Targeted approaches to childhood cancer: progress in drug discovery and development.

Review

Targeted approaches to childhood cancer: progress in drug discovery and development 1.

Introduction

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Background

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Recent advances in targeted

Steffen Hirsch, Lynley V Marshall, Fernando Carceller Lechon, Andrew DJ Pearson & Lucas Moreno† †

The Royal Marsden NHS Foundation Trust, Children and Young People’ s Unit, Sutton, UK

therapies for childhood solid

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by University of Connecticut on 04/12/15 For personal use only.

tumours 4.

Conclusion

5.

Expert opinion

Introduction: Cancer is a leading cause of death in childhood. Encouraging progress has been made in the treatment of childhood malignancies, but there is an unmet need for new drugs to improve survival and reduce treatmentassociated toxicities. Drug development in paediatric oncology has specific requirements with regard to the patient population and the regulatory background and presents several unique challenges that need addressing. Areas covered: This review discusses the current framework of paediatric oncology drug development and some of the specific challenges in pre-clinical and clinical research. The authors discuss the recent developments in the targeting of various signalling pathways. These pathways represent a selection of targets that have been identified by pre-clinical and clinical investigators to be highly relevant in paediatric malignancies. Expert opinion: The development of targeted agents in paediatric oncology must be driven by knowledge of tumour biology. Predictive and pharmacodynamic biomarkers should be incorporated within paediatric early clinical trials wherever possible. Faster dose-escalation, limited numbers of cohorts and novel adaptive designs can help to make paediatric early clinical trials more efficient. Close collaboration between academic/clinical researchers, the pharmaceutical industry, regulatory bodies and parent groups are crucial in overcoming the challenges associated with paediatric oncology drug development. Keywords: drug development, oncology, paediatric, targeted therapy Expert Opin. Drug Discov. [Early Online]

1.

Introduction

Over recent decades, great progress has been made in the treatment of patients with paediatric malignancies, but still 20 -- 25% of patients will die of their disease and 40% of survivors will have significant late effects of treatment during adulthood [1,2]. In particular, patients with high-risk cancers have not achieved maximal benefit from the progress made over recent years [3]. Improvements in survival outcomes overall have been achieved by the paediatric oncology community with the help of cooperative clinical trials testing traditional chemotherapies and multimodal treatments, including chemotherapy, surgery, radiotherapy and stem cell transplant. Significant advances have also been made in supportive care to better manage treatment-related toxicities, allowing for more intense treatment regimens. However, further intensification of therapy beyond current standards in recent studies has not resulted in increasing survival, and improvements in outcome for high-risk paediatric cancers have plateaued over the past decade.

10.1517/17460441.2015.1025745 © 2015 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .


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It is estimated that 20 -- 25% of paediatric cancer patients will die of their disease and 40% will have significant late effects of treatment, thus there is a huge unmet need for better medicines for childhood cancer. Drug development in paediatric oncology has specific challenges including the rarity of the various tumour types, vulnerability of this population, insufficient biological knowledge, concerns about developmental toxicity and regulatory challenges. The biology of paediatric tumours is often different to their adult counterparts and thus results from adult studies cannot necessarily be directly translated into paediatrics. It is essential to develop biomarkers specifically for paediatric patients to choose the right drug for the right patient and monitor for the development of resistance. The challenges of paediatric oncology can only be overcome with close collaboration of all stakeholders, including regulatory bodies, industry, academic groups and parent initiatives.

This box summarizes key points contained in the article.

Thus, there is an unmet need for new treatment options. New agents, which are effective in high-risk cancers and which have fewer toxic short and long-term side-effects, are desperately needed. In adult oncology drug development over recent years, there has been a clear paradigm shift towards hypothesis-driven early clinical trials of molecularly targeted agents. These studies are enriched with biomarker work: predictive biomarkers to inform patient selection and maximise benefit, and pharmacodynamic (PD) biomarkers to assess whether a particular agent is achieving the desired effect on the molecular target [4,5]. It is crucial that these approaches are now harnessed for paediatric cancer patients, with the ultimate aim of driving forward progress and further improving outcomes. In this article, we will review the progress that has been made in the development of agents against some of the most important currently known targets in childhood malignancies. These examples represent the most common scenarios for paediatric drug discovery and development: i) agents targeting oncogenic drivers that are common to completely different adult conditions; ii) drugs that target broader intracellular signalling pathways where some paediatric conditions coincide with those in adults (e.g., glioma or sarcoma); and iii) immunotherapeutics, where the development of antiGD2 monoclonal antibodies for neuroblastoma remains one of the very few examples of drugs developed specifically for a childhood cancer target without a preceding adult indication. Numerous advances have greatly improved our understanding of the biology of paediatric tumours. Whole genome and whole exome sequencing initiatives have profiled large series of the most common and aggressive paediatric tumour types. These profiling strategies have identified actionable oncogenic drivers with available inhibitors such as BRAF in 2

