Finl Arevited Clinicl Study Report Nme of Sponsor/Compny: Bristol-Myers Squi Ipilimum Individul Study Tle Referring to the Dossier (For Ntionl Authority Use Only) Nme of Finished Product: Yervoy Nme of Active Ingredient: Ipilimum SYNOPSIS Finl Arevited Clinicl Study Report for Study ABBREVIATED REPORT TITLE OF STUDY: A multi-center, open-lel, phse II study of ipilimum (MDX-010) extendedtretment monotherpy or follow-up for sujects previously enrolled in ipilimum (MDX-010) protocols INVESTIGATORS/STUDY CENTERS: A totl of 242 sujects were enrolled (nd treted/followed) t 75 sites in 21 countries including Argentin, Austrli, Austri, Belgium, Brzil, Cnd, Czech Repulic, Denmrk, Frnce, Germny, Isrel, Itly, Norwy, Peru, Polnd, Russi, South Afric, Spin, Sweden, Ukrine, nd the United Sttes PUBLICATIONS: None STUDY PERIOD: Study Initition Dte: 09-My-2006 CLINICAL PHASE: 2 Dt Cutoff Dte: 19-Sep-2012 INTRODUCTION: This study ws designed to evlute sfety in sujects with dvnced melnom enrolled from Bristol-Myers Squi (BMS) ipilimum prent studies CA184004, CA184007, CA184008, nd CA184022 or Medrex (MDX) studies MDX010-08 nd MDX010-15. Most sujects rolled over from prent studies CA184004, CA184007, CA184008, or CA184022, ll of which hd induction mintennce, ut no re-induction. Since is rollover study with primry ojective of sfety; limited efficcy results with primry focus on sfety t ipilimum 10 milligrm/kilogrm (mg/kg) first re-induction re presented in this finl revited Clinicl Study Report (CSR). An Extension Phse of protocol is ongoing; results will e presented in n ddendum to this CSR. OBJECTIVES: The primry ojective of this study ws to monitor the sfety of ipilimum dministered either s re-induction (3 or 10 mg/kg [10 mg/kg results re presented in this report]) or mintennce therpy (0.3, 3, or 10 mg/kg). The secondry ojectives with results presented in this report were: To estimte overll survivl (OS) from the first dose of ipilimum in the prent study (in enrolled sujects) To estimte survivl rte t 1, 1.5, nd 2 yers from the first dose of ipilimum in the prent study (in enrolled sujects) To estimte progression free survivl (PFS) from the first in this study To monitor sujects (except those in Survivl Follow-up only) who experienced immune relted dverse events (iraes) fter ipilimum tretment (in enrolled sujects) METHODOLOGY: This is multi-center, Phse 2 rollover study of extended tretment with ipilimum monotherpy or follow-up for sujects previously enrolled in prent ipilimum studies to evlute sfety of ipilimum dministered either s re-induction or s mintennce therpy. Eligile sujects entered the study into 1) re-induction (t time of progression), 2) extended mintennce (if no prior progression) or 3) follow-up.
Finl Arevited Clinicl Study Report Figure 1: Ipilimum Study Flow Digrm consisted of 5 phses: Screening, (first nd second), Mintennce, Follow-up, nd Extension Phse (currently ongoing). Re-Induction (with or without extended mintennce) sujects (N=122 treted) entered into re-induction phse initilly or following extended mintennce to receive ipilimum. Sujects treted t 0.3 mg/kg, 3 mg/kg nd 10 mg/kg initil therpy received open-lel first re-induction t 10 mg/kg nd other dose selections in prent study received open-lel first re-induction t 3 or 10 mg/kg in. These suject tretment groups re s follows: 0.3 mg/kg initil therpy to 10 mg/kg (N=24 treted), 3 mg/kg initil therpy to 10 mg/kg (N=34 treted), 10 mg/kg initil therpy to 10 mg/kg (N=53 treted), nd other dose selections from prent study to current study (N=11 treted). Extended Mintennce only sujects (N=62, 49 treted) entered into the mintennce phse nd could receive ipilimum in 12-week intervls. Some sujects entered mintennce with PR or CR tumor responses nd never received ipilimum tretment ut were followed y tumor ssessment. Sujects receiving ipilimum during extended mintennce received 0.3 mg/kg (N=4 treted), 3 mg/kg (N=13, 12 treted), nd 10 mg/kg (N=45, 33 treted). Mintennce sujects were initilly treted with linded study