Information regarding the pediatric clinical development program led by Roche iPODD (Innovative Pediatric Oncology Drug Development)

Roche Clinical Trials in Pediatric Oncology

All trials consistent with information on ClinicalTrials.gov as of February, 2020.

This booklet is not intended for physicians practising in the USA.

2 TABLE OF CONTENTS

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INTRODUCTION AND TABLE OF CONTENTS

ABOUT iPODDPAGE 5

ABOUT iMATRIX CLINICAL TRIAL PLATFORMPAGE 7

TABLE OF CONTENTS

INTRODUCTION

This booklet provides an overview of the current clinical iPODD Pediatric Oncology Drug Development program and approach to research. It has been designed to support Roche’s pediatric clinical research efforts and provide information regarding ongoing Roche-sponsored pediatric oncology trials.

ROCHE PEDIATRIC ONCOLOGY TRIALS

STARTRK-NG (Entrectinib; TRKA/B/C, ROS1, and ALK inhibitor) Phase I/II trialPAGES 10-11

iMATRIX-idasa (Idasanutlin; MDM2 inhibitor) Phase I/II trialPAGES 12-13

iMATRIX-cobi (Cobimetinib; MEK inhibitor) Phase I/II trialPAGES 14-15

iMATRIX-atezo (Atezolizumab; anti-PD-L1 antibody) Phase I/II trialPAGES 16-17

BERNIE (Bevacizumab; anti-VEGF antibody) Phase II trialPAGES 18-19

HERBY (Bevacizumab; anti-VEGF antibody) Phase II trialPAGES 20-21

4 ABOUT iPODD

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ABOUT iPODD (Innovative Pediatric Oncology Drug Development)

Children with cancer do not have timely access to safe and efficacious drugs. Additionally, physicians have limited information regarding the use of drugs in pediatric populations. The iPODD team is helping accelerate research of potential pediatric cancer treatments by leading the pediatric clinical study program for Roche pipeline molecules in the late stages of development.

OUR VISION• Provide children with unmet medical needs with

innovative, life-saving therapies and advance scientific knowledge regarding the treatment of pediatric oncology patients

OUR MISSIONS• Allow early access to drugs for children with high

unmet medical needs

• Improve pediatric patient care through pediatric product labelling

• Fulfill pediatric regulatory obligations to ensure timely registrations in adults

Entrectinib is approved by the US Food and Drug Administration and by Japan’s Ministry of Health, Labour and Welfare for the treatment of adult and pediatric patients aged ≥12 years with NTRK fusion-positive advanced recurrent solid tumors.

None of the other drugs in this booklet have been approved for pediatric cancer outside of the clinical trial setting in any country.

ABOUT iPODD

6 iMATRIX CLINICAL TRIAL PLATFORM

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iMATRIX CLINICAL TRIAL PLATFORMWith the iMATRIX protocol, Roche is using a basket trial design to accelerate research for the advancement of pediatric cancer treatment. Roche enrols patients in early-phase clinical trials by matching patients’ tumor biologies with a molecule’s mechanism of action (MOA). Agents and tumor types that show potential will be advanced to larger trials.

1. Match tumor biology with a molecule’s MOA to identify patients for inclusion in clinical trials

2. Once the dose-finding stage has been completed, a limited number of patients per tumor type cohort are enrolled

3. If efficacy meets a threshold superior to that observed in Phase I trials of that disease, expansion studies are conducted

4. Expansion study results will justify whether to proceed to pivotal trial

iMATRIX CLINICAL TRIAL PLATFORM

The iMatrix protocol design uses a 4-point development strategy when evaluating clinical trials for use in pediatric cancer.