high grade gliomas (HGGs) or anaplastic lymphoma kinase (ALK) in neuroblastoma. These targeted agents with robust biomarkers (originally developed for adult indications) are now being fast-tracked into early paediatric clinical trials. Drugs active against broader targets, such as intracellular signalling pathways, angiogenesis or the tumour microenvironment that are being developed for adult cancers, are also being explored in paediatric tumours. At the other end of the spectrum is the development of agents exclusively for a paediatric target. To date, this has been an exceptional occurrence, with immunotherapy against GD2 for neuroblastoma being the main example of a drug developed academically that has progressed to the clinic and demonstrated efficacy in a large randomised Phase III trial. The development of new therapeutic agents in paediatric oncology presents several specific and unique challenges. Children represent an especially vulnerable group of patients and should not be exposed to unnecessary clinical trials or avoidable risks [6]. The treatment of paediatric patients, quite rightly, raises concerns about safety. Nonetheless, it is important to stress that Phase I trials in the paediatric population are necessary, and have been shown to be safe when designed well and conducted in centres by experts with the appropriate experience in running first-in-child studies [7,8]. Paediatric cancer is rare and diverse; and thus the overall number of patients with a given diagnosis is invariably small. The combination of rare diseases with largely successful firstline treatments means that only a limited number of patients with relapsed or refractory disease are available for participation in early phase clinical trials, and thus enrolment can take time and usually requires international collaboration [9-12]. Currently, there are almost 800 oncology therapeutic agents in the developmental pipelines of pharmaceutical companies and academic research units [13]. These are primarily being developed for use in adult patients. With the limited number of paediatric patients eligible for early phase trials, it is difficult to prioritise agents to be taken forward for clinical development, and clear selection criteria have not been established [14]. The development of new agents for childhood cancers must be driven by a sound scientific approach using the increasing knowledge of the biology of paediatric tumours combined with a comprehensive approach from the bench to the bedside [13,14]. 2.

Background

Regulatory framework Due to the high cost of running international early phase clinical trials and the relatively small market in paediatric oncology, there is no financial incentive for pharmaceutical companies to develop drugs in a paediatric setting. Additionally, there is a perceived increased risk by pharma about the 2.1

Expert Opin. Drug Discov. (2015) 10(5)

Targeted approaches to childhood cancer: progress in drug discovery and development

conduct of paediatric studies, despite vast experience showing that they are safe if conducted in appropriate centres to the highest quality standards [7,8,15,16]. To address the previously limited motivation and engagement of the pharmaceutical industry to develop their therapeutic pipelines for paediatric indications, legislative efforts have been instituted both within the European Union (EU) and the US, albeit in somewhat different ways.

number of paediatric early phase studies via PIPs; however, as many of these have deferrals agreed (often for many years), the number of completed PIPs is rising more slowly. It has also facilitated improved interaction between industry, regulators, academic networks and parent/patient stakeholder groups and an earlier incorporation of paediatric considerations into commercial development plans. US regulations Since 1997, the US has developed two types of programmes. i) The Best Pharmaceuticals for Children Act (BPCA) is a programme incentivising pharmaceutical companies to voluntarily provide information on the use of drugs in children. According to this regulation, the FDA issues a formal Written Request to the product sponsor. A sponsor can voluntarily make a proposal and submit data from studies. The study results do not have to demonstrate efficacy in the paediatric population in order for a product to qualify for the 6 months of additional exclusivity offered. Studies with negative results are considered informative and may have important safety consequences. ii) Through the 1998 Paediatric Rule, which was followed by the Paediatric Research Equity Act (PREA) in 2003, the FDA mandates sponsors to study drugs in children if adult and paediatric indications are the same and if the product would be used in > 50,000 children or if it would represent a therapeutic advance [19]. More recently, the Creating Hope Act (2010), initiated in the US following the tireless efforts of a parent whose child who did not survive cancer, provides a transferable incentive to sponsoring pharmaceutical companies -- an FDA priority review voucher -- and shows that it is possible to improve incentives to favour paediatric drug development [15]. Overall, despite the differences in approaches followed on each side of the Atlantic, the most important result has been a substantial increase in interaction and dialogue between the pharmaceutical industry and the academic community. The consideration of childhood cancer in the development of new drugs for adult indications is increasingly being integrated into industry drug development strategies [20]. 2.1.2


