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Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings. • Regulatory decision-making in the context of product development life cycle. • PIP as a plan, allowing for evidence generation, able to be modified. • Fostering collaborative development environment, not competitive. • Need to identify priorities based on science. • Collaboration among all stakeholders key, as exemplified by ACCELERATE. [ABSTRACT FROM AUTHOR]

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities. • mTKIs are being evaluated in osteosarcoma and Ewing sarcoma. • Ongoing or planned randomised studies will inform further development. • Toxicity is tolerable when mTKIs are combined with chemotherapy. • Increased understanding of predictive biomarkers and tumour biology is crucial. • A joint academic-industry consortium should share and analyse biomarker samples. [ABSTRACT FROM AUTHOR]

Real-World Data (RWD) studies are increasingly used to support regulatory approvals, reimbursement decisions, and changes in clinical practice for novel cancer drugs. However, few studies have systematically appraised their quality or compared outcomes to pivotal trials. All RWD studies (2010–2019) for drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) from 2010 to 2015 for solid organ tumours in the non-curative setting were identified. Quality assessment was undertaken using the Newcastle Ottawa Scale. Survival differences between each RWD study and the pivotal trial were determined using a related sample Wilcoxon signed-rank test. 293 RWD studies for 45 of the 57 drug indications approved by the FDA/EMA were identified. The most common tumour types were prostate cancer (29%, n = 86) and melanoma (15%, n = 43). A quarter of the studies had industry funding. No high-quality studies were identified, and 78% were low quality. Comparative survival analysis between RWD and pivotal trials was possible for 224 studies (37 drug indications). Differences in median survival between the RWD studies and their corresponding trial ranged from −32 months to 21 months (IQR –4·2 months to 1·6 months). Low-quality studies were more likely to report superior survival outcomes (23%) compared to higher quality studies (8%) (p = 0.02). RWD study quality for novel cancer drugs is low and of insufficient rigour to inform reimbursement decisions and clinical practice. RWD studies seeking publication should provide a completed quality assessment tool on submission. Greater investment in properly designed RWD studies is required. • Study provides a systematic appraisal of FDA/EMA approved drugs in real-world practice. • Most novel FDA/EMA cancer drugs have real-world data (RWD) studies, but the quality is low. • Variability in survival outcomes exists, and findings should be applied cautiously. • Most RWD studies reported inferior survival outcomes compared to the pivotal trial. • Pre-publication critical appraisal checklists should be used for RWD studies. [ABSTRACT FROM AUTHOR]

To examine stage-specific trends in the incidence and survival of cutaneous melanoma in the Netherlands between 2003 and 2018, as well as the uptake of the sentinel lymph node biopsy (SLNB) and novel drugs during that period. Data were obtained from the nationwide population-based Netherlands Cancer Registry for all patients diagnosed with invasive primary cutaneous melanoma (n = 60,267). We presented age-standardized incidence rates, the proportion of patients with an SLNB, the proportion of patients who received a novel drug (for their primary diagnosis) and one- and five-year relative survival rates. Between 2003 and 2018, the incidence rate increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. This increase reflected the increasing incidence rate of patients with stage I and III. The proportion of patients with an SLNB increased from 23% to 64%. A reasonable increase was observed in the proportion of patients with a positive outcome (from 2% to 11%). For patients with stage IV, there was a shift from chemotherapy towards novel drugs as from 2013. The five-year relative survival rate increased from 81% to 92% for men and from 88% to 96% for women. This increase reflected the increasing five-year relative survival rate of patients with stage II, III, and IV. We observed an increase in incidence for patients with stage I and III and an improvement in survival for patients with stage II, III and IV. These trends can be partly explained by the introduction of the SLNB and the novel drugs. • Between 2003 and 2018, 60,267 Dutch patients were diagnosed with cutaneous melanoma. • Incidence rates increased from 10.9 to 23.9 for men and from 15.6 to 27.3 for women. • There was an increase in incidence for patients with stage I and III. • Five-year survival rates increased from 81% to 92% for men and from 88% to 96% for women. • There was an improvement in survival for patients with stage II, III and IV. [ABSTRACT FROM AUTHOR]

