Trials, not tribulations - Home | Association for ... Files/Event... · Trials, not tribulations: a collaborative model of early phase trials and palliative care Lynley Marshall

Trials, not tribulations: a collaborative model of early phase trials and

palliative care

Lynley Marshall MB BCH DCH MRCPCH PhD

Consultant in Paediatric & Adolescent Oncology Drug Development

The Royal Marsden Hospital & The Institute of Cancer Research, London

9th Association for Paediatric Palliative Medicine (APPM)

Palliative Care Study Day

Birmingham, 23 November 2018

The Royal Marsden Cancer Charity

Childhood Cancer • High risk groups remain poor

prognosis despite toxic

therapy:

Neuroblastoma

Metastatic sarcoma

Certain brain tumours -

pHGG, DIPG

High risk leukaemia

Relapsed lymphoma

• Need for earlier introduction of

agents targeting molecular

drivers of cancer.

Unmet need: Faster, more efficient drug development & ‘kinder’

treatments

Improvement in UK Survival Outcomes

(1971-2010)

Cancer in childhood is rare: (<1% of all cancers < 15 years; 1% in teenagers/TYA)

BUT remains most common cause of death < 15 years (developed countries)


UK Cancer Incidence: 0-14 years (1700/year)

CRUK: Number of New Cases per Year, Great Britain, 2006-2008


UK Cancer Incidence: 15-24 years (2300/year)

CRUK: Number of New Cases per Year, Great Britain, 2000-2009


Childhood cancers are different


The Long Process of Drug Development:

for a given drug

Phase I Phase II Phase III MA/CLINIC

First-in-man;

Dose finding:

• DLT

• MTD/OBD

• RP2D

Small

numbers;

disease-

specific;

activity

Preclinical

phase:

-Target

identification

-Drug Discovery

-Preclinical

testing in vitro &

in vivo

Large

randomised

controlled

trials against

standard

treatment

Long term

follow-up

data

Safety/PK Efficacy Adults

10-15 years


The Long Process of Drug Development:

for a given drug

Phase I Phase II Phase III MA/CLINIC

Phase I Phase II Phase

III??

Preclinical

phase:

-Target

identification

-Preclinical

testing in vitro &

in vivo

First-in-man;

Dose finding:

• DLT

• MTD/OBD

• RP2D

Small

numbers;

disease-

specific;

activity

Preclinical

phase:

-Target

identification

-Drug Discovery

-Preclinical

testing in vitro &

in vivo

Large

randomised

controlled

trials against

standard

treatment

Long term

follow-up

data

Safety/PK Efficacy

TYA Children

Adults

Lag:

Advantages and

disadvantages


Who are the TYA patients?

• Wide age range:

(13) 15 – 24 year olds.

• Broad spectrum: physical, intellectual,

emotional, educational, psychosocial &

sexual maturity; life stages & levels of

dependence/ independence.

• Type of cancer diagnosis:

- late ‘paediatric’ (embryonal tumours eg

rhabdomyosarcoma, medulloblastoma)

- early ‘adult’ (carcinomas eg breast,

bowel; soft tissue sarcoma )

- all age (eg leukaemia, some brain

tumours)

- ‘TYA’ cancers (eg Hodgkin’s,

germ cell tumours, bone sarcomas)

Recommended viewing: BBC Horizon 2018 - Teenagers vs Cancer: A User’s Guide


Where are TYA patients treated & by whom?

15 – 24 years

Aim for services & trials that embody the best of both worlds…

NOT

the worst of each.