2.1.1

EU regulations

The European Paediatric Regulation came into force in 2007 with the objective “to improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 -- 17 years, ensuring that medicines for use in children are of high quality, ethically researched and authorised appropriately and improving the availability of information on the use of medicines for children, without subjecting children to unnecessary trials or delaying the authorisation of medicines for use in adults” [17,18]. The key element of the Paediatric Regulation is that companies seeking marketing-authorisation for a new medicinal product or a new indication for an already authorised medicinal product have to have fulfilled their agreed paediatric obligations in relation to that drug prior to such authorisation being granted. The Paediatric Regulation is based on a system of obligations and rewards/incentives, with the main tools including Paediatric Investigation Plans (PIPs), class and product-specific waivers and deferrals. The regulation mandates that prior to authorisation for use in adults, all relevant new drugs must be investigated in children and adolescents according to a PIP agreed between the company and members of the European Medicine Agency’s Paediatric Committee (EMA PDCO). Each PIP may be made up of some or all of the following components: pre-clinical (including juvenile toxicity) studies, clinical studies, development of a paediatric formulation if considered necessary, as well as extrapolation from adult studies by way of modelling and simulation elements. Paediatric development can be deferred to gain more information on safety and efficacy in adults or waived if paediatric development is deemed unnecessary, unsafe or inappropriate for part or all of the paediatric population. Deferrals and waivers were introduced to protect children, but as the requirement for a PIP is based on the adult condition rather than on the mechanism of action of the drug or the molecular targets, potential important paediatric indications may be (and unfortunately have been) missed and paediatric development waived -- a missed opportunity. The Paediatric Regulation altered the regulatory environment for paediatric medicines not only in Europe but also internationally, since large pharma companies tend to have global drug development plans. More trials are being considered and conducted in Europe (rather than only in the US). By necessity, consideration is being given to paediatric development by companies at an earlier stage. The Paediatric Regulation has undoubtedly led to a notable increase in the

Academic efforts and international collaboration The classical approach to drug development in paediatric oncology historically has been to evaluate the safety and efficacy of drugs developed for adult cancer in children only after adult trials have been conducted and the drug has achieved market approval. Indeed, since 1990, clofarabine and Erwinia asparaginase are the only drugs approved specifically for use in paediatric haematology and oncology, both for acute leukaemia, the commonest paediatric malignancy. Multiple academic initiatives have been established to accelerate and improve pre-clinical drug development for childhood cancers. The Innovative Therapies for Children with Cancer (ITCC) European consortium has initiated and continues to oversee various projects to increase biological knowledge and 2.2


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identify potential novel molecular targets. Examples include the Kids Cancer Kinome project (a network of laboratories focused on the use of microRNA to identify vulnerable proteins in paediatric malignancies, testing their functional relevance via the use of short hairpin RNA technology), and the ITCC Biology Program, which includes several complementary national initiatives aimed at comprehensive paediatric tumour molecular profiling. In the US, the TARGET initiative (Therapeutically Applicable Research to Generate Effective Treatments) promoted by the National Cancer Institute (NCI) and the Children’s Oncology Group (COG) applies a comprehensive genomic approach to determine molecular changes that drive childhood cancers. This initiative promotes the collection of biological samples for genetic profiling with matching clinical data, making it available for researchers to identify potential targets. Potential targets are matched with drugs in development allowing for prioritisation and more effective pre-clinical and clinical development of the most promising candidate drugs [21,22]. The Paediatric Preclinical Testing Program (PPTP) has screened numerous molecules in a pre-clinical in vitro and in vivo panel of the most common paediatric tumours. Since the programme was started, > 50 different drugs have been evaluated [23]. To date, very important biological data have been gathered, although a clear correlation with success in early clinical trials (anti-tumour activity) has not been demonstrated. Specifics of paediatric drug development The phrase ‘children are not just little adults’ is well known and sometimes over-used, but it remains true for the specific considerations that apply to paediatric oncology drug development. 2.3

Paediatric tumour entities Cancer is generally regarded as a condition associated with ageing, and paediatric malignancies as a group are comparatively rare within the spectrum of oncological diagnoses, representing only 2% of all human cancers. Paediatric malignancies are biologically different from adult malignancies. Tumours are mostly derived from embryonal tissue rather than being epithelium-derived carcinomas. Paediatric tumours show fewer genetic changes than adult cancers at diagnosis [24]. Most common paediatric cancers include acute lymphoblastic leukaemia (ALL), acute myeloblastic leukaemia (AML), CNS tumours such as glioma and medulloblastoma, neuroblastoma, lymphoma and soft tissue and bone sarcoma. Among those, Philadelphia-positive ALL, high grade and diffuse intrinsic pontine glioma (DIPG), high risk neuroblastoma, FLT3-mutated AML and metastatic solid tumours (medulloblastoma and sarcoma) have the worst outcomes [25]. 2.3.1

Pre-clinical drug development Our understanding of the specific biology of paediatric cancers is constantly increasing. To date, there has been insufficient investment in pre-clinical research and a lack of 2.3.2

