1. Clinical trials in Europe
Professor Bruce Morland
Birmingham, UK

6. Change of Paradigm in Oncology Drug Development & Era of High-throughput Technologies - When Biology Meets Clinics …..
~ 1000 Anticancer compounds yearly under development
Targeted anticancer compounds
New mechanisms of action
New profile of activity
Distinct profile of toxicity
Oral and prolonged administration

7. SMO inhibition in Pediatric Patients

8. BRAFv600 inhibition in Pediatric Patients
ORR:
HGG 5/8 63%
anaplastic astrocytoma,
glioma, ganglioglioma,
pleomorphic xanthoastrocytoma,
gliobastoma multiforme
LGG 5/15 33%
Ganglioglioma,
pilocytic astrocytoma,
pilomyxoid astrocytoma,
pleomorphic xanthoastrocytoma
LCH 2/2 100%
Other 0%
HGG
Dose 4.5 mg/kg
Dose 3.75 mg/kg
Treatment
Dose 3.0 mg/kg
Dose 5.25 mg/kg
Primary Tumor Type
LGG
20 of 27 patients remain on dabrafenib
at data cut 7 March 2015
LCH
PTC NB
Treatment Duration (Weeks)

9. ALK inhibition in ALK+ IMT or ALCL
TRA
ALK Abnormality
AMP
IHC
RAR
TRA, translocation; AMP, amplification; RAR rearrangement, Doses are mg/m2 *
Prior Crizotinib
Inflammatory myofibroblastic tumor
ALCL
Myofibroblastic sarcoma
+ Treatment ongoing
First evidence of response
Time of progressive disease
+ 300; PR
+ 450; CR
+ 510; PR
450; CR
450; SD
510; SD
+ 450; PR (MRD only)
450; PR
560; PR (MRD only)
Weeks
ORR
IMT
63%
100%
IHC, immunohistochemistry; TRA, translocation; AMP, amplification; RAR, rearrangement. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown. Dose (300, 450, 510) is mg/m2
Last IMT pt listed (pt 7001/00005) had a PR, but this was unconfirmed. The pt went into liver and renal failure, but had 70% tumour shrinkage by Inv and thus went for resection.
Patient discontinuation details:
MT patient with CR discontinued due to physician’s decision
IMT pt at 450 with SD discontinued due to AEs
First ALCL patient (560) discontinued due to administrative problems; pt went on to have allo transplant
Second ALCL pt (450) discontinued due to physician’s decision; pt went on to have allo transplant
Details of prior crizotinib treatment:
First asterix: Patient was on criz 07MAY MAR2014, Best response reported was SD. They started on LD378 on 15APR2014
Second asterix: Patient was on criz 29JAN2014 – 18MAR2014. Best response was CR. They started on LDK378 on 20AUG2014.
Third asterix: Patient was on criz 12APR2013 – 30APR2014. Best response was CR. They started on LD378 on 08MAY2014
Forth asterix: Patient was on criz 07AUG2012 through 15OCT2014. Best response was CR. They started on LDK378 on 07NOV2014

10. Hallmarks of Cancer

11. Children small adults? ≠ Less frequent / distinct gene alterations
Lower patient numbers
Disease spectrum differs
Lack of identification of actionable targets ≠
Vogelstein et al., Science 2013

12. Pediatric cancers are (relatively) simple …
Courtesy of Stefan Pfister

13. Discrepancies between primary and relapse
Courtesy of Stefan Pfister

14. (France, Spain, Italy, Ireland, Israel) iTHER (The Netherlands)
Precision Medicine Program in ITCC
1. Generate invididual molecular information
MATCH
2. Match treatment and tumor profile
ESMART trial Multiarm
Phase 1 Trials (Industry and ISTs)
Phase 2 Trials (Industry and ISTs)
3. Evaluate activity of drugs and combinations
Genentech Roche
Matrix Trial
Molecular Matching Trials
MAPPYACTS
(France, Spain, Italy, Ireland, Israel)
INFORM (Germany)
iTHER (The Netherlands)
SM-PAEDs (UK)
INFORM2 trial series
SHARE
EU Clinico Biological (WES/RNAseq
Data Base
Project A
Project B
Project C
Project D
Project E
4. Generate new knowledge, new druggable pathways
Pediatric
New
Drug
Development

23. Target prioritization – how to translate “gut feeling“ into a score!?
Drug availability is currently not a criterium in the pediatric setting
(otherwise almost all targets would get a low score)

30. (France, Spain, Italy, Ireland, Israel) iTHER (The Netherlands)
Precision Medicine Program in ITCC
1. Generate invididual molecular information
MATCH
2. Match treatment and tumor profile
ESMART trial Multiarm
Phase 1 Trials (Industry and ISTs)
Phase 2 Trials (Industry and ISTs)
3. Evaluate activity of drugs and combinations
Genentech Roche
Matrix Trial
Molecular Matching Trials
MAPPYACTS
(France, Spain, Italy, Ireland, Israel)
INFORM (Germany)
iTHER (The Netherlands)
SM-PAEDs (UK)
INFORM2 trial series
SHARE
EU Clinico Biological (WES/RNAseq
Data Base
Project A
Project B
Project C
Project D
Project E
4. Generate new knowledge, new druggable pathways
Pediatric
New
Drug
Development

37. Ewing, rhabdo, neuroblastoma, Wilms, hepatoblastoma on backbone of temozolomide /irinotecan

39. Ongoing with rhabdoid/ATRT
A phase I/II study of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors (iMATRIX-Atezolizumab).
Geoerger et al. J Clin Oncol 35, 2017 (suppl; abstr 10524)
74 patients (median age 14 years; range 2–29) were enrolled: osteosarcoma, n = 12; Ewing sarcoma, n = 11; neuroblastoma, n = 11; rhabdomyosarcoma (RMS), n = 10; non-RMS soft tissue sarcoma, n = 10; Wilms tumor, n = 6; Hodgkin lymphoma (HL), n = 5; non-HL, n = 1; other tumor types, n = 8
17 patients (24%) had treatment-related grade 3–4 AEs. One AE (grade 3 transaminase increase) led to study drug discontinuation. Common AEs were pyrexia (37%), fatigue (34%) and constipation (32%)
2/5 patients with HL had a partial response (PR); the only patient with atypical rhabdoid tumor (RT) had an unconfirmed PR
Ongoing with rhabdoid/ATRT

40. Conclusions ITCC is a successful academic partnership
Biology-led/precision medicine programme is deliverable
Partnership/collaboration with Pharma is key
Joint discussion with clinicians, regulators, pharma and parent groups, Accelerate has proven very successful (
Portfolio expanding

43. תודה