1. PHITT the new international trial for hepatoblastoma and HCC
Professor Bruce Morland
Birmingham, UK

2. 2 linked European efforts

3. Where did it all start?

5. And then Los Angeles COG Spring meeting 2012

6. The LA papers!

7. And then Gdansk, Poland SIOPEL Spring meeting

8. Towards a new hepatoblastoma protocol

9. Gdansk principles Global study
SIOPEL, COG, JPLT, GPOH
Encompassing all liver tumours in children/young adults
HB, HCC, FLHCC, TCT……
Common risk stratification
Integral studies
Pathology, biology, radiology, surgery, late effects
Introduce new drugs
Relapse guidelines

10. Treatment philosophy “low risk”
Continue the COG strategy for upfront resection for a selected group of tumours
Establish an agreed definition of “resectable”
No chemotherapy for well differentiated fetal histology tumours (Pure fetal)
“Minimal” chemotherapy for non-WDF tumours

11. Treatment philosophy “standard risk”
Non metastatic, no adverse features
Build on the published SIOPEL experience (SIOPEL3) cisplatin monotherapy 95% 3y OS
Attempt to give less cisplatin 4 v 6 cycles

12. Treatment philosophy “high risk”
Non-metastatic, Pretext 4 tumours or other adverse features
These patients have challenging SURGICAL problems
3 chemotherapy regimens appear to yield similar results (C5VD, SIOPEL 4 and SIOPEL3HR)
?randomise between these 3

13. Treatment philosophy “very high risk”
Metastatic patients
Build on the encouraging results from SIOPEL4 19/20 survivors if cleared lung mets with “induction” chemo
Intensify therapy for patients who don’t clear metastases
what with?
VCR/irinotecan, carboplatin/etoposide, ICE, sorafenib….

14. SIOPEL Spring 2013 Bologna:PHITT is born!

18. Consent/Registration “Screening”
Consent for screening PRIOR to biopsy/surgery to allow full spectrum of biological samples to be collected
Allow trial entry if biopsy/surgery has already taken place
Protocol/study set up will promote/encourage pre-biopsy/surgery consent

19. Consent/Registration “Trial entry”
Consent for trial entry once
Histological confirmation HB/HCC
Treatment arm assignment confirmed
Eligibility criteria met

22. Published: Lancet Oncology, 21 November 2016
Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration
Prof Rebecka L Meyers, MD†, Rudolf Maibach, PhD†, Prof Eiso Hiyama, MD†, Beate Häberle, MD†, Mark Krailo, PhD†, Prof Arun Rangaswami, MD†, Daniel C Aronson, MD, Prof Marcio H Malogolowkin, MD, Prof Giorgio Perilongo, MD, Prof Dietrich von Schweinitz, MD, Prof Marc Ansari, MD, Prof Dolores Lopez-Terrada, MD, Yukichi Tanaka, MD, Prof Rita Alaggio, MD, Prof Ivo Leuschner, MD, Tomoro Hishiki, MD, Irene Schmid, MD, Kenichiro Watanabe, MD, Kenichi Yoshimura, PhD, Yurong Feng, MSe, Eugenia Rinaldi, Davide Saraceno, Marisa Derosa, Prof Piotr Czauderna, MD†
†These authors contributed equally
Published: Lancet Oncology, 21 November 2016

23. Risk Stratification
PRETEXT
VPEFR factors
Metastases
Age
AFP

39. HCC

43. 2014/15

44. ChiLTERN Children’s Liver Tumour European Research Network We will aim to cure more children with liver cancer, expose fewer children to toxic chemotherapy and ensure their surgery is both effective and safe
7.94m EURO
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No

45. The ChiLTERN Project Built around the PHITT trial
Run, manage, coordinate the PHITT trial
Undertake biology
Biobanking across Europe
Confirm existing molecular biomarkers
Seek new biomarkers (risk stratification and new therapy
Clinical risk stratification
Validate existing CHIC analysis
Develop new stratification
Toxicity biomarkers
Ototoxicity, renal, cardiac
Validate Surgical planning tool
Software planning of resection margins/tumour volume/liver volume

46. Pathology/Biology sampling

48. Toxicity biomarkers Hearing (Liverpool) Kidney (Cincinnati)
SNP array
Kidney (Cincinnati)
Urine: Cystatin C, KIM-1, NGAL
Heart (Cincinnati)
Blood: Troponin, NT-proBNP
PK/PD (Newcastle)
Correlation with toxicity biomarkers (Cmax, AUC)

49. Highlights from last 6 months
ECCO2016 – Amsterdam
SIOPE presentation. EU Commission present
“PHITT is my new favourite study, it’s my baby, I love it”
NCI Pediatric Steering Committee
Approval in February 2017
UK regulatory submissions
MHRA – approved with minor fertility clarification
National ethics
“This is one of the best applications this committee has ever seen……..”
First draft of COG protocol submitted to Scientific Council
First UK site initiation visit May 25th

50. Next steps Roll out of EU sites CRF generation
Agree surgical guidelines
Agree radiology guidelines
Agree pathology guidelines
EU path meeting 19th May Utrecht
“Merger” of COG/JPLT/EU protocols
1st patients summer 2017

51. Allow me to anticipate one of your questions!
How can my centre participate in PHITT?

52. Acknowledgements ChiLTERN PHITT Greg Tiao – COG Jim Geller – COG
Carolina Armengol – Barcelona
Beate Haeberle – Munich
Steven Warmann – Tuebingen
Gareth Veal – Newcastle
Louise Woodall, Neil Werrett, Steve Baker, Poonam Patel, Keith Wheatley – Birmingham CRCTU
Greg Tiao – COG
Jim Geller – COG
Eiso Hiyama – JPLT
All my SIOPEL colleagues
Jennifer Laidler, Veronica Moroz, Sam Munoz Vincente, Nicola Fenwick, Keith Wheatley - Birmingham CRCTU

53. תודה