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adequate biological material from these rare and aggressive tumour types for adequate study. More biological information is needed to understand the mechanisms of tumour evolution in paediatric patients, especially at disease relapse, and to drive the development of new agents. With increasing evidence that the biology may change with disease progression/relapse and with new targeted therapies becoming available, there is a stronger justification for biopsy at the time of relapse with the potential for direct clinical benefit if new actionable mutations and aberrations are found [26,27]. The lack of biological material also translates into a low number of established in vitro and in vivo models for paediatric cancers that are required both to further increase our biological understanding and for the pre-clinical evaluation of potential new drugs. Successful examples are genetically engineered murine models of MYCN-driven neuroblastoma [28] or sonic hedgehog-driven medulloblastoma [29], and recent efforts to create libraries of paediatric patientderived xenografts. These might prove more informative than a PPTP-type approach, although the two strategies are complementary and will need to be validated and correlated with clinical results in the future. Clinical drug development Design of paediatric trials has some specific requirements. In general, paediatric first-in-child trials only occur once the safety of the drug has been established in adults, and in most instances, the paediatric dose and the toxicity profile are similar to those in adult studies, with new unexpected toxicities being exceptional [30]. It may thus be possible to expedite the process of paediatric Phase I trials substantially. New adaptive trial designs and statistical models with fewer planned dose levels can help to reduce the periods in which enrolment is closed and avoid patients waiting unduly for treatment. These include Bayesian or Continual Reassessment Method (CRM) as well as other innovative designs [31-33]. This is especially critical for studies selecting for narrow populations (e.g., due to genomic biomarkers). First-in-child trials have traditionally started at the equivalent of 80% of the adult recommended Phase II dose (RP2D), but emerging data suggest that for most molecularly targeted agents, these trials could start at the equivalent of the adult RP2D unless there is a good reason not to do so. With classical chemotherapeutic agents, it was assumed that the maximal tolerated dose (MTD) would have the best anti-tumour effect; thus this was used for dosing in subsequent trials. New molecularly targeted agents require a different approach, as target inhibition is not necessarily dose-dependent [5,30]. Thus, it is crucial to define the Optimal Biological Dose (OBD) or recommended Phase II dose (RP2D) of targeted agents rather than the MTD [34]. This can be achieved using biomarkers to demonstrate effective target inhibition even before an MTD is reached and may spare patients from excessive toxicity. 2.3.3




It must be noted that paediatric patients are a heterogeneous group. Pharmacokinetics (PK) in older children and adolescents are generally similar to that of adults, with dosing corrected for body surface area or body weight. Infants below 2 years of age have a clearly distinct drug metabolism and PK profile with more immature organ development. Due to the low frequency of refractory cancers in infants and the vulnerability of the population, it is difficult to include a significant proportion of these patients in early clinical trials, and usually the full PK profile for infants can only be acquired during later stages of drug development [35]. Finally, acceptable oral formulations need to be developed specifically for younger children and patients who are not able to swallow tablets. Developmental toxicity aspects Many molecular pathways activated in cancer are important for normal development and growth. Therefore, blocking these pathways could potentially lead to specific and severe adverse effects in growing children. On-target and off-target toxicities can include impairment of growth, including premature closure of the growth plate and changes to dentition, infertility, neurocognitive impairment and endocrine changes [36]. Thus far, there is only limited knowledge on the long-term toxicity of targeted agents. Most paediatric patients have a long life expectancy after completion of cancer treatment, and therefore, long-term effects such as cardiotoxicity or second malignancies are more likely to be far more relevant once these new treatments have earned their place as part of front-line therapy. In addition, some toxicities might have a bigger impact when they occur at an earlier age, for example, ototoxicity in young children can have an irreversible impact in development of language skills. It is usually unclear how long treatment should be continued in the event of response to a targeted agent, or indeed whether the drug can be stopped and the patient re-challenged with the same drug in the event of disease relapse/progression. Little is known on cumulative toxicity of targeted agents, for example, tyrosine kinase inhibitors. The importance of this issue becomes clear if one considers that currently it is recommended to continue treatment for Philadelphia-chromosomepositive chronic myeloid leukaemia indefinitely, with effects on growth only recently recognised [37]. This is an area of emerging knowledge and experience, and the collection of long-term toxicity data is key in paediatrics. 2.3.4

Recent advances in targeted therapies for childhood solid tumours

3.

3.1

Agents targeting specific molecular aberrations The ALK pathway

3.1.1

Translocations involving the ALK gene were first described in anaplastic large cell lymphoma (ALCL) in the late 1980s. The development of ALK inhibitors was boosted after the