8 ROCHE PEDIATRIC CLINICAL TRIALS

9ROCHE PEDIATRIC CLINICAL TRIALS

ROCHE PEDIATRIC CLINICAL TRIALS

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STARTRK-NG (Entrectinib; TRKA/B/C, ROS1, and ALK inhibitor) · CO40778 · NCT02650401A Phase I/II study of entrectinib in children and adolescents with no curative first-line treatment option, recurrent or refractory solid tumors and primary CNS tumors, with or without TRK or ROS1 gene fusions

STUDY DESIGN

SOLID TUMORS

Phase I 3 + 3 dose escalation

DLT assessment Cycle 1 (28 days)

N=16

Part B CNS tumors with

NTRK1/2/3 or ROS1 gene fusion

(max 10 patients)

Inital efficacy assessment

If at least 4/10 responders

Additional expansion (additional 10 patients)

Part D Extracranial tumors with NTRK1/2/3 or ROS1

gene fusion (max 10 patients)

Inital efficacy assessment

If at least 4/10 responders

Additional expansion (additional 10 patients)

Phase II N=40

Phase I is now complete

PATIENT AGE• <22 years

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STARTRK-NG clinical trial

CBR=clinical benefit rate; CNS=central nervous system; DLT=dose-limiting toxicity; DOR=duration of response; MTD=maximum tolerated dose; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RANO=Response Assessment in Neuro-Oncology; RECIST=Response Evaluation Criteria in Solid Tumors; TTR=time to recurrence.

SOLID TUMORS

Primary Outcome Measures• MTD of entrectinib• Recommended Phase II dose of entrectinib• ORR as determined by the investigator and by

Blinded Independent Central Review using RECIST v1.1 or RANO

Secondary Outcome Measures• Safety• Pharmacokinetics• Efficacy: DOR, TTR, CBR, PFS, OS• Acceptability of the pediatric formulation• Additional follow-up of growth and development

PRIMARY ENDPOINTS

RECRUITMENT STATUSRecruiting: 21 sites in the US, 4 sites in Europe

Actively recruiting sitesChildren’s Hospital of Orange County, Orange, CA, USRady Children’s Hospital, San Diego, CA, USUCSF Benioff Children’s Hospital; UCSF Pediatrics Hematology Oncology, San Francisco, CA, USChildren’s Hospital Colorado; Center For Cancer/Blood Disorder, Aurora, CO, USChildren’s National Medical Center; Department of Pediatrics, Washington. D.C., USEgleston Children’s Hospital at Emory University Atlanta, Atlanta, GA, USUniversity of Chicago; Comer Children’s Hospital/Department of Pediatrics, Chicago, IL, USDana Farber Cancer Institute, Boston, MA, USJohns Hopkins University, Baltimore, MD, US

University of Minnesota Childrens’ Hospital, Minneapolis, MN, USWashington University, St. Louis Children’s Hospital, Saint Louis, MO, USMorgan Stanley Children’s Hospital; Herbert Irving Cancer Center, New York, NY, USMemorial Sloan Kettering Cancer Center; Pediatrics, New York, NY, USCincinnati Children’s Hospital Medical Center, Cincinnati, OH, USNationwide Children’s Hospital; Dept. of Pulmonology, Columbus, OH, USOregon Health & Science Uni, Portland, OR, USChildren’s Hospital of Philadelphia, Philadelphia, PA, USSt. Jude Children’s Research Hospital, Memphis, TN, USCook Children’s Medical Center, Fort Worth, TX, US

Texas Children’s Cancer and Hematology Center, Houston, TX, USPrimary Children’s Hospital, Salt Lake City, UT, USHôpital de la Timone, Oncologie Pédiatrique, Marseille, FranceCentre Léon Bérard, Lyon, FranceHospital Infantil Universitario Niño Jesus, Madrid, SpainRoyal Marsden Hospital, Sutton, London, UK

Find the most up-to-date information at ClinicalTrials.gov

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iMATRIX-idasa (Idasanutlin; MDM2 inhibitor) · GO40871 · NCT04029688A Phase I/II study evaluating the safety, tolerability, pharmacokinetics, and preliminary activity of idasanutlin in combination with either chemotherapy or venetoclax in pediatric and young adult participants with relapsed/refractory acute leukemias or solid tumors

Single-agent dose-escalation stage

Safety run-in combinations and RP2D

STUDY DESIGN

SOLID TUMORS

Pediatric patients with previously treated neuroblastoma or acute leukemia

Pediatric and young adult patients with previously

treated neuroblastoma or acute leukemia

Pediatric patients with previously treated

solid tumors

Expansion following signal seeking

Randomized combination testing stage

PATIENT AGE• Dose-escalation and safety run-in stage: <18 years• Randomized combination testing stage: 0–30 years