mediction s rndomized in the prent study until such study ws unlinded (CA184004 nd CA184022). Then these sujects were treted with open-lel ipilimum. Follow-Up sujects (N=58) entered into the follow-up phse nd did not receive dditionl study tretment ut continued on-study for the collection of survivl dt. Sujects entering the mintennce phse of directly from prent studies CA184004 nd CA184022 remined linded until the time tht unlinding occurred in the prent protocols. Sujects entering into the re-induction phse long with those entering mintennce on n unlinded dose received unlinded doses in. NUMBER OF SUBJECTS (Plnned nd Anlyzed): The numer of sujects enrolled in studies CA184004, CA184007, CA184008, CA184022, MDX010-08 nd MDX010-15 determined the numer of eligile sujects for this rollover study. It ws estimted tht 30% of the sujects (estimted n = 200) in the prent protocols would enter this rollover study. Of the 733 sujects in the prent studies, 248 (34%) were enrolled into this study (28, 42, 67, 103, 2 nd 6 from CA184004, CA184007, CA184008, CA184022, MDX010-08 nd MDX010-15, respectively). A totl of 242 sujects were enrolled nd treted/followed in. Six sujects did not meet screening criteri for. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: This rollover study includes sujects from prent protocols CA184004, CA184007, CA184008, CA184022, MDX010-08 nd MDX010-15.
Finl Arevited Clinicl Study Report Ipilimum : Sujects who received ipilimum t ny dose in prent study; nd met ech of the following criteri: Hd no uncceptle toxicity (except select reversile iraes - refer to the protocol) requiring ipilimum discontinution Hd experienced progressive disese (PD) fter expnded clinicl enefit Hd chieved expnded clinicl enefit on or fter Week 12 in the prent study or for CA184022 only, hd PD efore Week 12 or fter expnded clinicl enefit All sujects eligile for re-induction (s descried ove) must hve hd their cse discussed with BMS Medicl Monitor prior to enrolling in the re-induction phse of this rollover study to monitor sfety nd verify ppropriteness for re-induction therpy. Extended Mintennce: Received ipilimum t ny dose in prent study Achieved expnded clinicl enefit t the time of rollover study entry Follow-up: Received ipilimum t ny dose in closing prent study Deemed ineligile for re-induction or extended mintennce tretment or refused tretment s re-induction or extended mintennce suject t the time of screening in this rollover study, ut consented to follow-up TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT: Ech eligile suject received ipilimum dosing vi 90 minute intrvenous (IV) infusion in oth the or Mintennce Phse of this study. Refer to Sections 6.2.2 through 6.2.5 for further detiled instruction regrding ipilimum scheduling, dosing, skipping nd discontinution of tretment. Re-Induction Phse: Ipilimum t dose of 10 mg/kg or 3 mg/kg will e dministered in n open-lel mnner, s n individul dose every 3 weeks for the first 10 weeks of Re-Induction for totl of 4 seprte doses unless there is disese progression or withdrwl of consent; Sujects who hd chieved expnded clinicl enefit s defined in the protocol (Appendix 1.1), who permnently discontinued tretment under the prent study due to select iraes will receive 3 mg/kg; All other Re-Induction doses of ipilimum will e t 10 mg/kg regrdless of the previous dose ssignment in the prior/prent study or dose ssignment in the Mintennce Phse of this study; Sujects entering Re-Induction from the prior/prent protocol must wit 3 weeks from their prior/prent dose of ipilimum efore receiving Re-Induction dosing in this study. Sujects entering Re-Induction from Mintennce must wit 3 weeks from their lst dose of Mintennce Phse ipilimum efore receiving Re-Induction dosing. ws to continue enrolling sujects until ipilimum ecme commercilly ville t ll open sites or the Investigtionl New Drug Appliction (IND) ws closed y the Sponsor. This study will remin open until the lst enrolled suject discontinues from ny study phse, including Follow-up, or the study is otherwise terminted y the Sponsor. Thus, ll sujects who were enrolled in the study prior to pprovl of ipilimum could continue to receive tretment nd follow-up in this study. CRITERIA FOR EVALUATION: Sfety: Sfety ws evluted using the Ntionl Cncer Institute (NCI) Common Terminology Criteri for Adverse Events v3.0 (CTCAE). Sfety ssessments were sed on medicl review of dverse event (AE) reports nd the