EML4-ALK fusion gene was described in NSCLC in 2007 [38]. In adult oncology, NSCLC is by far the most common ALK positive malignancy, whereas ALCL is less prevalent. In paediatrics, the majority of patients with ALCL and inflammatory myofibroblastic tumour (IMT), a rare type of sarcoma, harbour ALK translocations. Moreover, ALK mutations and amplification were described in 2008 in neuroblastoma in 10 -- 15% of patients and are demonstrated oncogenic drivers. In rhabdomyosarcoma, ALK copy number alterations and ALK expression have been described, and it is known that ALK is downstream of the fusion gene that occurs in cases with alveolar histology [39,40] but the functional relevance of ALK aberrations in this tumour type remains to be established. The first commercially available ALK inhibitor crizotinib was licensed for use in adult NSCLC in 2011 [41]. Secondgeneration ALK inhibitors have been developed to overcome resistance and the first of these to be approved was ceritinib (LDK378), which was licensed in the US by the FDA in April 2014 for the treatment of crizotinib-resistant NSCLC. Many other agents are in development, including alectinib, which has better blood-brain-barrier penetration and which has been licensed for use in adult patients in Japan [42]. In paediatrics, ALK inhibitors are being developed for tumour types with ALK translocations (ALCL and IMT), ALK mutations or amplification or other ALK aberrations such as those present in rhabdomyosarcoma [43]. Given the difficulties in accessing drugs for paediatric trials, it was a great success that the first paediatric Phase I study with crizotinib, run by the COG’s Phase I consortium, opened in 2009, only very shortly after first safety data was available from adult studies. The study showed good results in tumours with ALK translocations (ALCL and IMT), but few objective responses in patients with neuroblastoma and rhabdomyosarcoma [44]. While ALK is a potentially valuable target in neuroblastoma, the most developed agents currently may not have the necessary activity against these tumours. It has been demonstrated how some ALK mutations, including the F1174L mutation common in neuroblastoma, can confer resistance to crizotinib. Ways to overcome resistance could be the use of more potent ALK inhibitors or combination therapies, for example, with mTOR inhibitors [45-48]. Table 1 summarises ongoing clinical trials with ALK inhibitors and other agents discussed. The MAPK pathway BRAF is a member of the Raf kinase family of growth signal transduction protein kinases. V600 mutations in BRAF, which result in constitutional activation of BRAF, has been reported in up to 67% of adult melanomas [49] and significant benefit has been demonstrated in several Phase III trials for patients harbouring V600 mutations. However, advanced melanoma is very rare in children and teenagers [50], but 3.1.2


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Table 1. Phases of development of selected targeted agents in adult and paediatric oncology. Target

Agent

Adult indication

Adult phase

Main paediatric indication

Paediatric phase

ALK

Crizotinib

NSCLC NSCLC

ALCL, IMT, RMS, neuroblastoma ALCL, IMT, RMS, neuroblastoma

II (r)

Ceritinib

EMA/FDA approved FDA approved

Alectinib Vemurafenib

NSCLC with brain metastases Melanoma

Dabrafenib

Melanoma

Vismodegib

Basal cell carcinoma


BRAF

SMO

Sonidegib Angiogenesis Bevacizumab Sorafenib

Sunitinib

Pazopanib Cilengitide Cediranib Regorafenib BET HDAC

PARP GD2

GSK525762 OTX015 Vorinostat Panobinostat Veliparib Olaparib ch14.18.CHO hu14.18K322A hu14.18-IL2 131 I-3F8 Anti-GD2 CARS

Basal cell carcinoma Multiple malignancies Renal cell carcinoma Hepatocellular carcinoma Thyroid cancer Pancreatic neuroendocrine tumours Renal cell carcinoma GIST Soft tissue sarcoma Renal cell carcinoma Glioblastoma Ovarian carcinoma

III EMA/FDA approved EMA/FDA approved EMA/FDA approved FDA approved EMA/FDA approved EMA/FDA approved EMA/FDA approved

EMA/FDA approved III III

Colorectal carcinoma GIST Multiple malignancies Multiple malignancies Cutaneous T-cell lymphoma Multiple myeloma

EMA/FDA approved I I FDA approved III

Breast cancer Ovarian carcinoma Melanoma

III III I

Melanoma Multiple malignancies Solid tumours

III I I

Melanoma

I (r) Pre-clinical I (r)

Glioma, melanoma, LCH (NCT01677741) Medulloblastoma, DIPG

II (r)

Medulloblastoma Multiple malignancies

II (c) I-III (r/)

AML, Hepatocellular carcinoma Multiple others Multiple malignancies

III (r)

II (r)

Multiple malignancies

III (r)

CNS tumours Sarcoma, CNS tumours Multiple malignancies

II (c) II (r)

Gliomas, AML Leukaemia, Lymphoma CNS tumours Gliomas, AML Neuroblastoma Neuroblastoma Neuroblastoma Multiple malignancies Neuroblastoma

I (r)

I (r) Pre-clinical Pre-clinical II/III (r) I (r) I/II (r) Pre-clinical III (r) II (r) II (c) I (r) I (r)

ALCL: Anaplastic large cell lymphoma; ALK: Anaplastic lymphoma kinase; AML: Acute myeloblastic leukaemia; BET: Bromodomain and extra-terminal; (c): Closed, currently no recruiting studies; DIPG: Diffuse intrinsic pontine glioma; EMA: European Medicine Agency; HDAC: Histone-deacetylase; IMT: Inflammatory myofibroblastic tumour; LCH: Langerhans cell hystiocytosis; PARP: Poly (ADP ribose) polymerase; (r): Currently recruiting studies; RMS: Rhabdomyosarcoma; SMO: Smoothened.