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iMATRIX-idasa clinical trial

AEs=adverse events; ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; CBR=clinical benefit rate; CRR=complete remission rate; DLTs=dose-limiting toxicities; DOR=duration of response; EFS=event-free survival; INRC=International Neuroblastoma Response Criteria; MRD=minimal residual disease; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors; RP2D=recommended phase II dose

SOLID TUMORS

Primary Outcome Measures• Percentage of participants with AEs or serious AEs• Percentage of participants with DLTs• ORR in participants with TP53 wild-type neuroblastoma as

determined by the investigator using INRC • CRR in participants with TP53 wild-type leukemia• MRD-negative rate in participants with TP53 wild-type ALL

Secondary Outcome Measures• CBR, DOR, and PFS as determined by the investigator using

INRC for neuroblastoma or RECIST v1.1 for other solid tumors

• ORR irrespective of TP53 mutation status• OS• Proportion of participants with leukemia receiving a

transplant after study treatment• DOR and EFS in participants with leukemia• CRR in participants with leukemia irrespective of TP53

mutation status• MRD-negative rate in participants with TP53 wild-type AML• Plasma concentrations of idasanutlin and venetoclax as

a single agent and in combination

PRIMARY ENDPOINTS

RECRUITMENT STATUSRecruiting: 10 sites in Europe, 9 sites in the US, 1 site in Canada

Actively recruiting sitesArkansas Children’s Hospital Research Institute, AR, USArnold Palmer Hospital for Children, Orlando, FL, USPenn State Hershey Children’s Hospital, Hershey, PA, USUniversity of Texas Health Science Center, San Antonio, TX, USHospital Infantil Universitario Niño Jesus, Madrid, Spain

Not yet recruitingPhoenix Children’s Hospital, Phoenix, Arizona, USLucile Packard Children’s Hospital at Stanford University, Palo Alto, CA, US

Memorial Sloan Kettering Cancer Center, New York, NY, USThe University of Texas MD Anderson Cancer Center, Houston, TX, USHuntsman Cancer Institute at The University of Utah, Salt Lake City, UT, USAlberta Children’s Hospital, Calgary, Alberta, CanadaCentre Leon Berard, Lyon CEDEX, FranceInstitut Curie, Paris, FranceCHU de Brabois, Vandoeuvre Les Nancy, FranceGustave Roussy, Villejuif CEDEX, FrancePrinses Maxima Centrum, Utrecht, NetherlandsHospital Sant Joan De Deu, Esplugues De Llobregas, Barcelona, Spain

Birmingham Children’s Hospital, Birmingham, UKThe Royal Victoria Infirmary, Newcastle Upon Tyne, UKRoyal Marsden Hospital, Surrey, UK

Find the most up-to-date information at ClinicalTrials.gov

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iMATRIX-cobi (Cobimetinib; MEK inhibitor) · GO29665 · NCT02639546A Phase I/II study of the safety and pharmacokinetics of cobimetinib in pediatric and young adult patients with previously treated solid tumors

Dose-escalation stage Dose-expansion stage in patients with low-grade glioma

STUDY DESIGN

SOLID TUMORS

Cobimetinib N=44

Cobimetinib N=12

Pediatric and young adult patients with previously treated solid tumors with evidence of

RAS/RAF/MEK/ERK activation

This medicinal product is subject to additional monitoring. Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Adverse events should be reported by email or phone to the Drug Safety Center of your local Roche affiliate.

PATIENT AGE• Dose-escalation stage: tablet formulation (≥6 years to <18 years); suspension (≥6 months to <18 years)• Dose-expansion stage: ≥6 months to <30 years

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iMATRIX-cobi clinical trial

DLTs=dose-limiting toxicities; DOR=duration of response; ERK=extracellular receptor kinase; MAD=maximum administered dose; MEK=mitogen-activated protein kinase; MTD=maximum tolerated dose; OS=overall survival; PFS=progression-free survival; RAF=rapidly accelerated fibrosarcoma; RAS=rat sarcoma.