Cancer is the second deadliest disease worldwide. Although recent advances applying precision treatments with targeted (molecular and immune) agents are promising, the histological and molecular heterogeneity of cancer cells and huge mutational burdens (intrinsic or acquired after therapy) leading to drug resistance and treatment failure are posing continuous challenges. These recent advances do not negate the need for alternative approaches such as chemoprevention, the pharmacological approach to reverse, suppress or prevent the initial phases of carcinogenesis or the progression of premalignant cells to invasive disease by using non-toxic agents. Although data are limited, the success of several clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational, appealing and viable strategy to prevent carcinogenesis. Particularly among higher-risk groups, the use of safe, non-toxic agents is the utmost consideration because these individuals have not yet developed invasive disease. Natural dietary compounds present in fruits, vegetables and spices are especially attractive for chemoprevention and treatment because of their easy availability, high margin of safety, relatively low cost and widespread human consumption. Hundreds of such compounds have been widely investigated for chemoprevention and treatment in the last few decades. Previously, we reviewed the most widely studied natural compounds and their molecular mechanisms, which were highly exploited by the cancer research community. In the time since our initial review, many promising new compounds have been identified. In this review, we critically review these promising new natural compounds, their molecular targets and mechanisms of anticancer activity that may create novel opportunities for further design and conduct of preclinical and clinical studies. • Table of natural compounds studied through preclinical and early clinical studies. • Comprehensive review of new promising natural compounds and their anticancer effects. • Summary of cellular processes affected by new promising compounds. • Comprehensive review of the molecular targets of promising new compounds. • Assessment of the future perspectives about these compounds. [ABSTRACT FROM AUTHOR]

The treatment of metastatic non–small-cell lung cancer (mNSCLC) patients with EGFR/HER2 exon 20 insertion mutation (i-mut) remains an unmet clinical need. Poziotinib, a new generation tyrosine kinase inhibitor, is currently under investigation as a potential targeted therapy. This compassionate study of its use aims to describe the activity/toxicity of poziotinib in mNSCLC with EGFR/HER2-exon-20-i-mut. NSCLC patients who were treated either with EGFR or HER2 exon 20-i-mut within an expanded access program were included in this study. Poziotinib (16 mg or less) was administrated orally quaque die (QD). The primary end-point was the overall response rate (ORR) assessed by central review using RECIST v1.1, and secondary end-points were median progression free survival (PFS), disease control rate (DCR), median overall survival (OS) and toxicity. The median age of all the 30 patients was 58 years (25–80 years), most of them were females (73%); ECOG 0–1 (83%), EGFR i-mut (73%) and pre-treated (83%). 73% started with poziotinib at a dose of 16 mg. At data cut-off, 22 of 33 patients (73%) experienced a progress in the disease and 12 of 30 (40%) died. Median PFS was 5.6 months (95% CI: 3.6–6.7 months) and the mOS 9.5 months (95% CI: 5.3 – not-reached months). The ORR was 30% (EGFR/HER2: 23/50%) and DCR 80%. G3 AEs were reported in 66% of the patients and were found with skin rash (50%), diarrhoea (17.6%), mucositis (7%) and paronychia (3%). G5, possibly associated with pneumonitis might also have occurred. Poziotinib exhibited effects in mNSCLC patients with EGFR/HER2-exon 20-i-mut. The toxicity rate was high leading to frequent dose interruption and reduction, thereby reducing mPFS in patients with good ORR/DCR. ZENITH20 trial is now being used to evaluate the low dose and new scheduled dose (e.g. bis in die (BID)). • Treatment of NSCLC patients with EGFR and HER2 exon 20 insertion mutation remains an unmet clinical need. • Poziotinib is currently under investigation as a potential targeted therapy. • Poziotinib demonstrated clinical activity in NSCLC. • Poziotinib rate was high leading to frequent dose interruption. • Poziotinib dose below 16 mg or a new scheduled dose (e.g. BID) with a high rate of tolerance. [ABSTRACT FROM AUTHOR]

Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion and thus is regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been largely applied for early clinical testing. In this review, we discuss some repurposed anticancer drugs for the treatment of COVID-19, which are under investigation in clinical trials or proposed for the clinical testing. Image 1 • Drug repurposing for COVID-19 is a solution to rapidly supply the therapeutic options. • Twenty potential antitumour drugs discussed in this review showed promising anti-COVID-19 efficacy. • A number of these anticancer molecules are currently investigated in clinical trials. [ABSTRACT FROM AUTHOR]

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy. • The Neuroblastoma New Drug Development Strategy initiative aims to accelerate new drugs development. •Twenty two of 40 targets were identified as high priority for neuroblastoma. •Targeting telomere maintenance, ATRX , BRIP1 , RRM2 are high priority for drug discovery. •Drugs targeting CDK2/9, CDK7, ATR should enter paediatric clinical development rapidly. •Combining targeted therapies with immunological agents is crucial. [ABSTRACT FROM AUTHOR]

AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791). • First study to assess safety and tolerability of the novel pan erbB inhibitor AZD8931 in oesophagogastric cancer (OGC). • Recommended phase II dose schedule determined to be 20-mg bd for 4 days on/3 days off, per cycle. • Feasibility of adding novel targeted therapies to standard-of-care for oesophago-gastric cancer is confirmed. [ABSTRACT FROM AUTHOR]

Nivolumab was the first immune checkpoint inhibitor approved for previously treated advanced non–small cell lung cancer (NSCLC). Before its introduction in the market, nivolumab was made available to NSCLC patients through an expanded access program (EAP). Here we present the Italian cohort of patients with non-squamous NSCLC enrolled in a worldwide nivolumab EAP, with subgroup analyses involving elderly patients, patients with central nervous system (CNS) metastases and patients receiving nivolumab beyond progression. Pretreated patients with advanced non-squamous NSCLC received nivolumab at 3 mg/kg every 2 weeks up to 24 months. Efficacy data (investigator-assessed tumour response, progression date and survival) and safety data were collected. 1588 patients were treated across 153 Italian centres. Overall response rate and disease control rate were 18% and 44%, respectively; median overall survival (OS) was 11.3 months (95% CI: 10.2–12.4). Elderly patients (≥70 n = 522; ≥75 n = 232) achieved outcomes similar to the global study population; patients with CNS metastases (n = 409) had an OS of 8.6 months (95% CI: 6.4–10.8), and a 1-year OS rate of 43%. Nivolumab was administered beyond progression to 276 patients (26%), 57 of whom achieved subsequent disease control; the median OS of patients receiving nivolumab beyond progression was 16.2 months (95% CI: 14.0–18.4), while 1-year OS rate was 62%. To date, this is the largest clinical experience with nivolumab in a real-world setting. Our data support its use in clinical practice for pretreated non-squamous NSCLC, including patients with older age or CNS metastases. • The Italian expanded access program (EAP) made nivolumab available to a wide population of non–small cell lung cancer (NSCLC) patients. • The outcomes of non-squamous NSCLC patients were consistent with the pivotal trial. • Nivolumab was effective and safe in subgroups poorly represented in clinical trials. • Postprogression benefit was observed with continued administration of nivolumab. • The Italian EAP is the largest real-life clinical experience with nivolumab to date. [ABSTRACT FROM AUTHOR]

Phase I clinical trials have become increasingly critical to regulatory approvals of novel agents. In phase I drug development, a global problem of unknown magnitude is the multiplicity of similar drugs being investigated against the same target, colloquially known as the 'me too' phenomenon. Ranging from December 2020 to December 2022 we annotated phase I clinical trials present on clinicaltrials.gov. Public databases were queried for annotation of investigational agents (IAs). Extensive literature research and data mining were performed to annotate agents not present in public databases. The Cancer Genome Atlas (TCGA) pan-cancer sequencing cohort was used to perform second-level analyses to evaluate tumour types with a higher number of IA matches. A total of 1054 unique drug targets were identified. The most frequent IA classes were: cell products (1223), small-molecule inhibitors (1110), antibodies (733), and vaccines (346). Only a minority (8.9%) of phase I IAs were explored against a target without a competitive agent; 7% of agents shared targets with 2–3 other agents. Unfortunately, the majority (84%) shared targets with at least four other agents. Using data from the TCGA pan-cancer sequencing potentially underserved histologies were identified. Analysis of alteration-IA matches revealed potentially frequent and unexplored alterations in many tumour types. The majority of IAs (86%) shared targets with at least three other agents. We argue that these duplicative efforts could be redirected toward unmet needs instead. • This paper describes a comprehensive portrait of current early drug development. • Investigational agents appear to be dominated by few target genes and drug technologies. • Some histologies appear to be underserved by current drug development compared to others. [ABSTRACT FROM AUTHOR]