Paediatric

services Adult

services

TYA


The European Paediatric Regulation (2006): Aims:

• Improve the health of children & adolescents in Europe

• Increase high quality, ethical research into medicines for

children

• Increase availability of authorised medicines for children

(including age-appropriate formulations)

• Increase information on medicines (safety, toxicity, dosing,

activity, efficacy; include in label/Summary of Product

Characteristics)

• Without unnecessary studies in children or delaying

authorisation for adults

Tools: Paediatric investigation Plans (PIPs), Waivers, Deferrals, Incentives & Rewards, Compliance Checks: Companies agree plans with the European Medicine Agency’s Paediatric Committee (PDCO)


Bottlenecks to cancer drug development for

paediatric /TYA patients

• Drug supply

– For preclinical & clinical studies

– Priorities – adult market; studies in patients <18yrs are perceived as high-risk by pharma

– High drug attrition rates at all stages of development (<10% paediatric phase 1)

• Funding

– Industry-sponsored: limited to PIP-driven trials; commercial income does not cover the cost of the academic studies

– Academic funding: limited; relatively few clinical trial units sponsor paediatric phase 1 trials

– Charity

• Rarity of paediatric cancers &

now molecular sub types

– Long recruitment / small

studies / multi-centre /

collaboration / expense

– Biology – less well

understood; fewer

recurrent mutations;

drivers vs passengers;

role of epigenetics

– Historical lack of biomarker

development/ incorporation

(Predictive; PD)

• Regulatory Issues

– Regulatory obligations

makes pharma fear

entrusting academic

investigators

with trial delivery,


Overall Goals & Ethos of Paediatric & TYA Drug Development

• To improve survival for poor prognosis childhood/TYA cancers by

accelerating the development of new drugs and advancing the best to

more frontline therapy as quickly and safely as possible

• To provide access to hypothesis-driven, biomarker-rich early clinical

trials of novel molecularly targeted agents within early phase trials –

paradigm shift – ‘right drug, right patient, right time’

• To provide excellent, holistic, individualised, ethical multidisciplinary

cancer care for children/young people & families – some are palliative

• To deliver high quality clinical trials data

to regulatory standards required & to facilitate

licensing of best new drugs

• To train a new generation of paediatric

oncology drug developers to drive forward

progress in the field in the context of providing

excellent care


Phase I & II trials: key strategies & priorities to help

move forward more quickly

• Wide & balanced portfolio:

– Phase I and II; momentum essential; no gaps between studies

(high attrition rate of drugs and studies)

– Inclusive age range – infants, TYA patients

– Broad eligibility and more targeted eligibility studies

– Solid tumours, CNS tumours, Lymphomas, Leukaemias

– Pharma-sponsored and investigator-led/academic studies

• Make every patient count – efficient trial designs, maximise data use

and biomarkers/biological information

• Extrapolate from adults where possible

• Increase access to trials and new drugs – lower age of inclusion in

adult studies

• Tumour-specific & target-specific experts and groups

driving drug development internationally

• Organised referral networks


Precision medicine and

Personalised therapy

Overall Goals: Paediatric & Adolescent Programmes


Children and adolescents with

refractory or recurrent tumors or

leukemia

Signed informed consent

BIOPSY/ Surgery

Molecular analysis: − WES − RNAseq (RT-PCR confirmatory) − IHC, FISH (confirmatory) Exploratory: - Methylation array - miRNA - Immune markers/modulators - Circulating tumour NA - Preclinical models

European Precision Medicine Programme: Paediatric Oncology-Haematology

Data interpretation & therapy suggestion

If actionable targets:

If no actionable targets:

Clinical Trials

Multidisciplinary Therapeutic Molecular

Tumour Board

Bio-informatics

Ongoing targeted Phase I/II trials

Ongoing non-targeted Phase I/II trials or “non-targeted” arms of ESMART

Registered targeted agents in paediatric or adult cancer with paediatric dose recommendation

Matrix Trial Genentech Roche

MAPPYACTS - France, Spain, Italy, Ireland

INFORM - Germany iTHER- Netherlands

SM-Paeds - UK

NGS Panels


eSMART ARMS


Tumour Molecular Profiling Pilot Study: expanding

as (SM-Paeds )Programme

Diagram of genes analysed

by NGS panel. The probes

capture 849 exonic and 30

intronic regions covering a

total of 311 Kb

E. Izquierdo Delgado, S.

George, D. Gonzalez de

Castro, L. Chesler

UK CI Prof Lou Chesler


Drug companies have global development plans; ‘First in Child’

studies typically involve UK/EU/US +/- Canadian/Australian sites

International/European landscape of paediatric

early phase trials

• ITCC: 56 member centres across

14 countries:

