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Clinical Study ARRAY 818 302 Array Biopharma Inc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ncorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) Array BioPharma Inc. Clinical Study ARRAY-818-302 PRINCIPAL INVESTIGATOR AGREEMENT I have read and understand the contents of the clinical protocol for Clinical Study ARRAY-818-302 dated 11 July 2019 and will adhere to the study requirements as presented, including all statements regarding confidentiality. In addition, I will conduct the study in accordance with the requirements of this protocol and also protect the rights, safety, privacy and well-being of study patients in accordance with the following: • International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6(R1) • All applicable laws and regulations, including, without limitation, data privacy laws and regulations • Requirements for reporting serious adverse events (SAEs) defined in Section 10.9 of this protocol • Terms outlined in the Clinical Study Site Agreement My signature also acknowledges that: • Neither my subinvestigators nor I are members of the Ethics Committee (EC) reviewing this protocol, or • I and/or my subinvestigators are members of the EC, but I/we will not participate in the initial review or continuing review of this study Name of Principal Investigator Signature of Principal Investigator Date Protocol Version 8.0 3 11 July 2019 Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) Array BioPharma Inc. Clinical Study ARRAY-818-302 PROTOCOL SYNOPSIS Title A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab with a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients with BRAF V600E-mutant Metastatic Colorectal Cancer Protocol Number ARRAY-818-302 Phase 3 Study Centers Approximately 300 international study centers Objectives Safety Lead-in In patients with BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC): Primary: • Assess the safety/tolerability of the combination of encorafenib + binimetinib + cetuximab Secondary: • Assess the activity of encorafenib + binimetinib + cetuximab as measured by blinded independent central review (BICR)- determined and Investigator-determined objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and time to response • Characterize the pharmacokinetics (PK) of encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032) Exploratory: • Assess the activity of encorafenib + binimetinib + cetuximab as measured by overall survival (OS) Randomized Phase 3 In patients with BRAFV600E mCRC: Primary: • Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab (Control Arm) as measured by overall survival (OS) Protocol Version 8.0 4 11 July 2019 Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) Array BioPharma Inc. Clinical Study ARRAY-818-302 • Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by ORR per BICR Key Secondary: • Compare the activity of encorafenib + cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by OS Other Secondary: • Compare the Investigator-determined ORR of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) • Compare the BICR-determined and Investigator-determined ORR of encorafenib + cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/ cetuximab (Control Arm) • Compare the BICR-determined and Investigator-determined progression-free survival (PFS) of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) • Compare the BICR-determined and Investigator-determined PFS of encorafenib + cetuximab (Doublet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) • Compare the activity of Triplet Arm vs. Doublet Arm as measured by OS • Compare BICR-determined and Investigator-determined ORR of Triplet Arm vs. Doublet Arm • Compare the BICR-determined and Investigator-determined PFS of Triplet Arm vs. Doublet Arm • Compare BICR-determined and Investigator-determined DOR of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm • Compare BICR-determined and Investigator-determined time to response