These results re supplied for informtionl purposes only. Prescribing decisions should be mde bsed on the pproved pckge insert in the country of prescription. Sponsor / Compny: Snofi Drug substnce(s): AVE0005 (flibercept) Study Identifiers: NCT01930552, U1111-1115-7286 Study code: TCD11470 Title of the study: A phse I study of the sfety, tolerbility, nd phrmcokinetics of flibercept in combintion with FOLFIRI dministered every 2 weeks in Chinese ptients with dvnced solid mlignncies Study center(s): 2 clinicl sites in Chin Study period: Dte first ptient enrolled: 26/Sep/2013 Dte lst ptient completed: 17/Dec/2014 Cut-off Dte for core prt dt nlysis: 29/Sep/2014 Phse of development: Phse 1 Objectives: Primry objective: To ssess the sfety nd phrmcokinetics (PK) of the dose of intrvenously (IV) flibercept used in western studies in combintion with FOLFIRI given IV every 2 weeks in Chinese ptients with solid tumors. Secondry objectives: To mke preliminry ssessment of ntitumor effects of the combintion of FOLFIRI plus flibercept in ptients with mesurble disese (Response Evlution Criteri for Solid Tumors [RECIST] 1.1), To evlute the immunogenicity of IV flibercept. Methodology: This open-lbel study of flibercept dministered IV every 2 weeks in combintion with FOLFIRI ws designed to ssess the sfety nd phrmcokinetics profile of the dose of flibercept (4.0 mg/kg) in Chinese ptients with solid tumors. Number of ptients: Plnned: 20 Evluted: Rndomized: 20 Treted: 20 Sfety: 20 Dignosis nd criteri for inclusion: Phrmcokinetics: 20 I 01. I 02. Histologiclly or cytologiclly confirmed solid mlignncy tht is metsttic or unresectble for which FOLFIRI tretment is pproprite. Ptients must hve received t lest one prior line of tretment with ny stndrd of cre, who hve filed the tretment, or who hve not been eligible for stndrd of cre for ny resons. According to templte: QSD-001970 VERSION N 4.0 (07-JUN-2012) Pge 1
Study tretments Investigtionl medicinl product: flibercept Formultion: in 5 mm phosphte, 5 mm citrte, 100 mm sodium chloride, 20% (w/v) sucrose, nd 0.1% (w/v) polysorbte 20, ph 6.0, supplied in seled, sterile, single-use 10 ml vils filled with 8.4 ml content with withdrwl content of 8.0 ml t concentrtion of 25 mg/ml. The content of the vil must be diluted prior to infusion with 0.9% sodium chloride or 5% dextrose solution. Route of dministrtion: IV Dose regimen: Aflibercept 4 mg/kg IV infusion for 1 hour, repeted every 2 weeks Noninvestigtionl medicinl products: irinotecn, 5-FU, nd leucovorin (FOLFIRI) Formultion: Mrketed formultions were used for irinotecn, 5-FU, nd leucovorin Route(s) of dministrtion: IV Dose regimen: Aflibercept dministrtion ws immeditely followed by FOLFIRI: irinotecn 180 mg/m 2 IV infusion for 90 minutes, together with leucovorin 400mg/m 2 IV infusion for 2 hours on Dy (D) 1, followed by 5-FU 400 mg/m² IV bolus then 2400 mg/m² continuous IV infusion for 46 hours strting on D1, repeted every 2 weeks Durtion of tretment: Ptients were given flibercept followed by FOLFIRI repeted every 2 weeks in the bsence of study withdrwl criteri. Durtion of observtion: From dte of informed consent until lst study tretment dministrtion + 90 dys. Criteri for evlution: Efficcy: Tumor burden ws ssessed by CT or MRI scns. Tumor ssessments were performed ccording to RECIST 1.1 criteri. Sfety: Sfety ws ssessed through the collection of dverse events (AEs), lbortory dt (hemtology, chemistry, nd urinlysis), nd vitl signs. Immunogenicity: Presence of nti-flibercept