Austria, Belgium, Denmark, France,

Germany, Ireland, Israel, Italy,

Spain, Sweden, Switzerland,

Netherlands, UK & Northern

Ireland, Australia

• 19 are ITCC-designated ‘first in

child’ study centres


UK national landscape of paediatric early phase

trials

10 Phase I/II centres in the UK;

5 are ITCC-designated ‘first in child’

study centres:

Phase I studies open in 2-5 centres

(but international pharma-driven

phase I studies open in 1-2 sites;

especially ‘first in child’ studies)

Phase II studies open in 5-10

centres; some in the larger network

(20 centres)


A whole package: infrastructure, investment, expertise

Integrated

Paediatric Drug

Development

Unit

Centre for

Molecular

Pathology

Adult Drug

Development Unit

Biomarkers

• The incorporation of

scientific hypothesis with

biomarkers into early clinical

trials will accelerate and

improve drug development

for childhood cancers

• Uniquely placed to bring

them into frontline treatment

• Purpose-built teams Clinical/Academic/Pharma Partners


RMH Facilities & Infrastructure • Paediatric inpatient unit (18 beds) for pts < 16 yrs

• Purpose built inpatient TYA unit (13 beds) for pts 16-24 yrs

• Outpatient clinic area

• Age-appropriate Day care with theatre

• ‘Hot lab’ for on site sample processing (PK etc)

• Increased capacity – 35% of early phase patients referred from out of region

• Research Team & Symptom Care Team – open access to both; joint consults :

Cancer and drug related symptoms


Number of Paediatric Early Phase Trials: Royal Marsden

Increasing number overall; first in child, molecularly targeted &

immunotherapy agents


Ethical Questions

• When is it appropriate to use children as experimental subjects? How

are their rights protected?

• Nuremberg Code - protect the rights of people participating in human

research, in response to Nazi Germany

• The Declaration of Helsinki (1964) and the Belmont Report (1979)

require informed consent.

• Ackerman (1995) notes: “Adequately informed families may

choose to participate in a phase I trial and this decision may

genuinely reflect their values and goals”

• The psychological burden of “giving up” may be too great for some

parents to consider.


In Whose Best Interest?

• Exposing the ethical dilemmas reveals a balance between

researchers wanting to advance medicine, drug companies

wanting to get their drug to market and patients wanting to live.

• Some say it is unethical NOT to give children access to novel

therapies.

• Phase I trials typically enrol patients whose tumours are resistant to

available therapies; objective response rate is therefore generally

low 5% - 7.5% NEMJ (2005). Higher if predictive biomarkers used

for patient selection.

• Benefit/value of stable disease should not be underestimated –

prolonged survival with good quality of life.


Phase I Trials and Palliative Care

• Eligibility criteria for entry into phase I trials usually failure of all

recognised conventional treatments.

• Difficulty in reconciling the natural desire of parents and children

themselves to proceed with treatment at any cost and the need to

provide good quality palliative care to children who will, in many/most

cases die.

• Agrawal and Danis (2002)contend that “research subjects with

terminal illness should not have to forgo the standard of care in

palliative medicine in the course of enrolling in research”

• Combining Phase I trials with palliative care services offers the child and

family who choose this option some chance of hope alongside the best

end-of-life care; earlier acceptance of symptom care

• Dual model of care: CYPOONS and research team –close links.

Families have direct access to both teams.