SOLID TUMORS

Primary Outcome Measures• PFS as determined by the investigator• Percentage of participants with DLTs• MTD and MAD of cobimetinib• Plasma cobimetinib concentrations• Percentage of participants with objective response

Secondary Outcome Measures• DOR as determined by the investigator• OS

PRIMARY ENDPOINTS

Recruiting: 19 sites in Europe, 9 sites in the US, 1 site in Canada, 1 site in Israel

Actively recruiting sitesPhoenix Children’s Hospital, Phoenix, AZ, USStanford University/Lucile Packard Children’s Hospital, Palo Alto, CA, USArnold Palmer Hosp-Children, Orlando, FL, USPenn State Milton S. Hershey Medical Center, Hershey, PA, USUniversity of Texas Health Science Center at San Antonio, San Antonio, TX, USAlberta Children’s Hospital, Calgary, Alberta, CanadaHopital Des Enfants; Service d’Hemato-Oncologie, Toulouse, FranceSchneider Children’s Medical Center, Petach-Tikva, IsraelPoliclinico Universitario Agostino Gemelli; Oncologia Pediatrica, Roma, Lazio, ItalyGreat Ormond Street Hospital; Dept. Of Pediatric Oncology, London, UK

Alderhey Children’s Trust, Liverpool UKThe Royal Victoria Infirmary, Newcastle Upon Tyne, UK

Completed sitesArkansas Children’s Hospital, Little Rock, AR, USDana Farber Cancer Institute, Boston, MA, USMemorial Sloan Kettering Cancer Center, New York, NY, USHôpital de la Timone, Oncologie Pédiatrique, Marseille, FranceInstitut Curie, Oncologie Pédiatrique, Paris, FranceInstitut Gustave Roussy; Service Pediatrique, Villejuif, FranceUniversitätsklinikum Freiburg Zentrum f.Kinderheilkunde Klinik III, Frankfurt, GermanyUniversitäetsklinikum Muenster, Muenster, GermanyFondazione IRCCS Istituto Nazionale dei Tumori, Milano, Lombardia, ItalyHospital Universitari Vall d’Hebron, Barcelona, SpainHospital Infantil Universitario Niño Jesus, Madrid, SpainHospital Universitari i Politecnic La Fe de Valencia, Valencia, Spain

Withdrawn sitesMD Anderson Cancer Center, Houston, TX, USUniversity Hospital Essen; Department of Pediatric Oncology, Essen, GermanyUniversitätsklinikum Frankfurt, Frankfurt, GermanyUniversitätsklinikum Gießen und Marburg GmbH Standort Gieße, Gießen, GermanyMedizinische Hochschule Hannover, Hannover, GermanyKlinik Kinderheikunde I des Zentrums für Kinder- und Jugendmedizin, Universität Heidelberg, Heidelberg, Germany

RECRUITMENT STATUS

Find the most up-to-date information at ClinicalTrials.gov

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iMATRIX-atezo (Atezolizumab; anti-PD-L1 antibody) · GO29664 · NCT02541604A Phase I/II single-arm study evaluating the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of atezolizumab in pediatric and young adult participants with solid tumors

STUDY DESIGN

Atezolizumab

SOLID TUMORS

Primary publicationGeorger B, et al. Lancet Oncol 2020;21:134-144.

PATIENT AGE• <30 years

Pediatric and young adult patients with previously treated

solid tumors

N=90

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Primary Outcome Measures• Percentage of participants with objective response• PFS• Percentage of participants with AEs, serious AEs, and AEs

of special interest• Cmax of atezolizumab after the infusion on Day 1 of Cycle 1• Cmin of atezolizumab prior to the infusion• Atezolizumab serum concentration at washout• Percentage of participants with ATA

Secondary Outcome Measures• DOR as determined by the investigator using RECIST v1.1• OS• PFS as determined by investigator using irRC• Percentage of participants with ORR as determined by

investigator using irRC• DOR as determined by investigator using irRC

PRIMARY ENDPOINTS

iMATRIX-atezo clinical trial

AEs=adverse events; ATA=anti-therapeutic antibody; Cmax=maximum serum concentration; Cmin=minimum serum concentration; DOR=duration of response; irRC=immune-related response criteria; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria In Solid Tumors.

