing breast cancer surgery, at risk of postoperative upper limb morbidity, randomised (1:1) to usual care with structured exercise (n=196) or usual care alone (n=196). INTERVENTIONS: Usual care (information leaflets) only or usual care plus a physiotherapy led exercise programme, incorporating stretching, strengthening, physical activity, and behavioural change techniques to support adherence to exercise, introduced at 7-10 days postoperatively, with two further appointments at one and three months. MAIN OUTCOME MEASURES: Disability of Arm, Hand and Shoulder (DASH) questionnaire at 12 months, analysed by intention to treat. Secondary outcomes included DASH subscales, pain, complications, health related quality of life, and resource use, from a health and personal social services perspective. RESULTS: Between 26 January 2016 and 31 July 2017, 951 patients were screened and 392 (mean age 58.1 years) were randomly allocated, with 382 (97%) eligible for intention to treat analysis. 181 (95%) of 191 participants allocated to exercise attended at least one appointment. Upper limb function improved after exercise compared with usual care (mean DASH 16.3 (SD 17.6) for exercise (n=132); 23.7 (22.9) usual care (n=138); adjusted mean difference 7.81, 95% confidence interval 3.17 to 12.44; P=0.001). Secondary outcomes favoured exercise over usual care, with lower pain intensity at 12 months (adjusted mean difference on numerical rating scale -0.68, -1.23 to -0.12; P=0.02) and fewer arm disability symptoms at 12 months (adjusted mean difference on Functional Assessment of Cancer Therapy-Breast+4 (FACT-B+4) -2.02, -3.11 to -0.93; P=0.001). No increase in complications, lymphoedema, or adverse events was noted in participants allocated to exercise. Exercise accrued lower costs per patient (on average -£387 (€457; $533) (95% confidence interval -£2491 to £1718; 2015 pricing) and was cost effective compared with usual care. CONCLUSIONS: The PROSPER exercise programme was clinically effective and cost effective and reduced upper limb disability one year after breast cancer treatment in patients at risk of treatment related postoperative complications. TRIAL REGISTRATION: ISRCTN Registry ISRCTN35358984.

Development and validation of an improved classification and risk stratification system for carotid body tumors: Multinational collaborative cohort study.

BACKGROUND: This study aims to develop and validate a new classification system that better predicts combined risk of neurological and neurovascular complications following CBT surgery, crucial for treatment decision-making. METHODS: Multinational retrospective cohort study with 199 consecutive cases. A cohort of 132 CBT cases was used to develop the new classification. To undertake external validation, assessment was made between the actual complication rate and predicted risk by the model on an independent cohort (n = 67). RESULTS: Univariate analyses showed statistically significant associations between developing a complication and the following factors: craniocaudal dimension, volume, Shamblin classification, and Mehanna types. In the multivariate prognostic model, only Mehanna type remained as a significant risk predictor. The risk of developing complications increases with increasing Mehanna type. CONCLUSIONS: We have developed and then validated a new classification and risk stratification system for CBTs, which demonstrated better prognostic power for the risk of developing neurovascular complications after surgery.

Concurrent cisplatin or cetuximab with radiotherapy for HPV-positive oropharyngeal cancer: Medical resource use, costs, and quality-adjusted survival from the De-ESCALaTE HPV trial.