Finl Arevited Clinicl Study Report Ipilimum results of vitl sign mesurements, physicl exmintions nd clinicl lortory tests. The incidence of AEs will e tulted nd reviewed for potentil significnce nd clinicl importnce. The reporting period for sfety dt will either e: 1) from the dte of the first dose of ipilimum received in this study (re-induction nd mintennce sujects) to 70 dys (5 hlf-lives) following the lst dose received; or 2) 70 dys from the lst dose of ipilimum received in the prior/prent study (Follow-up sujects). Efficcy: The Investigtor mde ll tumor evlutions sed on modified World Helth Orgniztion (WHO) criteri. Throughout the study, ech respective Investigtor will determine disese sttus of sujects t the protocol-defined timepoints nd s cliniclly indicted. Immunogenicity: Humn nti-humn ntiodies (HAHA) nd serum ipilimum concentrtion will e evluted (with the exception of the Extension Phse). STATISTICAL CONSIDERATIONS: The study ws designed to evlute sfety in sujects enrolled from prent ipilimum protocols where it ws estimted 200 sujects or 30% in the prent protocols would enter this rollover study depending upon the numer of sujects ultimtely enrolled in studies CA184004, CA184007, CA184008, CA184022, MDX010-08 nd MDX010-15. Of the 733 sujects in the prent studies, 248 (34%) were enrolled into this study (28, 42, 67, 103, 2 nd 6 from CA184004, -007, -008, -022, MDX010-08 nd -15, respectively). The study treted/followed totl of 242 sujects who did not fil screening. In ddition to the nlysis of sfety, the OS, nd the progression free survivl (PFS) from the first dose of ipilimum in the prent study (in enrolled sujects) ws lso computed. Sujects were rndomized in prent studies nd once unlinded (for sujects in prent studies CA184004 nd CA184022 only), tretment ws dministered open lel in. The originl nlysis pln ws truncted to the current revited presenttion in Ferury, 2012 to trget on the sfety nd OS in first re-induction sujects. The decision to limit the nlysis ws due to the complexity of the study, the mixture of tretments nd popultions, nd the difficulty in interpreting such results. The primry nlysis focus is on sujects receiving first re-induction since this represents the lrgest group (n = 122) nd is potentilly the most informtive s sfety of mintennce dosing ws estlished in prent studies. The nlysis lso includes sujects receiving extended mintennce (n = 62, 49 treted, see Figure 1; some sujects entered mintennce with tumor responses of PR or CR nd never received ipilimum tretment ut were followed y tumor ssessment.) nd follow-up sujects (n = 58), for whom dt is ville in listings. The ssessment of sfety ws summrized using descriptive sttistics nd ws sed on AEs, serious AEs (SAEs), iraes, deths, physicl exmintions, clinicl lortory tests, nd exposure to study therpy. The secondry efficcy nlyses estimted nd plotted OS for ech dose group with the Kpln-Meier product-limit method. OS ws defined from the time of the first dose of ipilimum in the prent study until deth or censor. No forml sttisticl testing ws done. Survivl rtes t 1, 1.5, nd 2 yers with corresponding two-sided 95% CIs were clculted for ech tretment group using the Kpln Meier product-limit method. Progression free survivl (PFS) ws plotted for ech dose grouping with the Kpln-Meier product-limit method. SUMMARY OF RESULTS: Disposition nd Bseline/Demogrphic Chrcteristics: Disposition (Tle 1) nd seline/demogrphic chrcteristics (Tle 2) presented in this report focus on sujects in first re-induction who received prent study ipilimum doses of 10, 3, or 0.3 mg/kg or other doses of ipilimum.