A New Agent Merits Consideration of Clinical

Study if…

• It is biologically plausible that the agent may have activity in

cancer based on mechanism of acton (target seems valid and agent

affects it)

• There is reason to expect benefit for patients (preclinical or other

evidence of activity/efficacy)

• There is reasonable expectation of safety (toxicology)

• Sufficient data on which to base starting dose

Hirschfeld S, 2004

• Adult data may help but full extrapolation is seldom possible and

paediatric studies are necessary


Important Tenets of Phase I Studies in Children

• Key aims/endpoints are safety (define DLT & MTD) & PK

• Aim to define recommended phase II dose:

• Safely (fewest serious toxicities)

• Efficiently (lowest number of patients)

• Reliably (statistical confidence)

Importantly

• Paediatric phase I starting dose is always at least 70-80% of adult

MTD and increasingly at adult dose corrected for body surface area

• No use of placebo-only arms in paediatric cancer trials

• Limited number of patients per cohort (3-6)


Early Phase Clinical Trials - Giving information

• Patient Information Sheets (PIS) 20-25 pages

– Main & sub-studies (eg biobanking, biomarker)

• Very detailed information

– Definitions; purposes of early phase studies

– Alternatives (any?)

– Toxicity – potential and unexpected

– Schedule

– Additional biomarker studies / procedures

– Contraception

• Age of consent for a clinical trial = 16 yrs

– Below 16 yrs (always)

– Assent (real understanding and agreement).

– 1 parents/guardian need to sign consent.

– Specific age-related patient information sheets.


“Conventional” eligibility criteria - examples:

• Advanced solid/CNS tumours (or leukaemia) unresponsive to

standard therapies or for which there is no known effective

treatment

• Performance status (Lansky/Karnofsky/ECOG)

• Adequate organ function (e.g. FBC, platelets, renal, liver)

• Specification about prior therapy allowed

• Specification about time interval between prior therapy and

initiation of study treatment (‘washout period’) – includes

radiotherapy

• No serious uncontrolled medical disorder or active infection

• Recovery from prior treatments to < grade II (CTCAE criteria)

Phase I Patient Population


“Agent-specific” eligibility criteria - examples:

• Restricted to certain patient populations –usually by biological

rationale (eg BRAF, Sonic Hedgehog…)

• Specific organ functions:

• cardiac function; no uncontrolled hypertension if cardiotoxic drug

• Sometimes only baseline screening but not exclusion (eg

audiology for IGF1R inhibitors; bone & dental x-rays for SHH)

• Prohibited medications if risk of interaction with study drug,

especially cytochrome P450 interactions which may increase risk

of toxicity or reduce chance of activity (commonly certain

anticonvulsants; levatiracetam (Keppra) safe in most cases.

• Some antibiotics/antifungals are generally not (eg clarithromycin

but not azithromycin; azoles)

Phase I Patient Population


Responsibilities

– Communication with referring team and local/shared care/community

services is vital & central to our practice including symptom care

– Assistance with Adverse Events (AE) and Adverse Reaction (AR)

monitoring and prompt reporting of Serious Adverse Events (SAEs)

– SAE: any untoward event experienced by a clinical trial participant

once enrolled on a clinical trial, whether thought to be related to study

drug or not, that:

- Results in death

- Is life-threatening

- Requires hospitalisation or prolongs existing hospitalisation

- Results in persistent/significant disability/incapacity

- Results in a congenital anomaly or birth defect

– Written information is sent out to all services / health care

professionals involved informing about the drug, side effects profile,

prohibited drugs and contact information.


Multi-stake-holder interaction is crucial

Parents

Patients

Survivors

• Dialogue about prioritisation of drugs / targets / studies eg Novel Drug

Development Strategy (NDDS); ACCELERATE Paediatric Strategy Forums

• Mechanism of action-based drug development

• Novel trial designs; combinations; multi-company; adaptive

• Extrapolation from adult data; inclusion of adolescents > 12 years

• Personalised medicine & molecular profiling strategies

• Long term follow up data collection initiatives

Academia: Paediatric /

TYA Oncology & Symptom

care

Pharma Regulators


Simple therapy Frequent breaks

Simple therapy Greater intensity

Intensified therapy for all patients

Risk directed therapy Based on age and WCC

and early response

Improving outcomes:

Childhood ALL led the way through clinical trials

• UKALL 2003 – one vs 2 DI; MRD; further improvements • UKALL 2011 – dexamethasone, pulses, HD MTX rand - ongoing • 2019 - ALL TOGETHER – RISK GROUPBASED, TARGETED THERAPY,

PATH TO CAR-T CELL FORRELEVANT GROUPS

TREATMENT INTENSITY AND OVER-TREATMENT

Courtesy of Simone Stokley


Targeted therapy : Leukaemia led the way in

adults...extrapolated to rare paediatric population

Imatinib (Glivec):

• Targeting BCR-ABL/the Philadelphia

chromosome t(9;22) in chronic

myeloid leukaemia in 2001

Dasatinib...Nilotinib...Bosutinib.