BACKGROUND: The De-ESCALaTE HPV trial confirmed the dominance of cisplatin over cetuximab for tumour control in patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). Here, we present the analysis of health-related quality of life (HRQoL), resource use, and health care costs in the trial, as well as complete 2-year survival and recurrence. MATERIALS AND METHODS: Resource use and HRQoL data were collected at intervals from the baseline to 24 months post treatment (PT). Health care costs were estimated using UK-based unit costs. Missing data were imputed. Differences in mean EQ-5D-5L utility index and adjusted cumulative quality-adjusted life years (QALYs) were compared using the Wilcoxon signed-rank test and linear regression, respectively. Mean resource usage and costs were compared through two-sample t-tests. RESULTS: 334 patients were randomised to cisplatin (n = 166) or cetuximab (n = 168). Two-year overall survival (97·5% vs 90·0%, HR: 3.268 [95% CI 1·451 to 7·359], p = 0·0251) and recurrence rates (6·4% vs 16·0%, HR: 2·67 [1·38 to 5·15]; p = 0·0024) favoured cisplatin. No significant differences in EQ-5D-5L utility scores were detected at any time point. At 24 months PT, mean difference was 0·107 QALYs in favour of cisplatin (95% CI: 0·186 to 0·029, p = 0·007) driven by the mortality difference. Health care costs were similar across all categories except the procurement cost and delivery of the systemic agent, with cetuximab significantly more expensive than cisplatin (£7779 [P < 0.001]). Consequently, total costs at 24 months PT averaged £13517 (SE: £345) per patient for cisplatin and £21064 (SE: £400) for cetuximab (mean difference £7547 [95% CI: £6512 to £8582]). CONCLUSIONS: Cisplatin chemoradiotherapy provided more QALYs and was less costly than cetuximab bioradiotherapy, remaining standard of care for nonsurgical treatment of HPV-positive OPSCC.

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.

BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.

Management of hot flushes in UK breast cancer patients: clinician and patient perspectives.

INTRODUCTION: Menopausal problems are among the most prevalent and distressing problems following breast cancer treatment, with 70% women experiencing hot flushes and night sweats (HFNS). A working party was set up to support the development of new research into the management of these problems. METHODS: We conducted surveys to explore the need as perceived by women with breast cancer and establish current UK management practices. A patient survey was conducted through a charity, Breast Cancer Care, and a health professional survey via the UK Breast Intergroup. The HFNS Problem Rating Scale was used, as well as specific questions addressing the aims of the study. RESULTS: Six hundred and sixty-five patients responded and 185 health professionals. Twenty-eight percent women had considered stopping adjuvant endocrine treatment because of HFNS, yet 34% had never been asked about HFNS by any health professional. The most commonly offered interventions were SSRIs, such as venlafaxine, yet only 25% patients had been offered these drugs. Cognitive behavioural therapy was rarely suggested (2%) despite good evidence. DISCUSSION: This study shows a lack of coherence in the management of HFNS in breast cancer survivors, which may lead to reduced adherence to adjuvant therapy. There is an urgent need to develop guidelines to support management of HFNS after breast cancer.

A literature review of applied adaptive design methodology within the field of oncology in randomised controlled trials and a proposed extension to the CONSORT guidelines.

BACKGROUND: The application of adaptive design methodology within a clinical trial setting is becoming increasingly popular. However the application of these methods within trials is not being reported as adaptive designs hence making it more difficult to capture the emerging use of these designs. Within this review, we aim to understand how adaptive design methodology is being reported, whether these methods are explicitly stated as an 'adaptive design' or if it has to be inferred and to identify whether these methods are applied prospectively or concurrently. METHODS: Three databases; Embase, Ovid and PubMed were chosen to conduct the literature search. The inclusion criteria for the review were phase II, phase III and phase II/III randomised controlled trials within the field of Oncology that published trial results in 2015. A variety of search terms related to adaptive designs were used. RESULTS: A total of 734 results were identified, after screening 54 were eligible. Adaptive designs were more commonly applied in phase III confirmatory trials. The majority of the papers performed an interim analysis, which included some sort of stopping criteria. Additionally only two papers explicitly stated the term 'adaptive design' and therefore for most of the papers, it had to be inferred that adaptive methods was applied. Sixty-five applications of adaptive design methods were applied, from which the most common method was an adaptation using group sequential methods. CONCLUSIONS: This review indicated that the reporting of adaptive design methodology within clinical trials needs improving. The proposed extension to the current CONSORT 2010 guidelines could help capture adaptive design methods. Furthermore provide an essential aid to those involved with clinical trials.