of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm • Assess the safety/tolerability of Triplet Arm, of Doublet Arm and of Control Arm • Compare the effect on quality of life (QoL) of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm Protocol Version 8.0 5 11 July 2019 (QFRUDIHQLE %5$)9PXWDQWLQKLELWRU %LQLPHWLQLE 0(.LQKLELWRU $UUD\%LR3KDUPD,QF &OLQLFDO6WXG\$55$< x &KDUDFWHUL]HWKH3.RIHQFRUDIHQLEFHWX[LPDEELQLPHWLQLE DQGWKHDFWLYHPHWDEROLWHRIELQLPHWLQLE $5 x $VVHVVIRUGUXJLQWHUDFWLRQVEHWZHHQHQFRUDIHQLEFHWX[LPDE ELQLPHWLQLEDQGWKHDFWLYHPHWDEROLWHRIELQLPHWLQLE $5 EDVHGRQ3.PRGHOLQJ CCI (QGSRLQWV 6DIHW\/HDGLQ 3ULPDU\ x ,QFLGHQFHRIGRVHOLPLWLQJWR[LFLWLHV '/7V x ,QFLGHQFHDQGVHYHULW\RIDGYHUVHHYHQWV $(V JUDGHG DFFRUGLQJWRWKH1DWLRQDO&DQFHU,QVWLWXWH 1&, &RPPRQ 7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV &7&$( YHUVLRQ Y DQGFKDQJHVLQFOLQLFDOODERUDWRU\SDUDPHWHUV YLWDOVLJQVHOHFWURFDUGLRJUDPV (&*V HFKRFDUGLRJUDP (&+2 PXOWLJDWHGDFTXLVLWLRQ 08*$ VFDQVDQG RSKWKDOPLFH[DPLQDWLRQV x ,QFLGHQFHRIGRVHLQWHUUXSWLRQVGRVHPRGLILFDWLRQVDQG GLVFRQWLQXDWLRQVGXHWR$(V 6HFRQGDU\ x 255 E\%,&5DQG,QYHVWLJDWRU SHUWKH5HVSRQVH(YDOXDWLRQ &ULWHULDLQ6ROLG7XPRUV 5(&,67 YHUVLRQ Y GHILQHG DVWKHQXPEHURISDWLHQWVDFKLHYLQJDQRYHUDOOEHVWUHVSRQVHRI FRPSOHWHUHVSRQVH &5 RUSDUWLDOUHVSRQVH 35 GLYLGHGE\WKH WRWDOQXPEHURISDWLHQWV x '25 E\%,&5DQG,QYHVWLJDWRU GHILQHGDVWKHWLPHIURP ILUVWUDGLRJUDSKLFHYLGHQFHRIUHVSRQVHWRWKHHDUOLHVW GRFXPHQWHGGLVHDVHSURJUHVVLRQRUGHDWKGXHWRXQGHUO\LQJ GLVHDVH x 3)6 E\%,&5DQG,QYHVWLJDWRU GHILQHGDVWKHWLPHIURPILUVW GRVHWRWKHHDUOLHVWGRFXPHQWHGGLVHDVHSURJUHVVLRQRUGHDWK GXHWRDQ\FDXVH x 7LPHWRUHVSRQVH E\%,&5DQG,QYHVWLJDWRU GHILQHGDVWKH WLPHIURPILUVWGRVHWRILUVWUDGLRJUDSKLFHYLGHQFHRIUHVSRQVH 3URWRFRO9HUVLRQ -XO\ Encorafenib (BRAF V600-mutant inhibitor)/Binimetinib (MEK inhibitor) Array BioPharma Inc. Clinical Study ARRAY-818-302 • PK parameters of encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032) Exploratory: • OS, defined as the time from first dose to death due to any cause Randomized Phase 3 Primary: • OS, defined as the time from randomization to death due to any cause, of Triplet Arm vs. Control Arm • Confirmed ORR (by BICR) per RECIST, v1.1 of Triplet Arm vs. Control Arm Key Secondary: • OS of Doublet Arm vs. Control Arm Other Secondary: • Confirmed ORR (by Investigator) per RECIST, v1.1 of Triplet Arm vs. Control Arm • Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Doublet Arm vs. Control Arm • PFS (by BICR and Investigator), defined as the time from randomization to the earliest documented disease progression or death due to any cause, of Triplet Arm vs. Control Arm • PFS (by BICR and Investigator) of Doublet Arm vs. Control Arm • OS of Triplet Arm vs. Doublet Arm • Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Triplet Arm vs. Doublet Arm • PFS (by BICR and Investigator) of Triplet Arm vs. Doublet Arm • DOR (by BICR and Investigator) of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm • Time to response (by BICR and Investigator), defined as the time from randomization to first radiographic evidence of response, of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm Protocol Version 8.0 7 11 July 2019 (QFRUDIHQLE %5$)9PXWDQWLQKLELWRU %LQLPHWLQLE 0(.LQKLELWRU $UUD\%LR3KDUPD,QF &OLQLFDO6WXG\$55$< x ,QFLGHQFHDQGVHYHULW\RI$(VJUDGHGDFFRUGLQJWR1&, &7&$(YDQGFKDQJHVLQFOLQLFDOODERUDWRU\SDUDPHWHUV YLWDOVLJQV(&*V(&+208*$VFDQVDQGRSKWKDOPLF H[DPLQDWLRQV x &KDQJHIURPEDVHOLQHLQWKH(XURSHDQ2UJDQL]DWLRQIRU 5HVHDUFKDQG7UHDWPHQWRI&DQFHU (257& 4XDOLW\RI/LIH 4XHVWLRQQDLUHIRU&DQFHU3DWLHQWV 4/4& )XQFWLRQDO $VVHVVPHQWRI&DQFHU7KHUDS\&RORQ&DQFHU )$&7& (XUR4RO'/ (4'/ DQG3DWLHQW*OREDO,PSUHVVLRQRI &KDQJH 3*,& RI7ULSOHW$UPYV&RQWURO$UPRI'RXEOHW $UPYV&RQWURO$UPDQGRI7ULSOHW$UPYV'RXEOHW$UP x 0RGHOEDVHG3.SDUDPHWHUVRIHQFRUDIHQLEFHWX[LPDE ELQLPHWLQLEDQGWKHDFWLYHPHWDEROLWHRIELQLPHWLQLE $5 x 0RGHOEDVHG3.DVVHVVPHQWRIGUXJGUXJLQWHUDFWLRQVEHWZHHQ HQFRUDIHQLEFHWX[LPDEELQLPHWLQLEDQGWKHDFWLYHPHWDEROLWH RIELQLPHWLQLE $5 CCI 'HVLJQ 7KLVLVDPXOWLFHQWHUUDQGRPL]HGRSHQODEHODUP3KDVHVWXG\
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