• 2nd /3rd generation tyrosine kinase

inhibitors

• Overcome resistance/intolerance to

imatinib

• Delay/avoid BMT – CML as a

manageable chronic condition


Targets are important • Melanoma

• Adult disease; rare in children

• BRAF V600E mutations in 50%

– BRAF inhibitors very

successful

• Paediatric melanoma studies

unfeasible & terminated early

• But BRAFv600E mutations are

relevant in other more common

paediatric diseases: HGG,

LGG,LCH, PTC

Vemurafenib


BRAF fusions in LGG

BRAFv600 point mutations in SOME HGG & SOME LGG

BRAF as an oncogenic driver in HGG & LGG:


Building on this:

Dabrafenib: BRAFV600E inhibitor (BRAFV600)

Trametinib: MAP Kinase inhibitor (BRAF fusions)

Combination – improve efficacy; overcome resistance

ASCO


Moving forward BRAF & MEK inhibitors in

BRAFv600mutant HGG & LGG: Study

DRB436G2201

Global effort in a rare population - 49 participating

sites from 17 countries


Moving forward MEK inhibitors in LGG vs standard of

care chemotherapy : upfront randomized phase III

To identify the optimum treatment regimen for tumour

growth control and improvement of neurological and

visual function comparing Carbo+VCR versus weekly VBL

versus MEKi as first line treatment in (non) NF1-related LGG


• Only radiotherapy is of (transient) benefit; reirradiation studies ongoing • Discovery of Histone mutations; ACVR mutations; other – targetable for

treatment? • Biopsy can be justified: average prognosis 9 months

Midline Gliomas: DIPG


Diagnosis - H3K27me3 - H3.3K27M Biomarkers - EGFR (IHC) - PTEN (IHC) - PDGFRA (FISH)

Genomics

- Sequencing

H3.3 and H3.1

- WES (+ blood)

- RNAseq

NEM271 (H3.1)

Avatars

BIOMEDE Phase II

Study: Biology


R2 R1

No R

R1

R3

R2

R3

PTEN LOSS

PDGFRA AMP

EGFR POS

R1=Erlotinib/Dasatinib; R2=Everolimus/Dasatinib; R3=All 3

Concomitant with and adjuvant to radiotherapy

BIOMEDE


Neuroblastoma:

• Commonest extra-cranial solid tumour in children (8% of childhood cancers) & most common malignancy of infancy

• Tumour of sympathetic nervous system; primary may arise anywhere from neck to pelvis

• Symptoms and signs:

– Localised (primary; lump)

– Metastatic – bone, bone marrow, liver, skin, CNS

– Paraneoplastic

• Catecholamine secretion: hypertension

• Opsoclonus-myoclonus syndrome

• Other: vasoactive intestinal peptides- flushing, sweating, watery diarrhoea

• Prognosis: age (18months), stage, biology


Neuroblastoma:

a spectrum of diverse biology & clinical behaviour

Undifferentiated neuroblastoma

Differentiating neuroblastoma

Ganglioneuroma

Degree of malignancy/aggressive biological features


Induction Chemotherapy

Surgical Resection

Myeloablation & Autologous Stem Cell Rescue

Radiotherapy Minimal Residual Disease Therapy

Standard treatment of high risk neuroblastoma:


Induction Chemotherapy

Surgical Resection

Myeloablation & Autologous Stem Cell Rescue

Radiotherapy Minimal Residual Disease Therapy

Standard treatment of high risk neuroblastoma:

refining through randomised studies

0.0

00.2

50.5

00.7

51.0

0

0 5 10 15

Rapid

StandardOS

(%)

Survival Time (years)

.