BRAF V600 mutations have also been identified in other paediatric cancers such as in 11% of low grade gliomas (LGG) and HGG and in 57% of Langerhans cell histiocytosis. The following example shows the importance of thorough biological research to drive paediatric drug development. The most frequent genomic aberration in paediatric LGG is the BRAF fusion that leads to a different activation of the target [51,52]. In these tumours, treatment with selective BRAF inhibitors would lead to a paradoxical activation of the MAPK pathway and indeed increased tumour growth [52]. Vemurafenib is currently being investigated in teenagers with 6

unresectable or metastatic melanoma (NCT01519323) and children with V600E positive glioma (NCT01748149). A dabrafenib Phase I/II study (NCT01677741) is enrolling paediatric subjects with various BRAF V600E positive solid tumours. Both agents have shown promising signs of activity in paediatric cancers [53,54]. Like with other targeted therapies, there is also emerging resistance to BRAF inhibitors via activation of downstream proteins or escape pathways. Pre-clinical and clinical studies have suggested that this can be overcome by using combination treatments, for example, with MEK inhibitors [55].



MEK inhibitors may also be a valid treatment option for patients with BRAF fusions. Several MEK inhibitors are currently in paediatric development (including selumetinib, trametinib, binimetinib and cobimetinib, amongst others) and are of particular interest in NF1-related tumours and LGG as well as in certain haematological malignancies such as ALL, juvenile myelomonocytic leukaemia and myelodysplastic syndrome [56,57]. The Hedgehog pathway Activation of the Hedgehog (Hh) pathway has been described in multiple malignancies, the most common of which is basal cell carcinoma (in which up to 90% have an activated Hh pathway). In paediatrics, the most prominent example is medulloblastoma. The importance of the Hh pathway in medulloblastoma has been identified by efforts to molecularly stratify this disease with gene expression profiling. Hh-activated tumours account for a large group (28%) of medulloblastomas [58]. Development of drugs targeting the Hh signalling cascade has been largely driven by basal cell carcinoma -- common in adults but exceedingly rare in children. There are currently several drugs in development, most of which are antagonists of the G protein-coupled receptor Smoothened (SMO). Two agents have undergone paediatric Phase I testing, vismodegib and sonidegib. Following the strong pre-clinical data and a successful Phase I demonstrating safety and preliminary efficacy [59], vismodegib has now entered Phase II testing in children with newly diagnosed medulloblastoma (NCT01878617). During the Phase I study for sonidegib, it was possible to validate a five-gene signature for the response to sonidegib in Hh-activated medulloblastomas [60-62]. After these promising results, a Phase II study for relapsed patients was initiated (NCT01708174) [63]. There are however concerns that it will be difficult to identify enough patients to power a large paediatric Phase III study. Although Hh-medulloblastoma account for 28% of all cases, these occur mainly in infants and adult patients [58]. Special consideration should be paid to adverse effects on growth or development. Pre-clinical studies reported the detrimental effect of inhibition of the Hh pathway with SMO inhibitors on bone and dental health in animal models. Temporary inhibition of the Hh pathway in juvenile mice lead to premature closure of the growth plate, and the Hh pathway has also been reported to have a role in dental development [64,65]. Results of Phase II trials for sonic hedgehog inhibitors in medulloblastoma will become available during the coming years.


3.1.3

Agents targeting signalling pathways relevant in paediatric malignancies 3.2.1 Angiogenesis 3.2

Angiogenesis and neo-vascularisation are hallmarks of cancer [66]. Neo-vascularisation supports the nutrition and growth of malignancies as well as infiltration and metastasis.

Bevacizumab is a monoclonal humanised antibody against VEGF-A. It was the first clinically available anti-angiogenic agent and one of the first targeted agents. Bevacizumab was first approved by the FDA in 2004 for metastatic colorectal carcinoma and has since been approved in multiple malignancies, including certain lung, renal and ovarian cancers, and adult glioblastoma multiforme. Pre-clinical investigation had shown potential activity in several paediatric malignancies. Bevacizumab has been investigated in paediatric Phase I and II trials, both as a single agent and in various combinations with chemotherapy [67]. Toxicity has been acceptable and the results of several randomised Phase II studies in HGG, soft tissue sarcoma and neuroblastoma are eagerly awaited (NCT01390948 and NCT01236560, NCT00643565 and EudraCT2012-000072-42). A considerable number of other anti-angiogenic agents are currently being investigated. Most of them are multi-tyrosine kinase inhibitors targeting the VEGF receptor 2, as well as other angiogenic and oncogenic pathways. Prominent examples include sorafenib, sunitinib [68], pazopanib [69], cilengitide [70], cediranib [71] and regorafenib (NCT02085148). Many of these are now being taken forward in a variety of paediatric malignancies, especially solid and CNS tumours. Most anti-angiogenic toxicities seen in children mirror those seen in adults (hypertension, fatigue and proteinuria) [67,72,73] while severe side-effects previously reported in adults, such as thrombo-embolic events and intracranial haemorrhages, as well as gastrointestinal perforations have not been documented in children thus far. However, there are ongoing concerns about the detrimental effect of bevacizumab and other anti-angiogenic agents on growth and development; especially that the treatment may lead to impairment or a premature closure of the growth plate [74-76]. In a recent COG analysis, almost 10% of patients treated with selective VEGF inhibitors have developed growth plate changes [76]. Epigenetic regulation The epigenetic regulation of transcription has gained considerable interest and has been identified as a potential mechanism of hitting some of the targets that have previously been difficult to drug effectively. An important example is the utilisation of inhibitors of Bromodomain and Extra-Terminal (BET) proteins to target MYC-amplified tumours, including high risk neuroblastoma [77]. BET is an important transcription factor of the MYC family of proteins. Inhibition of BET with the pre-clinical inhibitor JQ1 showed promising results in in vitro and in vivo models of MYCN-amplified neuroblastoma [78]. Two BET inhibitors have recently entered clinical development in adults -- GSK525762 and OTX015 -- and paediatric trials of these agents are eagerly awaited. Another example worth mentioning is the recent discovery of the importance of histone H3 mutations in DIPG, an almost uniformly lethal paediatric brain tumour. These mutations do not occur in adult HGG at all, proving the different 3.2.2