The lag time between initial human studies of oncology agents and the first-in-child clinical trials of these agents has not been defined. We conducted a systematic analysis of time from first-in-human trials to first-in-child trials (age of eligibility <18 years) of agents first approved by the US Food and Drug Administration (FDA) for any oncology indication from 1997 to 2017. We used clinical trial registry data, published literature and oncology abstracts to identify relevant trials and start dates. From 1997 to 2017, 126 drugs received initial FDA approval for an oncology indication. Of these, 117 were non-hormonal agents used in subsequent analyses. Fifteen of 117 drugs (12.8%) did not yet have a paediatric trial, and six of 117 drugs (5.1%) had an initial approval that included children. The median time between the first-in-human trial and first-in-child trial was 6.5 years (range 0–27.7 years). The median time from initial FDA approval to the first-in-child clinical trial was –0.66 years (range −43 to +19 years). These values were stable regardless of year of initial FDA approval, drug class and initial approved disease indication. The median lag time from first-in-human to first-in-child trials of oncology agents that were ultimately approved by FDA was 6.5 years. These results provide a benchmark against which to evaluate recent initiatives designed to hasten drug development relevant to children with cancer. • From 1997 to 2017, six of 117 (5.1%) drugs had an initial approval that included children. • The median lag from the first human trial to first paediatric trial was 6.5 years. • First paediatric trials commonly begin within a year before initial FDA approval or often later. • In the past decade, 0.6% of early-phase trials were open to children only. [ABSTRACT FROM AUTHOR]

Background Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children. Methods The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members. Results Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III–IV haematologic toxicities that were transient or asymptomatic and grade III–IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition. Conclusion DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials. [ABSTRACT FROM AUTHOR]

For decades, doxorubicin alone or in combination with ifosfamide has been used in advanced soft tissue sarcoma (STS). In 2014, a comparison of doxorubicin alone versus the combination with ifosfamide (in the randomised phase III EORTC 62012) showed no difference in overall survival (OS), but a difference in response and progression-free survival (PFS) were observed in favour of the combination but at the expense of increased toxicity. Newer fosfamides, with slightly different modes of action, and potentially less toxicity, namely evofosfamide and palifosfamide have recently been tested in randomised phase III clinical trials in STS. The TH CR-406/SARC021 (June 2017) and the PICASSO III (September 2016) studies compared doxorubicin, as the standard arm, to doxorubicin in combination with evofosfamide and palifosfamide, respectively. In both studies, the combination arm produced increased response rates but at the expense of higher toxicity. However, there was no difference in OS or PFS in favour of the combination. Importantly, the median OS of patients receiving standard of care, doxorubicin, in both studies appeared improved from 12.8 months (95.5% CI 10.5–14·III) in the EORTC 62012 to 16.9 months (95% CI 14.8 to 22.9) in PICASSO III and 19.0 months (95% CI 16.2–22.4) in TH CR-406/SARC021. The results of these three randomised phase III studies highlight several critical issues related to the design and conduct of such trials in STS. We discuss these issues aiming to contribute to the ongoing debate about the optimal approach to perform clinical research in STS. [ABSTRACT FROM AUTHOR]

