Clinical trials in Europe Professor Bruce Morland Birmingham, UK

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

SMO inhibition in Pediatric Patients

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)

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 3002-00003 was on criz 07MAY2013-31MAR2014, Best response reported was SD. They started on LD378 on 15APR2014 Second asterix: Patient 1051-00010 was on criz 29JAN2014 – 18MAR2014. Best response was CR. They started on LDK378 on 20AUG2014. Third asterix: Patient 3002-00006 was on criz 12APR2013 – 30APR2014. Best response was CR. They started on LD378 on 08MAY2014 Forth asterix: Patient 2001-00006 was on criz 07AUG2012 through 15OCT2014. Best response was CR. They started on LDK378 on 07NOV2014

Hallmarks of Cancer

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

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

Discrepancies between primary and relapse Courtesy of Stefan Pfister

(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

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)

(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

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

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

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 (www.accelerate-platform.eu) Portfolio expanding

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