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biology underlying this paediatric disease. Finding ways to target these mutations most likely holds the key to unlocking new treatments and improving outcomes [79-82]. One more area of active clinical research in this field is the inhibition of histone-deacetylases (HDACs). HDAC inhibition is thought to re-activate silenced tumour suppressor pathways. Agents in clinical development include vorinostat, panobinostat, romidepsin and entinostat. HDAC inhibitors have been widely investigated in vitro and in vivo, and showed positive results for leukemia, CNS tumours including glioma, as well as neuroblastomas [83-88]. Both vorinostat and panobinostat have completed paediatric Phase I studies [89,90] and are currently being developed in the Phase II setting in different combinations for both solid and haematological malignancies. Cell cycle checkpoints and DNA repair The maintenance of genomic integrity is essential to cellular survival. A multitude of proteins are involved in the interlocked processes of cell cycle regulation and DNA repair [91]. In malignant cells, aberrations in these pathways have been linked to enhanced survival and chemotolerance/chemoresistance. Inhibition of key proteins on the other hand may help to increase the efficacy of radiotherapy and drugs inducing DNA damage. Enhanced effects by such synthetic lethal action are expected in tumours deficient in alternative DNA damage repair pathways or with combination treatments. Poly (ADP ribose) polymerase (PARP) inhibitors were developed to target BRCA1/2-deficient tumours, lacking in an alternative pathway for DNA double strand repair. While BRCA1/2 mutations are rare in paediatrics, failure of other DNA repair mechanisms has been widely reported in paediatric cancer [92] and there is pre-clinical evidence supporting the activity of PARP inhibitors in glioma, neuroblastoma or Ewing’s sarcoma. It is also of interest as a radiosensitiser for HGG/DIPG. Several agents (veliparib, olaparib, BMN673, niraparib and rucaparib) have undergone clinical trials in adult patients and are starting their paediatric clinical development. 3.2.3

Anti-GD2 monoclonal antibodies A prominent example of a target and a drug that has been developed primarily for use in paediatrics is the advent of anti-GD2 immunotherapy for the treatment of high-risk neuroblastoma. Since first being found on neuroblastoma cells, GD2 expression has also been identified in soft tissue sarcoma, Ewing’s sarcoma, osteosarcoma, small cell lung cancer and melanoma. However, the development of anti-GD2 antibodies has been mostly driven by paediatric academic research teams targeting neuroblastoma. The first monoclonal antibodies that specifically targeted the disialoganglioside GD2 on tumour cells of neuroectodermal origin (including neuroblastoma and melanoma) were described in 1985 and entered clinical trials in 1992. 3.3

8

The chimeric monoclonal antibody Ch14.18CHO entered paediatric Phase I trials both in the EU and US shortly after its initial development [93,94]. In further studies, GM-CSF and IL2 were given together with ch14.18CHO in an attempt to mobilise immuno-mediators and increase antibodydependent cell-mediated cytotoxicity [95-97]. The COG Phase III study ANBL0032 demonstrated significant improvement of overall (OS) and event free survival (EFS) using ch14.18CHO in combination with IL2 and GM-CSF versus standard therapy with 13-cis-retinoic acid [98] at 2 years, although recent data showed that the results at 4 years show an OS benefit but not for EFS, deserving further investigation and long-term follow up [99]. Preliminary results from the European study SIOPEN HR-NBL showed similar results to COG trial using anti-GD2 with and without IL2 [100]. Efforts continue to identify more tolerable regimens to administer immunotherapy with anti-GD2 monoclonal antibodies [101], including humanised antibodies, fusion proteins with IL2 and more recently as antibody drug conjugates, or chimeric antigen receptors (CARs). 4.