Purpose In tumours with wild-type TP53 , the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours ( NCT01636479 ). Methods In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible. In the MTD expansion cohort, only patients with de-differentiated liposarcoma were included. Primary end-points were MTD and efficacy in the MTD expansion cohort. Secondary end-points included safety, pharmacokinetics and pharmacodynamics biomarkers. Results Seventy-four patients were treated with SAR405838 (50–800 mg once daily [QD], 800–1800 mg weekly and 1800 mg twice weekly). Two patients treated with SAR405838 400 mg QD had thrombocytopaenia as a dose-limiting toxicity (DLT). The MTD for the QD schedule of SAR405838 was 300 mg QD. No DLTs were observed with the weekly schedule; one patient had a DLT of nausea with the 1800 mg twice-weekly dose. Treatment with SAR405838 was associated with increased plasma MIC-1, reflecting p53 pathway activation. In the de-differentiated liposarcoma MTD cohort, 89% of the patients had HDM2 amplification at baseline and no TP53 mutations were observed; best response was stable disease in 56% and progression-free rate at 3 months was 32%. Conclusion SAR405838 had an acceptable safety profile with limited activity in patients with advanced solid tumours. The MTD of SAR405838 was 300 mg QD; MTD was not reached with the weekly schedule. [ABSTRACT FROM AUTHOR]

Background Desmoid tumours describe a rare monoclonal, fibroblastic proliferation characterised by an often unpredictable clinical course. Surgery is one therapeutic option for progressing patients, except if mutilating and associated with considerable function loss. Different systemic treatment approaches have been investigated and promising results could be demonstrated using imatinib. Patients and methods We initiated a phase II trial within the German Interdisciplinary Sarcoma Group (GISG) evaluating imatinib to induce progression arrest in desmoid tumour patients being Response Evaluation Criteria in Solid Tumours (RECIST) progressive, not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss (NCT01137916). Thirty-eight patients (median age 44 years [range: 19–80]; 68% female; 90% Eastern Cooperative Oncology Group (ECOG) performance status 0) were treated with a daily dose of 800 mg imatinib planned over 2 years. The progression arrest rate after 6 months of imatinib treatment (PAR 6mo ) was the primary end-point. Patients showing disease progression under imatinib could be treated with nilotinib 800 mg daily. Accrual started in July 2010 in four GISG centres and finalised in September 2013. Results The final analysis for the primary end-point in the evaluable patients of the full analysis set revealed a PAR 6mo of 65%. Subsequent progression arrest rates at 9, 12, 15, 18, 21 and 24 months were 65%, 59%, 53%, 53%, 50% and 45%, respectively. None of the patients died within the study observational period. Best reported response was seven partial responses at 21 months revealing an overall response rate of 19%. Eight patients treated with nilotinib demonstrated a PAR at 3 months of 88% (7/8); no more disease progressions occurred until end of study. In general imatinib adverse events were mild to moderate. Conclusions Imatinib induces sustained progression arrest in RECIST progressive desmoid tumour patients. In addition, nilotinib had the potential to stabilise desmoid tumour growth after treatment failure with imatinib. [ABSTRACT FROM AUTHOR]

Background Accelerated partial breast irradiation (APBI) represents a valid option for selected early breast cancer (BC). We recently published the 5-year results of the APBI-IMRT-Florence phase 3 randomised trial ( NCT02104895 ), showing a very low rate of disease failure, with acute and early–late toxicity in favour of APBI. We present the early and 2-year follow-up health-related quality of life (HRQoL) results. Methods Eligible patients were women aged more than 40 years with early BC suitable for breast-conserving surgery. APBI consisted of 30 Gy in five fractions delivered with IMRT technique. Standard whole breast irradiation (WBI) consisted of 50 Gy in 25 fractions plus a 10 Gy in five fractions boost on tumour bed. A total of 520 patients were enrolled in the phase 3 trial. Overall, 205 patients (105 APBI and 100 WBI) fully completed all the given questionnaires and were therefore included in the present analysis. As HRQoL assessment, patients were asked to complete the European Organisation for Research and Treatment of Cancer QLQ-C30, and the BR23 questionnaires at the beginning (T0), at the end (T1) and after 2 years from radiation (T2). Findings No significant difference between the two arms at QLQ-C30 and BR23 scores emerged at T0. Global health status (p = 0.0001), and most scores of the functional and symptom scales of QLQ-C30 at T1 showed significant differences in favour of the APBI arm. Concerning the BR23 functional and symptom scales, the body image perception, future perspective and breast and arm symptoms were significantly better in the APBI group. Similar significant results emerged at T2: significant differences in favour of APBI emerged for GHS (p = 0.0001), and most functional and symptom QLQ-C30 scales. According to QLQ-BR23 module, among the functional scales, the body image perception and the future perspective were significantly better in the APBI group (p = 0.0001), whereas among the symptom scales significant difference emerged by breast and arm symptoms with better outcomes in APBI arm (p < 0.01). Interpretation Early BC treated with APBI showed an improved short-term, and 2-year follow-up HRQoL outcome as compared with WBI. Early BC treated with APBI showed an improved short-term, and 2-year follow-up HRQoL outcome as compared with WBI. APBI should be strongly considered in the treatment choice for selected low-risk patients. Mature local control results from ongoing adequately powered randomised trials are awaited. [ABSTRACT FROM AUTHOR]

Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1–8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine. [ABSTRACT FROM AUTHOR]

Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and β-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to ‘step on the gas’ while ‘cutting the brakes’, although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field. [ABSTRACT FROM AUTHOR]

Introduction Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients. Methods Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995–2003 (24 trials, n = 603) and 2004–2013 (25 trials, n = 750) for comparative purposes. Results From 1995–2003 to 2004–2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004–2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line setting and to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995–2003) to 36.0% (2004–2013; P = 0.0033) due to higher rates of disease stabilisation. Conclusion Changes in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable. [ABSTRACT FROM AUTHOR]

Background Monoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown. Methods Medical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT. Results Of 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6 months (range: 0.2+, 23.0). 1-year and 2 year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41–72%) and 36% (95% CI: 18–54%), respectively. Conclusion Both VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade. [ABSTRACT FROM AUTHOR]

Background Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. Patients and methods The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept ( n = 612) or placebo ( n = 614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. Results The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. Conclusions The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3–4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation. [ABSTRACT FROM AUTHOR]

Abstract: Background: LY2584702 tosylate (hereafter referred to as LY2584702) is an oral, selective ATP competitive inhibitor of p70 S6 kinase. Preclinical studies with LY2584702 demonstrated significant synergistic activity with erlotinib and everolimus. The primary objective was to determine a phase II dose and schedule. Secondary objectives included evaluation of safety, toxicity and pharmacokinetics of LY2584702 in combination with erlotinib or everolimus. Methods: Patients with advanced solid tumours were treated with a total daily dose of 50–200mg of LY2584702 in combination with erlotinib 150mg once daily (Arm A) or everolimus 10mg once daily (Arm B). Dose escalation was based on 3+3 design and used the Common Terminology Criteria for Adverse Events Version 4.0. Results: Twenty-nine patients were enrolled, 17 in Arm A and 12 in Arm B. Dose limiting toxicities (DLTs) in cycle 1 were observed in Arm A in four patients and consisted of Grade 3 vomiting, hypophosphataemia, pulmonary embolism and decreased clotting factor V. No DLTs were observed in Arm B at cycle 1, and the most frequent treatment-emergent adverse events related to study drug were: fatigue, anorexia, diarrhoea, nausea and vomiting. Seven patients received ⩾4 cycles (3 in A, 4 in B). Best overall response was stable disease. Exposure accumulation of LY2584702 occurred with BID (twice daily) dosing. Exposure of erlotinib increased when administered in combination with LY2584702. Conclusion: LY2584702 was not well tolerated when administered with erlotinib, therefore this combination is not feasible. The combination with everolimus was better tolerated but yielded very limited clinical benefit. [Copyright &y& Elsevier]

Abstract: Background: LY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis. Methods: Patients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0. Results: Thirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n =22) began with 300mg BID (n =2). Due to toxicity, this was scaled back to doses of 25mg (n =3), 50mg (n =8), 100mg (n =3), and 200mg (n =6) QD. Part B dose escalation (n =12) included 50mg (n =3), 75mg (n =3), and 100mg (n =6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis. Conclusion: The MTD was determined to be 75mg BID or 100mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose. [Copyright &y& Elsevier]

Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumour in the United States of America (USA) with a median survival of approximately 14months. Low survival rates are attributable to the aggressiveness of GBM and a lack of understanding of the molecular mechanisms underlying GBM. The disruption of signalling pathways regulated either directly or indirectly by protein kinases is frequently observed in cancer cells and thus the development of inhibitors of specific kinases has become a major focus of drug discovery in oncology. To identify protein kinases required for the survival of GBM we performed a siRNA-based RNAi screen focused on the human kinome in GBM. Inhibition of the polo-like kinase 1 (PLK1) induced a reduction in the viability in two different GBM cell lines. To assess the potential of inhibiting PLK1 as a treatment strategy for GBM we examined the effects of a small molecule inhibitor of PLK1, GSK461364A, on the growth of GBM cells. PLK1 inhibition arrested cells in the mitotic phase of the cell cycle and induced cell kill by mitotic catastrophe. GBM engrafts treated with GSK461364A showed statistically significant inhibition of tumour growth. Further, exposure of different GBM cells to RNAi or GSK461364A prior to radiation resulted in an increase in their radiosensitivity with dose enhancement factor ranging from 1.40 to 1.53 with no effect on normal cells. As a measure of DNA double strand breaks, γH2AX levels were significantly higher in the combined modality as compared to the individual treatments. This study suggests that PLK1 is an important therapeutic target for GBM and can enhance radiosensitivity in GBM. [Copyright &y& Elsevier]

Background: The safety and cost-effectiveness of aflibercept, approved in combination with fluorouracil/irinotecan chemotherapy (FOLFIRI) in treating patients with metastatic colorectal cancer (mCRC) after failure to oxaliplatin-based regimen, is largely unknown in our patient setting. We report the efficacy and safety of aflibercept/FOLFIRI, used in the second line setting in a series of mCRC patients at our institution. Methods: This consecutive case series included all patients who fulfilled the aflibercept patient assistance programme (PAP) inclusion and exclusion criteria. We recorded data on demography, tumour, and prior treatment characteristics, aflibercept-related adverse events and treatment outcome. We measured 24-h urine protein, blood pressure, full blood count, liver and kidney function tests at baseline and at each aflibercept cycle. We assessed tumour response with serum CEA and CT scan after the forth to sixth treatment cycle. We reported severe adverse events (SAE) in the PAP SAE reporting documents. Findings: From October 2012 to January 2014, out of nine patients granted approval by the PAP, five failed oxaliplatin-based regimen for mCRC while four progressed within 6months of oxaliplatin-based adjuvant chemotherapy. Mean age was 54 (range 48-68). Two patients died before commencing therapy, leaving seven patients assessable for efficacy and safety analyses. Median number of cycles was five (range 1-11). At the sixth cycle, three patients had progressive disease and three had disease stabilisation. A decrease in CEA was observed in all three patients who achieved disease stabilisation. One patient has died, one patient remains on therapy while five patients remain alive, achieving survival duration of between 2-18months at the time of analysis. Grade 3-4 adverse events were as follows: neutropenia, 5.26%; urinary tract infection, 5.26%; perinephric infection, 2.63%; proteinuria, 7.89%; scrotal ulcer, 2.63%; hypertension, 2.63%. No treatment-related deaths were observed. Interpretation: Aflibercept seems to be a modestly effective regimen with acceptable toxicity in our small case series. [ABSTRACT FROM AUTHOR]