Standard vs

Rapid

Induction:

Previous Trial

– ENSG5

• US gold standard - CEM vs EU gold standard - BuMel

• Randomisation on SIOPEN trial: BuMel vs CEM

Differentiation

therapy

Immunotherapy


High-Risk Neuroblastoma Immunotherapy: Regulatory

approval of anti-GD2 Ab (Dinutuximab-beta)

• Challenge of getting approval in a paediatric only target – most children

very young – safety, toxicity, PK, efficacy

• Orphan drug designation EU 8/11/2012 – rare population

• Conditional approval EU 8/5/2018 on basis of high unmet medical need,

positive benefit:risk ratio; more follow up & data to be provided.

• 3 studies:

2 studies in 88 pts in relapsed/refractory pts in combination with IL2 &

isotretinoin:

- Refractory pts: 70% & 78% 2yr OS

- Relapsed pts: 42% & 69% 2yr OS

1 study in 370 pts responding to upfront treatment, in combination with

isotretinoin +/- Ils

- CR: 71% 3yr OS (irrespective of IL2 or not)

- PR: 63% 3yr OS + IL2; 54% 3yr OS – IL2


BEACON-Neuroblastoma: European Study

Phase II Randomised Trial for Relapsed/Refractory Neuroblastoma;

Adaptive Multifactorial Design

• European target across 10 countries - enrolment of 160 patients

• Bevacizumab randomization was planned to closes after 120 – increased by

DMC

• Molecular characterisation of tumours

• Functional imaging to elucidate the role of anti-angiogenic therapy

• Measurement of neuroblastoma mRNAs

• Due completion 2019 • BEACON2 multi-arm, multi-stage in development (new

arms; newer targets)

T – Temozolomide

I – Irinotecan

To - Topotecan

B - Bevacizumab


Neuroblastoma – ALK as a target

Kaplan-Meier and long rank analysis of ALK-

mutated and ALK-amplified tumours –

F1174 mutated versus wild-type cases

Brouwer et al, Clin Cancer Res 2010;16:4353-4362

• Mutations of ALK gene in 10% of neuroblastomas - F1174 & R1275

• F1174 mutation - 58.8% have MYCN amplification

Strategies 1. Direct inhibitors – crizotinib 2. Combination approach – CRISP

(crizotinib + temsirolimus) 3. Novel compounds – ceritinib,

lorlatinib

Chesler lab, The ICR


Key Messages

• Parents/patients want access to novel therapies: Rationally-

designed, biomarker-driven Phase I studies provide a good

therapeutic option for many patients in conjunction with good

palliative care – in terms of stabilising disease and quality of life.

• Phase II studies test strong disease-relevant hypotheses in a

relapse or upfront setting

• Patients are living longer (years) with a good quality of life,

sometimes choosing to enrol on successive studies.

• Infrastructure and a strong multidisciplinary team including

paediatric/TYA oncology and symptom/palliative care experts

providing excellent patient care & communication with families & referring clinicians is the underpinning philosophy of our work


Patient & Parent Comments

• “Being part of this study shows that you’ve (doctors / nurses) not given up –

that’s important to me.” 16yr old phase I patient

• “I wasn’t ready to accept there was nothing else. Having the new medicine

helped us to come to terms with where we were at...and that the disease had

come back.” Parent of 5yr old phase I patient

• “Sadly E died today at lunchtime, at home, with both parents with her at the

end. We wish to send you and your great team our sincere gratitude for the

care you showed all of us.” Parent of 13 year old phase I patient

• “We’ve never had care like this before” 16yr old phase I patient

• ‘’ Thank you for everything. You made us feel that the most important

person in our world was also the most important person in yours.”

Parent of 9 year old phase I patient

• “ It gives us a little bit of hope for a little bit longer.”

Parent of 3yr old phase I patient

51

Thank You for your attention… Questions & Comments?

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Trials, not tribulations - Home | Association for ... Files/Event... · Trials, not tribulations: a collaborative model of early phase trials and palliative care Lynley Marshall