SOLID TUMORS

Completed

RECRUITMENT STATUS

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BERNIE (Bevacizumab; anti-VEGF antibody) · BO20924 · NCT00643565A Phase II study of bevacizumab in combination with standard chemotherapy in children and adolescents with sarcoma

Randomized

STUDY DESIGN

Standard chemotherapy + bevacizumab

Standard chemotherapy

SOFT TISSUE SARCOMAS

Primary publicationChisholm JC, et al. Eur J Cancer 2017;83:177-184.

PATIENT AGE• ≥6 months to <18 years

Children and adolescent patients with sarcoma

N=154

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Primary Outcome Measures• Percentage of participants who experienced EFS

events as per IRC assessment• EFS duration as per IRC assessment

Secondary Outcome Measures• Percentage of participants with objective

response prior to first local therapy assessed by RECIST v1.0

• Percentage of participants who experienced EFS events among participants who had objective response

• DOR• Percentage of participants who died• OS• AUCss of bevacizumab• Volume of distribution of bevacizumab• Half-life of bevacizumab• Clearance of bevacizumab

PRIMARY ENDPOINTS

AUCss=area under the curve at steady state; DOR=duration of response; EFS=event-free survival; IRC=independent review committee; OS=overall survival; RECIST=Response Evaluation Criteria In Solid Tumors.

SOFT TISSUE SARCOMAS

Completed

RECRUITMENT STATUS

BERNIE clinical trial

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HERBY (Bevacizumab; anti-VEGF antibody) · BO25041 · NCT01390948A Phase II study of bevacizumab in combination with temozolomide and radiotherapy in pediatric and adolescent participants with high-grade glioma

STUDY DESIGNBevacizumab + temozolomide

Young participant cohort

Chemoradiation + temozolomide

Arm A

Chemoradiation + bevacizumab + temozolomide

Arm B

RandomizedPediatric and adolescent patients

with high-grade glioma

N=124

HIGH-GRADE GLIOMA

Primary publicationGrill J, et al. J Clin Oncol 2018;36:951-958.

PATIENT AGE• Young participants: ≥6 months to <3 years• Pediatric participants: ≥3 to <18 years

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Primary Outcome Measure• EFS defined as the earliest occurrence of any one of the

following: tumor progression, tumor recurrence, second primary non-HGG malignancy or death attributable to any cause as determined by the CRRC

Secondary Outcome Measures• OS• 1-year OS• 6-month and 1-year EFS defined as the earliest

occurrence of any of the following: tumor progression,

recurrence, second primary non-HGG malignancy or death due to any cause as determined by the CRRC

• Neurological psychological function as measured by the Wechsler Scale between the treatment arms

• Percentage of participants with AEs• Percentage of participants with overall response

as determined by the CRRC based on RANO criteria• Functional changes in tumor assessed by MRI• Health status as measured by the HUI between the

treatment arms

PRIMARY ENDPOINTS

AEs=adverse events; CRRC=Central Radiology Review Committee; EFS=event-free survival; HGG=high-grade glioma; HUI=Health Utility Index; MRI=magnetic resonance imaging; OS=overall survival; RANO=Response Assessment in Neuro-Oncology.

HIGH-GRADE GLIOMA

Completed

RECRUITMENT STATUS

HERBY clinical trial

Global Development Team LeaderHubert CaronEmail: hubert.caron@roche.com

AtezolizumabGianluca Rossato Email: gianluca.rossato@roche.com

BevacizumabCecile Guizani Email: cecile.guizani@roche.com

CobimetinibRonald BernardiEmail: bernarr9@gene.com

EntrectinibGuillaume Bergthold Email: guillaume.bergthold@roche.com

IdasanutlinBeate WulffEmail: beate.wulff@roche.com

Supported trialsVesna Sneller HarmachEmail: vesna.sneller_harmach@roche.com

For more information on clinical trials

iPODD medical lead contacts

Published byF. Hoffmann-La Roche Ltd4070 Basel, Switzerland

Visit:ClinicalTrials.gov or Roche-Trials.com

© 2020www.roche.comFebruary 2020M-XX-00000862

Child model on front cover is for illustrative purposes only.