Finl Arevited Clinicl Study Report Tle 1: Numer of Sujects: Enrolled Treted Discontinued Primry Reson: Suject Disposition, Sujects Disese progression Still on Tretment Ipilimum 10 to 10 mg/kg 3 to 10 mg/kg 0.3 to 10 mg/kg Other Dosge 53 53 44 (83.0%) 34 34 29 (85.3%) 24 24 21 (87.5%) 11 11 8 (72.7%) 29 (54.7%) 21 (61.8%) 13 (54.2%) 4 (36.4%) 9 (17.0%) 5 (14.7%) 3 (12.5%) 3 (27.3%) An other dosge in the prent study esides 10, 3, or 0.3 mg/kg ipilimum; receiving either 3.0 or 10.0 mg/kg in. Discontinution dt includes sujects in ctegories of documented disese progression nd deteriortion without documented disese progression. Tle 2: Bseline nd Demogrphic Chrcteristics, Sujects Other Dosge 10 to 10 mg/kg 3 to 10 mg/kg 0.3 to 10 mg/kg (N=53) (N=34) (N=24) Femle 21 (39.6) 11 (32.4) 4 (16.7) 1 (9.1) Mle 32 (60.4) 23 (67.6) 20 (83.3) 10 (90.9) White 51 (96.2) 34 (100.0) 24 (100.0) 10 (90.9) Blck 1 (1.9) Asin 1 (9.1) 1 (1.9) 55.4 (11.7) 58.8 (9.9) 56.0 (15.3) 57.8 (13.7) Medin 56.0 56.5 57.0 57.0 Min-Mx 27-82 34-79 31-82 40-82 (N=11) Gender (n %) Rce (n %) Other Age (yers) Men (SD)
Finl Arevited Clinicl Study Report Tle 2: Ipilimum Bseline nd Demogrphic Chrcteristics, Sujects 10 to 10 mg/kg 3 to 10 mg/kg 0.3 to 10 mg/kg Other Dosge (N=53) (N=34) (N=24) 0 37 (69.8) 22 (64.7) 10 (41.7) 9 (81.8) 1 16 (30.2) 11 (32.4) 13 (54.2) 2 (18.2) 2 1 (2.9) 1 (4.2) 3 (N=11) ECOG Performnce Sttus Other dosge in the prent study; receiving either 3.0 or 10.0 mg/kg in. Mixed prentge - cpe colored Arevitions: ECOG = Estern Coopertive Oncology Group, SD = stndrd devition Extent of Exposure: A medin numer of 4 doses per suject were dministered in the 10 to 10 mg/kg nd 3 to 10 mg/kg groups nd 2 doses per suject were dministered in the 0.3 to 10 mg/kg group during the study. Of the 111 treted first re-induction sujects in this rollover study, 30 sujects eventully received mintennce tretment (indicted y >4 doses in 16 sujects in the 10 to 10 mg/kg group, 10 sujects in the 3 to 10 mg/kg group, nd 4 sujects in the 0.3 to 10 mg/kg group). Sfety Results: An overll summry of sfety in treted first re-induction sujects is presented in Tle 3. Sfety findings during first re-induction in treted sujects re s follows: Totl frequencies of drug-relted AEs were similr cross the groups (79% to 87%). The most common drug-relted AEs were iraes, with grde 3/4 iraes of 7/53, 2/34 nd 6/24 in ipilimum 10 to 10 mg/kg, 3 to 10 mg/kg, nd 0.3 to 10 mg/kg groups, respectively. Dirrhe, pruritus, nd rsh were the most frequently reported iraes. In treted first re-induction sujects, the most frequent AEs leding to discontinution during first re-induction tht were considered relted to study drug y the investigtor were colitis, dirrhe, nd nemi. Ftl AEs leding to discontinution included disese progression, pneumoni, nd mlignnt melnom. There were no Grde 5 drug-relted AEs or drug-relted deths.
Finl Arevited Clinicl Study Report Tle 3: Ipilimum Summry of Sfety, Treted Sujects 10 to 10 mg/kg (N = 53) Sujects with ny On-study: AE, n (%) 3 to 10 mg/kg (N = 34) 0.3 to 10 mg/kg (N = 24) 51 (96.2) 33 (97.1) 24 (100.0) Severe (Grde 3/4) 18 (34.0) 10 (29.4) 10 (41.7) Ftl (Grde 5) 4 (7.5) 7 (20.6) 8 (33.3) 13 (24.5) 6 (17.6) 8 (33.3) Severe (Grde 3/4) 9 (17.0) 3 (8.8) 6 (25.0) Ftl (Grde 5) 1 (1.9) 2 (5.9) 1 (4.2) 23 (43.4) 19 (55.9) 14 (58.3) Severe (Grde 3/4) 13 (24.5) 8 (23.5) 5 (20.8) Ftl (Grde 5) 4 ( 7.5) 7 (20.6) 8 (33.3) Drug-relted AEs, n (%) 42 (79.2) 28 (82.4) 21 (87.5) Severe (Grde 3/4) 9 (17.0) 3 (8.8) 9 (37.5) Ftl (Grde 5) 30 (56.6) 23 (67.6) 18 (75.0) Grde 3/4 irae 7 (13.2) 2 (5.9) 6 (25.0) Grde 5 (ftl) 36 (67.9) 27 (79.4) 19 (79.2) AEs leding to study drug discontinution, n (%) SAEs, n (%) irae, n (%) Deths, n (%) Includes deths more thn 70 dys fter lst dose dte. Note: On-study dverse events (AEs) include ll AEs reported etween the first dose nd 70 dys fter the lst dose of study drug. Arevitions: AE = dverse event; irae = immune-relted dverse event; SAE = serious dverse event Other Results: Efficcy: Tle 4 summrizes efficcy results. Tle 4: Efficcy Summry Suject Group (No. of Sujects) OS Medin, months (95% CI) Kpln-Meier Estimted Survivl Rtes (%) PFS Medin, months (95% CI) 1 yr 1.5 yrs 2 yrs 10 to 10 mg/kg (N=53) 30.8 (24.2, 41.1) 80.9 71.3 63.6 3.4 (2.6, 7.8) 3 to 10 mg/kg (N=34) 18.7 (9.7, 30.4) 55.9 50.0 38.2 2.6 (2.6, 2.8) 0.3 to 10 mg/kg (N=24) 15.2 (10.7, 21.4) 65.6 35.0 30.6 2.6 (2.0, 11.1)
Finl Arevited Clinicl Study Report Tle 4: Suject Group (No. of Sujects) Ipilimum Efficcy Summry Kpln-Meier Estimted OS Medin, months (95% CI) Survivl Rtes (%) PFS Medin, months (95% CI) Extended Mintennce 1 yr 1.5 yrs 2 yrs 10 mg/kg (N=45) NE (NE, NE) 100.0 100.0 91.1 NA 3 mg/kg (N=13) NE (28.4, NE) 100.0 84.6 84.6 NA 0.3 mg/kg (N=4) NE (11.3, NE) 75.0 75.0 75.0 NA 1 yr 1.5 yrs 2 yrs 87.8 79.0 65.0 Follow-Up Not dosed (N=58) 40.2 (27.1, NE) NA Estimted from first dose of ipilimum in prent study Estimted from first re-induction in CA194025 Arevitions: CI = confidence intervl; NA = not nlyzed; NE = not evlule; PFS = progression free survivl; OS = overll survivl For sujects who received 10 mg/kg ipilimum re-induction, there ws numericlly higher OS percent for those who received 10 mg/kg versus 3 mg/kg ipilimum in prent study. For OS, the contriution of the originl prent protocol re-induction nd mintennce cnnot e dissected. Similrly, sujects treted t 10 mg/kg in prent study hd numericlly higher survivl t 1, 1.5 nd 2 yers reltive to sujects who initilly were treted with 3 mg/kg nd re-induced t 10 mg/kg. Sujects who received 10 mg/kg extended mintennce therpy hd numericlly higher improved survivl t 1, 1.5 nd 2 yers reltive to sujects who initilly were treted with 3 mg/kg extended mintennce. The medins were not reched in ll 3 of the ipilimum extended mintennce therpy rms. For sujects who received 10 mg/kg ipilimum re-induction, there ws no numericl difference in PFS etween those who received 3 versus 10 mg/kg in prent study. Immunogenicity: Immunogenicity smples were collected during the study nd nlysis results will e reported seprtely from this CSR. CONCLUSIONS: The focus on the nlysis trgeted sujects eligile for re-induction t 10 mg/kg followed y extended mintennce therpy. Results re sed on smll smple sizes in non-rndomized context with potentil is due to eligiility criteri nd tht only suset of those eligile enrolled. Specificlly, enrollment required tht sujects experienced clinicl enefit from ipilimum in prent study nd tolerted ipilimum with no dose limiting toxicity. t 10 mg/kg ipilimum ws sfely dministered nd tolerle regrdless of dose in prent study. The incidence nd severity of iraes during re-induction ws lower thn tht for the generl popultion in the prent study. For sujects who received 10 mg/kg ipilimum re-induction, there ws lower incidence of iraes for those who received ipilimum t 3 nd 10 mg/kg in prent study compred to those who received ipilimum t 0.3 mg/kg in prent study. Sujects who tolerted ipilimum t 0.3 mg/kg in prent study received fewer doses t 10 mg/kg thn those sujects who tolerted 3 or 10mg/kg in prent study.
Finl Arevited Clinicl Study Report Ipilimum DATE OF REPORT: 10-Jul-2013