Background: Identification of agents that are non-toxic but that can delay onset and/or progression of breast cancer is highly desirable. Methods: In this study, novel quinuclidinone derivatives have been synthesised to investigate their impact on human MCF-7 breast cancer cell lines and MCF-12a normal breast epithelial cells after an initial screening study. Findings: We identified a novel derivative that induced apoptosis in MCF-7 cells more than in MCF-12a, which was further confirmed by TUNEL assay. Our novel quinuclidinone derivative abrogated G2/M checkpoint as confirmed by the increased expression levels of cyclin B and reduction of cyclin D levels. It reduced expression levels of survival proteins Mdm2, Akt, and ERK1/2 and increased expression levels of Bad and PUMA. Furthermore, it increased expression of p53 and its translocation from cytoplasm to nucleus, and also significantly increased Bax expression at both the mRNA level and protein level. Moreover, the apoptosis induction by our derivative was inhibited by the p53 inhibitor PFT-α, as evidenced by non-significant induction of apoptosis after treatment of MCF-7 cells with both quinuclidinone derivative and PFT-α. Our molecular docking experiments revealed a docked pose of quinuclidinone derivative bound to p53 regulatory domain using the Molecular Operating Environment module. Our in vivo studies in a breast cancer animal model showed that our novel derivative significantly reduced tumour volumes after 6weeks and significantly improved physiological processes. Interpretation: Together, the results of the present study show that our novel quinuclidinone derivative provokes apoptosis in human breast cancer cells (MCF-7) by targeting p53 signalling without any apparent toxicity in rats. [ABSTRACT FROM AUTHOR]

Background: Cancer cells are characterised by uncontrolled replication involving loss of control of cyclin-dependent kinases (CDKs) and cyclins, and by abolished differentiation. In this study we introduce KGI, a nanoparticle with a Quillaja saponin as an active molecule. Methods: By the use of RNA array analysis and confirmation at the protein level, we studied the effects of KGI on myeloid leukaemia cells. Findings: KGI affects myeloid leukaemia cells (particularly the U937 monoblast cancer cell) by the following mechanisms: ceasing cell replication via proteasome degradation; down-regulation of key molecules at check points between G1/S and G2/M phases; reduction of thymidine kinase activity; followed by exit to differentiation and production of IL-8, eventually leading to apoptosis. Leukaemia cell lines (U937 and HL-60 cells) were exposed to KGI for 8h, after which the drug was removed. The cancer cells did not revert to replication over the following 10days. Interpretation: Our findings suggest that the nanoparticle KGI inhibits proliferation and promotes differentiation in leukaemic cells by interfering with the cell cycle process. [ABSTRACT FROM AUTHOR]

Background: We aimed to identify causes of change in cancer treatment costs over time. Methods: This study used trend analyses to assess the percentage of cancer patients who had received a specific treatment type and the mean cost of care for patients who had received that treatment. Findings: Analyses of patients diagnosed in 2007 showed that the National Health Insurance (NHI) system paid, on average, $10,780 for initial care of a gastric cancer patient and $10,681 for initial care of a lung cancer patient, which were inflation-adjusted increases of $6234 and $5522, respectively, over the 1996 care costs. During the same interval, the mean NHI payment for initial care for five specific cancers increased significantly (p<0.05). Hospitalisation costs comprised the largest portion of payments for all cancers. During 1996-2007, the use of chemotherapy and radiation therapy significantly increased in all cancer types (p<0.05). Interpretation: In 2007, NHI payments for initial care for the studied five cancers exceeded $12 billion, and gastric and lung cancers accounted for the largest share. Therefore, the NHI must accurately predict the economic burden of new chemotherapy agents and radiation therapies and may need to develop programmes for stratifying patients according to their potential benefit from these expensive treatments. [ABSTRACT FROM AUTHOR]

Background: Iniparib, a novel agent with poly (ADP-ribose) polymerase (PARP) inhibitory activity, has demonstrated anticancer activity through poorly defined mechanisms. Furthermore, the effects of iniparib in tongue cancer have not been explored. Findings: In the present study, we demonstrated that iniparib time-dependently and concentration-dependently inhibited the cell viability of human tongue cancer Tca8113 cells in vitro. Iniparib treatment strongly induced apoptosis in Tca8113 cells. Consistent with these results, the pro-apoptotic protein Bax was up-regulated and the anti-apoptotic proteins Bcl-2 and Bcl-XL were down-regulated in iniparib-treated cells. Moreover, constitutive NF-κB activation and IκBα phosphorylation were inhibited, and total IκBα expression was increased in iniparib-treated cells. Interpretation: These results indicate antiproliferative effects of iniparib in Tca8113 cells through induction of apoptosis via suppression of NF-κB activation and enhancement of the apoptotic signalling pathway. [ABSTRACT FROM AUTHOR]