London - Institute of Cancer Research Paediatric ECMC

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Overview

Our Centre

The Royal Marsden (RM)’s 31-bed Oak Centre for Children and Young People opened at the Sutton site in September 2011 following a substantial £20 million new build, and is one of the largest comprehensive cancer centres for children and teenagers in Europe. Almost 600 inpatients and more than 5,000 day patients are seen at the Oak Centre every year. There are approximately 220 new malignant registrations in children and adolescents per year, including of leukaemia, central nervous system and extracranial solid tumours.

Patients are referred to the Centre from south of the Thames, Kent and the south coast, although for early phase clinical studies patients are referred from all around the UK via clearly defined referral networks, with at least a third of patients recruited to paediatric early phase studies coming from out of region.

Our Centre runs the largest Paediatric and Adolescent Drug Development Programme in the UK and one of the largest in Europe and internationally. We have been formally designated by the Innovative Therapies for Children with Cancer (ITCC) European Early Phase Clinical Trials Consortium as a First-In–Child Study Centre. Investigators from our Paediatric and Adolescent Drug Development Unit are currently leading and involved in multi-centre national and international trials evaluating new therapeutic strategies, including trials of molecularly targeted agents and immunotherapies.

The Research activities of the RM Paediatric/Teenage and Young Adult (TYA) Clinical Unit (Head – Dr Julia Chisholm) and the Paediatric and Adolescent Drug Development Team are closely integrated with the Divisions of Cancer Therapeutics and Clinical Studies at The Institute of Cancer Research (ICR). Following the recent retirement of Prof Andy Pearson, the international recruitment process for his successor as ICR/RM Professor of Paediatric Oncology Drug Development and Academic Lead is currently underway.

The joint ICR/RM Centre’s comprehensive Paediatric and Adolescent Oncology Targeted Drug Development Programme comprises drug discovery, pre-clinical evaluation, early clinical trials and the Oak Foundation clinical facility. The clinical facility includes 18 children’s inpatient beds, a dedicated 13 bed TYA Cancer unit, outpatient chairs and day care beds for both children and TYA patients, (including those on Phase I/II clinical trials), together with an adjacent on site laboratory for pharmacokinetic and pharmacodynamic sample processing, and two suites for radioisotope therapy to help facilitate novel studies involving radioisotope components eg MIBG therapy. We are one of very few European centres with the facilities and expertise to run functional imaging biomarker studies within the context of Paediatric/TYA early clinical studies.

The goal of the Paediatric and Adolescent Oncology Targeted Drug Development Programme research strategy is to improve the five year survival of childhood and adolescent cancer by accelerating drug development for children and young people, via the following specific aims:

To increase the number of hypothesis-driven, first-in-child early phase clinical studies of molecularly targeted anticancer agents with embedded predictive and pharmacodynamic biomarkers, initiated and led by the RM/ICR Paediatric and Adolescent Drug Development Team.
To develop functional imaging approaches for incorporation into early clinical trials of molecularly targeted agents for childhood cancers.
To increase the number of children and young people in early clinical studies.

Over the past 9 years, investment by the Oak Foundation and other key sources such as the ECMC and NIHR Biomedical Research centre (BRC) has facilitated the development of a strong Paediatric and Adolescent Drug Development Team with knowledge and expertise in the field of drug development, and provided crucial infrastructure for the successful running of early clinical trials, in partnership with international academic networks major and pharma companies.

The team includes Paediatric and Adolescent Drug Development Consultants (integrated closely with the wider Consultant team within the Children & Young People’s Unit, who provide additional disease-specific expertise and who are chief investigators on international clinical trials themselves), Drug Development Fellows, Research Nurses, Trial Co-ordinators, Data Managers, and Tissue Collectors. The Team also integrates closely with translational scientists with extensive international research experience.

This supporting infrastructure has allowed the Paediatric and Adolescent early phase clinical trials portfolio to increase from just 2 open studies in 2006 to 26 open studies in 2015-16 (18 phase I, 8 phase II; 18 molecularly targeted agents; 15 first in child), with further new studies opening this year. This is the largest portfolio of paediatric early phase trials in the UK and one of the largest in Europe.

A Phase I trial of AZD2014 and paclitaxel (TAX-TORC) is an example of how the infrastructure and support from ECMC were utilised in early phase studies, & expediting the transition to Phase II study. The Phase-I trials were successful and went into expansion on ovarian and squamous Lung carcinoma eventually leading to development of Phase II, randomised trial in ovarian cancer.

The Phase I trial was conducted by Investigator Initiated Studies Team at the ICR Centre. The infrastructure developed with ECMC support has enabled this cutting edge early phase trial to be fast tracked and progress to next stages. The results from the Phase I trial were presented at the AACR Clinical Plenary session in April 2015.

The TAX-TORC study is Phase I trial of the combination of AZD2014 (dual mTORC1 and mTORC2 inhibitor) and weekly paclitaxel in patients with solid tumours. The study is led by Dr.Udai Banerji, to assess the safety and tolerability of the combination drugs.