ntibodies ws ssessed throughout the study before, during nd fter flibercept tretment. Phrmcokinetics: Concentrtion-time profiles to clculte following PK prmeters: Aflibercept: - At Cycle 1: - Free flibercept, mximum plsm concentrtion (Cmx), time to rech Cmx (tmx), lst concentrtion bove lower limit of quntifiction (LLOQ) (Clst), time of Clst (tlst), re under the plsm concentrtion-time curve (AUC) up to lst quntifible time point (AUClst), AUC extrpolted to infinity (AUC), AUC over the dosing intervl (AUC0-14dy), clernce (CL), volume of distribution t stedy stte (Vss) nd terminl elimintion hlf- life (t1/2z) - VEGF-bound flibercept,: Cmx, tmx, Clst, tlst, AUClst nd AUC0-14 dy - Throughout the study: - Plsm concentrtion observed just before strting infusion on Dy 1 of ech odd-numbered cycle (Ctrough) Irinotecn: Cmx, tmx, AUC, t1/2z for both irinotecn nd SN-38 (ctive metbolite of irinotecn). Additionlly, CL nd Vss for irinotecn only 5-FU: stedy-stte concentrtion (Css), clernce t stedy-stte (CLss) According to templte: QSD-001970 VERSION N 4.0 (07-JUN-2012) Pge 2
Phrmcokinetic smpling times nd bionlyticl methods: Aflibercept (Free nd VEGF-bound flibercept): Cycle 1: prestrt of flibercept infusion, just before the end of infusion (EOI, 1 hour [h]), nd 1h, 3h, 7h (Dy 1), 23h, 29h (Dy 2), 47h (D3) nd 167 h (D8) fter the end of flibercept infusion. Other Cycles fter Cycle 1: pre-strt of flibercept infusion on D1 of Cycle 2 nd every odd-numbered cycle; nd then 30 nd 90 dys fter the lst dministrtion of flibercept. Free nd bound flibercept were mesured in plsm using vlidted direct enzyme linked immunosorbnt bsed ssy (ELISA, Methods SOP PCL113 nd SOP PCL2088, respectively). Concentrtions of vsculr endothelil growth fctor (VEGF)-bound flibercept were expressed s free flibercept equivlent (ie, normlized to the mount of flibercept present in the complex s djusted bound flibercept) before PK nlysis. The corresponding lower limit of quntifiction (LLOQ) of free nd VEGF-bound flibercept were 15.6 ng/ml nd 31.5 ng/ml, respectively. Irinotecn nd SN-38: prestrt of flibercept infusion, just before EOI (1.5h), 2h, 4h, nd 23h poststrt of irinotecn infusion during Cycle 1 only. Concentrtions of irinotecn nd SN-38 were determined in plsm by liquid chromtogrphy with tndem mss spectrometry method (LC/MS-MS, Method PBRL-RD-1285). The LLOQ of irinotecn nd SN-38 were 10.0 ng/ml nd 1.00 ng/ml, respectively. 5-FU: prestrt of flibercept infusion, then 3h, 21h nd 45h fter IV bolus of 5-FU infusion during Cycle 1. The plsm concentrtions of 5-FU ws determined by LC/MS-MS using LLOQ of 5.00 ng/ml (Method Covnce 8278-371). Immunogenicity: Smples for immunogenicity ssessment were collected prestrt of first flibercept infusion, then on predose of ech odd-numbered cycle nd then 30 nd 90 dys fter the lst dministrtion of flibercept, nd in specific circumstnces when ptient developed grde 2 systemic immunologic AE considered t lest possibly relted to the study drug, proteinuri >3.5 g/24h, or proteinuri of renl origin ssocited with hemturi. The presence of nti-flibercept ntibodies ws evluted in serum using nonquntittive ssy, titer-bsed bridging immunossy (Method SOP PCL2375). Sttisticl methods: The sfety nlysis nd efficcy-relted nlysis were performed in ll treted popultion, which included ptients who took t lest 1 dose (including prtil dose) of study tretment (ie, flibercept or FOLFIRI, regrdless of correct/incorrect dose ssignment) in this study. The sfety nlysis ws descriptive