Developing New Drugs for Pediatric Patients with Cancer in Japan. Ayumu Arakawa MD National Cancer Center Hospital (NCCH) JAPAN

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1 Developing New Drugs for Pediatric Patients with Cancer in Japan Ayumu Arakawa MD National Cancer Center Hospital (NCCH) JAPAN

2 Problems in Pediatric Drug Development in Japan Japan has no specific regulation for obligatory development of medicines for pediatric use. Sponsors have been reluctant to act aggressively on the drug development for children. Conducting domestic pediatric studies and verifying high-level evidence in pediatric cancer has been challenging.

3 Global Pediatric Clinical Trials Planning of more investigator-initiated trials is warranted for the new drug development Citation:

4 Limited number of pediatric patients with cancer in Japan Number of children (age 0 14 y) in 2014 Japan US EU 16.5 millions 61.1 millions 79.2 millions Over 100 pediatric cancer centers in Japan!! As a single country, enrolling adequate number of patients in phase II trials to evaluate the efficacy of new drugs is challenging. Centralization of relapsed/refractory patients is essential for efficient enrollment in trials. Citation:

5 Medical drug lag in pediatric cancer COG-ANBL0032 study (NEJM2010) 13-cis-Retinoic acid Not approved Anti-GD2 Not approved (trial ongoing) 131-MIBG therapy Not approved (trial ongoing)

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8 Concept of Extrapolation in Japan Overseas Adult Study Overseas Pediatric Study Domestic Adult Study Domestic Pediatric Study ICH E11 Extrapolation from domestic adult data Extrapolation from overseas pediatric data ICH E5 Extrapolation for Japanese pediatric studies conforms with the concept of extrapolation suggested by the EMA/FDA. Pediatric efficacy data Available from EU/USA If full extrapolation is possible Safety trial and PK study in Japan (5-10 Patients) Application for Drug Approval

9 Strategy of new drug development for pediatric cancer in Japan 1. If extrapolation is possible Overseas pediatric data Domestic adult data Planning Pediatric safety trial in Japan 5-10 Patients PK Study 2. Participating international studies International pediatric PII trial Efficacy data from trial Enrolling 3 5 patients from Japan Safety /PK data from Japanese patients Application for Drug Approval

10 National Cancer Center Hospital Tsukiji Fish Market Development of new drugs for children with cancer!! Pharmaceutical companies

11 Rare Cancer Center in NCC (2014-) Mission Statements 1. Establish a vital network of diagnosis, treatment and research for rare cancers in the National Cancer Center. 2. Review the problems associated with rare cancers in Japan and making proposals and taking up the issues as medical professionals. Advice Patient Advocacy Clinics Rare Cancer Education Basic Research Clinical Research Sarcoma Melanoma Unknown primary GIST Lymphoma NET/NEC Brain tumor Eye tumor Mesothelioma Duodenal ca. Gonadal tumor Paget's disease ATL Thymoma Others Diagnosis (n = 2,356) 400 MFH Desmoid Ewing's sa. Osteosarcoma Leiomyosarcoma Liposarcoma 1072 Diagnosis of Sarcoma

12 TOP GEAR PROJECT NCC in-house clinical sequencing program 1st period (2013-) Evaluate the clinical utility Clinical sequencing at a research institute Results fed back to doctors Some patients enrolled in phase I studies 2nd period (2016-) Evaluate feasibility in the clinical practice Clinical sequencing at a quality-assured lab Results fed back to patients and doctors Customized multiple gene panels (NCC Oncopanel) 3rd period (2018-) Clinical trial aiming at national health insurance reimbursement for NCC Oncopanel 12

13 RNA seq will be introduced to detect sarcoma/pediatric cancerspecific mutations 13

14 MASTER KEY PROJECT Molecular diagnostic testing (e.g., TOP GEAR) Rare Cancer Patients I.C. Registration Registry part May Review biomarkers Assignment to mutation-based trials Sub-study part Biomarker A Biomarker B Biomarker C Biomarker Negative Drug A Phase II Drug B Phase II Drug C Phase II Drug X Phase II Drug Y Phase II All pts Follow-up

15 Registry part Aim Comprehensive database for rare cancer Establish reliable historical control data Assignment to mutation-based basket trials Some trials target marker-negative patients Collaboration with industries Joint project with 11 industries Funding, study drugs Industry-sponsored sub-study Accrual target 100 patients/year Pediatric patients with cancer (>1-year old) will be enrolled from April

16 Sub-study Several sub-studies are under way Marker(+): Marker(-): BRAF V600, ALK, HER2, etc. Immune checkpoint inhibitor Typical sub-study design Aim to expand drug indication to rare cancer Drug approved for any major cancer Recommended dose fixed Single-arm phase II Response rate patients with Bayesian design Pediatric cohort in sub-studies is a plan. 16

17 Planned or ongoing IIT in Japan Check point inhibitor (PI) PARP inhibitor (PI) ALK inhibitors (PI) Proteasome inhibitors (PII) EZH inhibitor (PI) (discovered in Japan) Anti-GD2 (PII) MIBG therapy CART cell

18 Thank you!!