Conclusion

Since the first paediatric patients were treated with early targeted therapies such as imatinib or anti-GD2 antibodies, major progress has been made in paediatric oncology drug development. New regulations and professional networks have led to an improvement of the structures for pre-clinical and clinical drug development in paediatrics. With the help of research collaborations, it has been possible to identify new targets and potential treatments even in rare tumour types. International co-operation has also allowed for trials with small eligible patient cohorts to complete enrolment in a reasonable time frame. Experience with targeted drugs to date has been very encouraging. Several targeted agents against druggable oncogenic drivers such as imatinib have successfully demonstrated safety and efficacy [102] and more agents are transitioning towards later stages of clinical development. Progress with multi-targeted inhibitors or drugs without a clear selection biomarker has been slower. New therapies such as anti-GD2 antibodies have already led to substantial clinical benefits for patients with high-risk malignancies like neuroblastoma. The experience with BRAF, ALK and SMO inhibitors highlight the significance of concomitant development of valid biomarkers specifically developed for paediatric patients during Phase I trials. These biomarkers can help to select the ‘right drug for the right patient’ and to ensure only the patients with the best chances of response are treated on the respective later stage trials. The increasing understanding of biology can help to guide future drugs and combinations for future studies. It will be necessary to harness synergistic mechanisms and to attack escape pathways in paediatric tumours.




While the experience with targeted agents in paediatrics is encouraging, attention must be paid to emerging adverse effects of treatment. Most targeted drugs used in cancer medicine manipulate pathways that are also involved in normal growth and development. Blocking these in growing children and teenagers could lead to increased toxicity or stalled development, and this will only be shown if current clinical trials include long-term follow up. In summary, significant progress has been made in our knowledge of paediatric cancer biology, and this will drive drug development for childhood cancers. Academic and regulatory initiatives are promoting better trials and more collaboration between all stakeholders involved. These advances will ultimately lead to improved survival and less toxic therapies. 5.

Expert opinion

Substantial progress has been made in the development of targeted agents in paediatric oncology. The clinical success of these new therapeutic options will be founded on an increasing understanding of the specific biology of paediatric malignancies. Future biological studies should investigate the specific mechanisms that lead to the development of cancer in childhood. Understanding these processes will allow the identification of new targets and drug candidates. Given the huge number of oncology drugs currently being developed for adult malignancies, a thorough understanding of biology is required to prioritise the most promising targets and drugs. Drugs targeting oncogenic drivers identified in the tumours should be prioritised and fast-tracked to early clinical trials. Given the occurrence of new actionable mutations at the time of relapse, repeat biopsy with tumour profiling at relapse should be encouraged with the double aim of providing therapeutic options and gaining further knowledge about the tumour biology. New techniques are needed that are able to predict the efficacy of potential drugs in the pre-clinical setting more accurately. These include in vitro and in vivo models that better reflect the biology of the tumours, including microenvironment and immune response. Pre-clinical and clinical

studies for targeted agents need to incorporate PD biomarkers to monitor the biologic effect of the drug to allow ongoing re-assessment of biologic activity in the patient cohort and to monitor for the development of resistance. As new mechanisms of resistance develop, it will be vital to know which combination of drugs will be able to counteract this. Therefore, we need to understand better which escape pathways the tumour can activate during treatment and how this can be avoided by using combinations of targeted agents with conventional cytotoxic treatments. With more drugs becoming available and molecular profiling of tumour samples entering the clinical routine, tailored treatment is becoming a clinical reality. First clinical trials are already investigating the addition of targeted agents to standard therapy in patients with identified molecular aberrations. It is important that the designs of future early clinical trials are optimised for efficient recruitment and timely completion to allow promising drugs to move forward into front-line treatment more rapidly. These challenges can only be addressed via close collaborations between all stakeholders in paediatric oncology. The European Paediatric Regulation has led to a change of culture and improvement in the communication between regulatory bodies, pharmaceutical companies, the academic paediatric oncology community and parent groups. Further imaginative incentives to develop drugs specifically for use in children are needed following the example of the US ‘Creating Hope Act’.

Declaration of interest L Moreno and LV Marshall are funded by the Oak Foundation. ADJ Pearson is supported by Cancer Research UK (programme grant C1178/A10294)----Chair in Paediatric Oncology. L Moreno is a consultant/advisory board member for Astra Zeneca, Novartis, and Roche Genentech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


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Affiliation Steffen Hirsch1,2, Lynley V Marshall1,2, Fernando Carceller Lechon1,2, Andrew DJ Pearson1,2 & Lucas Moreno†1,2,3 † Author for correspondence 1 The Royal Marsden NHS Foundation Trust, Children and Young People’s Unit, Sutton, Surrey, SM2 5PT, UK Tel: +44 0 20 8915 6161; E-mail: [email protected] 2 The Institute of Cancer Research, Division of Clinical Studies and Cancer Therapeutics, Sutton, UK 3 Spanish National Cancer Research Centre (CNIO), Clinical Research Programme, Madrid, ES, Spain

13

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