Address

Institute of Cancer Research
Department of Medicine
Sycamore House
15 Cotswold Road
Sutton, SM2 5NG

Team Members

Scientific & Operational Team

Lynley Marshall

Paediatric Lead

Expertise:

Paediatric

LynleyVanessa.Marshall@icr.ac.uk

Louis Chesler

Translational Research and Precision Medicine Lead

louis.chesler@icr.ac.uk

Paediatric Expertise

An important achievement has been to ensure as broad an early phase trial portfolio as possible to provide access to new drugs and thus additional therapeutic options to as many paediatric/adolescent patients as have need of them and choose to be enrolled. Our Centre has a well-balanced trial portfolio, with early clinical studies available across the disease spectrum: leukaemias and lymphomas, solid tumours and central nervous system (brain and spinal) tumours, with a balance between trials with broad inclusion criteria and those requiring specific molecular pre-selection, and a balance between oral drugs (often more outpatient-based regimens) and intravenously administered agents (which may require inpatient admissions or longer day care administration times).

We run trials of chemotherapeutic regimens, trials of molecularly targeted agents, and immunotherapy trials. Additionally, we have trials for patients across the wide paediatric/TYA age spectrum, with a balance of phase I and II studies, and a balance between pharma-sponsored and academic-sponsored studies.

We are increasingly able to:

Select novel agents based on newer, more relevant pre-clinical models (which we believe will be more predictive of clinical activity), and tumour molecular biology
Increase the availability of new agents for paediatric investigation by strong links with pharma companies and academic networks
Base clinical trials on strong biological hypotheses, including pharmacodynamic biomarkers to show proof-of-target inhibition and downstream effects
Develop clinical trial designs that do not require large numbers of patients, thus allowing for the more rapid completion of trials and movement of the most promising drugs into more frontline therapy;
Play a leading role in recruiting into international collaborative early clinical trials
Help accelerate the development of new drugs for children and young people by taking leading roles in international working groups influencing the regulatory landscape of new medicines development.

Treatment Modalities

1. Chemotherapy

2. Small molecules

3. Immunotherapy

4. Biologics

Facilities/Translational Research

ECMC funding provides infrastructure support for early phase and translational research. From the ECMC Institute of Cancer Research portfolio, the following trials have been carried out.

Case Study

Case Studies

BEACON-Neuroblastoma Phase II: Enormous progress has been made in the academic-sponsored BEACON-Neuroblastoma phase II trial designed and led by RM/ICR investigators and the first randomised trial for patients with relapsed neuroblastoma in Europe. The study is now open in 27 sites across 9 European countries and has been recognised by SIOPEN (the European clinical and research network for neuroblastoma) as the official trial for patients with relapsed neuroblastoma. Overall 160 patients are being enrolled and the trial is recruiting well. Importantly, it is one of the first adaptively designed early phase trials, which will efficiently answer multiple important research questions concurrently: the optimal choice of backbone chemotherapy to which novel agents can be added, and whether the first novel agent tested in the study (Bevacizumab) has a role to play in improving outcomes.

This adaptive design has already allowed a third new potential backbone regimen to be added based on emerging data in the scientific community, and the next choice of novel agents to add are formally under discussion within the SIOPEN committees. The Bevacizumab research question will be answered in 2016 and the backbone regimen question in 2017, with the likelihood of the most promising arms being moved forward into frontline treatment. The BEACON 2 study (based on the results of this original BEACON study) is already in planning as a multi-arm, multi-stage (MAMS) adaptively designed trial for testing further novel agents, to ensure there that all patients who relapse can access a relevant clinical trial. The international co-ordinating sponsor of the BEACON-Neuroblastoma study is the CRUK Clinical trials Unit in Birmingham, and it has attracted significant international charity funding.

LDK378 (Ceritinib) Phase I: (Sponsor: Novartis). This international first-in-child, predictive biomarker-driven study of an ALK inhibitor was developed jointly with the RM, one of just two UK sites, and we are a lead recruiting site internationally. The study is open to patients whose tumours have genetic aberrations in the ALK gene. The phase I dose escalation and food effect parts of the study have recently been completed and the study has move to further cohorts at the disease-specific recommended doses for expansion/phase II phase.

PD1-PD-L1 Immune Checkpoint Inhibitor Studies: The international Merck-sponsored Pembrolizumab Phase I/II study and the Roche-Genentech-sponsored Atezolizumab Phase I/II study both opened at RM/ICR (the UK lead site for both studies) in late 2015 and are recruiting very well, to time and target. These very promising immunotherapy agents are being studied in children and adolescents with a variety of solid tumour types including lymphomas.

Tumour Profiling Study – next Generation Sequencing Pilot Study: This ICR/RM pilot study of a molecular profiling initiative has recently opened and is based on a next-generation sequencing (NGS) panel of 80 genetic aberrations mutated in cancers that was developed at The ICR/RM. The hope is that the profiling will help find ‘actionable mutations’ driving paediatric cancers and potentially help guide future patient treatment.

TAX-TORC - The first study from NIHR-ECMC alliance to progress to Phase II randomised, national study in ovarian cancer

London - Institute of Cancer Research Paediatric ECMC

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Scientific & Operational Team

Treatment Modalities

Facilities/Translational Research

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