on tretment emergent dverse events (TEAEs) nd lbortory vlues. Toxicities were grded ccording to the Ntionl Cncer Institute Common Terminology Criteri for Adverse Events Version 3.0 (NCI CTCAE v.3.0). PK prmeters of free nd VEGF-bound flibercept, irinotecn nd its ctive metbolite SN-38, nd 5-FU were estimted using noncomprtmentl method nd summrized with descriptive sttistics (number of observtions by tretment, rithmetic, nd geometric mens, stndrd devition (SD), stndrd error of the men (SE), coefficient of vrition (CV), minimum, medin, nd mximum vlues). RECIST 1.1-defined best overll response ws determined for efficcy nlysis. According to templte: QSD-001970 VERSION N 4.0 (07-JUN-2012) Pge 3
Summry: Popultion chrcteristics: A totl of 20 Chinese ptients were enrolled nd treted in this study. Overll, 13 ptients (65.0%) were mle, the medin ge of ll ptients ws 52 yers (rnge: 26 to 70 yers), nd ll ptients hd n estern coopertive oncology group (ECOG) performnce sttus of 1 t study entry. Prior tretment of the disese included: chemotherpy (20 ptients, 100%), surgery (14 ptients, 70.0%), rdiotherpy (2 ptients, 10.0%), nd biologics (2 ptients, 10%). The medin number of prior nticncer regimens ws 1.0 (rnge: 1 to 3). The vst mjority of the ptients hd colorectl cncer s the primry tumor site (15 ptients, 75.0%). Efficcy results: All of the 20 ptients treted were evluble for tumor response. Per RECIST 1.1, there were 6 confirmed prtil responses (PR): 4 ptients out of the 15 ptients with colorectl cncer, 1 ptient out of the 2 ptients with esophgus cncer, nd 1 ptient out of the 2 ptients with esophgel-gstric junction (EGJ) cncer. Sfety results: All ptients hve discontinued the study tretment t the time of the finl dtbse lock (23 Jnury 2015): 12 ptients discontinued due to disese progression, 7 ptients due to ptient s request, nd 1 ptient due to AE. Overll, 20 ptients received totl of 193 cycles of study tretment (medin number of cycles per ptient: 9.0 cycles, rnge: 2 to 20 cycles). The totl number of cycles with flibercept ws 170 cycles (medin number of cycles per ptient: 9.0 cycles, rnge: 2 to 19 cycles). Eighteen ptients (90.0%) hd cycle delys, minly due to hemtologicl toxicities (9 ptients, 45.0%), stheni (8 ptients, 40.0%), gstrointestinl disorders (6 ptients, 30.0%), proteinuri (4 ptients, 20.0%), nd hypertension (3 ptients, 15.0%). Four ptients (20.0%) required t lest 1 dose reduction of flibercept, while 5 (25.0%) nd 6 (30.0%) ptients required t lest 1 dose reduction of irinotecn nd 5-FU, respectively. The min resons for dose reduction were gstrointestinl disorders (7 ptients, 35.0%), protein urine present (6 ptient, 30.0%), hypertension (3 ptients, 15.0%), nd hemtologicl toxicities (3 ptients, 15.0%). All 20 ptients experienced t lest 1 TEAE while on study tretment. The most commonly reported ll grde TEAEs were decresed ppetite (18 ptients, 90.0%), nuse (17 ptients, 85.0%), vomiting (14 ptients, 70.0%), hypertension (14 ptients, 70.0%), leukopeni (11 ptients, 55.0%), neutropeni (10 ptients, 50.0%), stheni (9 ptients, 45.0%), dirrhe (9 ptients, 45.0%), bdominl pin (8 ptients, 40.0%), stomtitis (8 ptients, 40.0%), protein urine present (7 ptients, 35.0%), nd epistxis (7 ptients, 35.0%). The most commonly reported Grde 3/4 TEAEs were neutropeni (7 ptients, 35.0%), leukopeni (3 ptients, 15.0%), febrile neutropeni (3 ptients, 15.0%), hypertension (6 ptients, 30.0%), protein urine present (4 ptients, 20.0%), stomtitis (4 ptients, 20.0%), nd dirrhe (3 ptients, 15.0%). Hypertension (14 ptients, 70.0%), hemorrhge events (7 ptients, 35.0%), impired wound heling (2 ptients, 10.0%), nd venous thrombosis (1 ptient, 5.0%) were reported s TEAEs of specil interest in this study. Of note, lbortory bnormlities were only reported s AEs when they were considered cliniclly significnt by the Investigtor; therefore, the lbortory dt is the primry source of dt for comprehensive nd objective evlution of the incidence of lbortory bnormlities (see below). No deth during study period ws observed. Three ptients ech experienced serious TEAE of venous thrombosis limb, hemorrhoids, nd nstomotic stenosis, respectively; the events of venous thrombosis limb nd hemorrhoids were considered to be possibly relted to the study tretment. One ptient discontinued the study tretment due to TEAE of nstomotic stenosis, which ws serious nd considered s unrelted to the study tretment by the Investigtor. The most common lbortory bnormlity ws hemtologic toxicity. Neutropeni ws reported in 15 ptients (75.0%), nd 11 ptients (55.0%) experienced Grde 3 or 4 neutropeni. Anemi nd thrombocytopeni were reported in 13 ptients (65.0%) nd 10 ptients (50.0%), respectively, nd most of the bnormlities were Grde <3. Liver nd renl function test bnormlities were observed in few ptients, nd ll were Grde 1. Proteinuri bsed on lbortory mesurements ws observed in 13 ptients (65.0%), nd 4 ptients (20.0%) experienced Grde 3 proteinuri. No unexpected significnt chnges in vitl signs, ECG, nd physicl findings were observed. Immunogenicity results: No nti-flibercept ntibodies were detected in ny of the ptients evluble for immunogenicity ssessment (19 out of the 20 treted). According to templte: QSD-001970 VERSION N 4.0 (07-JUN-2012) Pge 4
Phrmcokinetic results: Aflibercept Men (CV %) PK prmeters of free nd VEGF-bound flibercept obtined t Cycle 1 re summrized in the tble below: Aflibercept 4 mg/kg (N=20) Free flibercept tmx C mx AUC 0-14 dy AUC CL CL/Weight V ss Vss/Weight t 1/2Z (dy) (µg/ml) (µg.dy/ml) (µg.dy/ml) (L/dy) (L/dy/kg) (L) (L/kg) (dy) 0.04 64.8 249 291 b 0.915 b 0.0143 b 5.87 b 0.0915 b 4.97 b (0.04-0.17) (26) (18) (19) (27) (21) (31) (25) (13) VEGF-bound flibercept t mx (dy) 14.01c (12.88-15.94) C mx (µg/ml) AUC 0-14 dy (µg.dy/ml) t lst (dy) 14.01c (12.88-15.94) AUC lst (µg.dy/ml) 2.78c (22) 19.8c (31) 20.8c (28) Medin (Min-Mx), b N=19, c N=18, d N=13 Following first dministrtion of flibercept (4 mg/kg), medin tmx ws observed t the end of infusion (medin tmx=1h) for free flibercept while VEGF-bound flibercept concentrtions incresed regulrly over first cycle nd reched Cmx t the end of Cycle 1 (medin tmx=14 dys). Free flibercept ws eliminted with clernce of 0.9 L/dy nd terminl hlf-life of 5 dys. Volume of distribution ws round 6 L. Vribility on both free nd VEGF-bound flibercept PK prmeters ws low to moderte (13% to 31%). Concomitnt drugs: Irinotecn: Following first dministrtion of irinotecn (180 mg/m 2 ), men (CV %) of Cmx nd AUC of irinotecn ws 2160 ng/ml (25%) nd 15200 ngh/ml (20%), respectively. Irinotecn ws eliminted with clernce of 11.8 L/h/m² (31%) nd terminl hlf-life of bout 5h. SN-38 showed lower exposure with Cmx nd AUClst of 35.8 ng/ml (48%) nd 265 ngh/ml (36%), respectively, corresponding to round 3% of the prent drug exposure (on molr bsis). 5-FU: During IV infusion of 5-FU t 2400 mg/m², men (CV%) stedy stte clernce ws 79.4 L/h/m² (44%). Issue dte: 01-Dec-2015 According to templte: QSD-001970 VERSION N 4.0 (07-JUN-2012) Pge 5