Recombinant human interleukin 6 in metastatic renal cell cancer: a phase II

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1 Britsh Journl of Cncer (1996) 73, Stockton Press All rights reserved 7-92/96 $12. $ Recominnt humn interleukin 6 in metsttic renl cell cncer: phse II tril JML Stouthrd', H Goey2, EGE de Vries3, PH de Mulder4, A Groenewegen5, L Pronk2, G Stoter2, HP Suerwein6, PJM Bkker1 nd CHN Veenhof 'Deprtment of Medicl Oncology, Acdemic Medicl Center, University of Amsterdm, PO Box 227, 11 DE Amsterdm; 2Dr Dniel Den Hoed Kliniek, Groene Hillendijk 31, 375 EA Rotterdm; 3University Hospitl Groningen, Oostersingel 59, 9713 EZ Groningen; 'University Hospitl St. Rdoud, G. Grooteplein 8, 6525 GA Nijmegen; 5Sndoz Medicl Reserch Deprtment, PO Box 91, 54 AB Uden; 6Metolic Reserch Group, Deprtment of Internl Medicine, Acdemic Medicl Center, University of Amsterdm, PO Box 227, 11 DE Amsterdm, The Netherlnds. Summry A phse II tril investigting the nti-tumour effects of recominnt humn interleukin 6 (rhil-6) in ptients with metsttic renl cell cncer ws crried out. RhIL-6 (15,g) ws dministered s dily sucutneous injection for 42 consecutive dys on n outptient sis. Forty-nine ptients were studied, 12 with nd 37 without previous immunotherpy. Forty ptients were evlule for response. A prtil remission ws noted in two ptients, stle disese in 17 nd progressive disese in 21. Toxicity ws moderte nd reversile nd consisted minly of fever, flu-like symptoms, nuse, weight loss nd heptotoxicity. Anemi, leucocytosis nd thromocytosis nd induction of cute phse protein synthesis were noted in most ptients. In 15% of the ptients nti-il-6 ntiodies developed, nd were neutrlising in only one ptient. Bseline plsm IL-6 concentrtions did not correlte with tumour ehviour efore or fter rhil-6 tretment. In conclusion, rhil-6 cn e sfely dministered on n outptient sis for prolonged period of time nd hs moderte, reversile toxicity. Its dministrtion induces IL-6-ntiody production in only minority of ptients. Antitumour effects of rhil-6 in metsttic renl cncer re limited. Keywords: renl cell cncer; interleukins; interleukin 6; humn Metsttic renl cell crcinom hs poor prognosis for most ptients, with medin survivl of less thn 1 yer (Mrston et l., 1989). Efforts to improve this survivl y chemotherpeutic gents hve een lrgely unsuccessful (Ygod et l., 1993). Recently, immunotherpy hs received much ttention (Wirth, 1993). Although moderte effectiveness of oth IL-2 nd interferon- hs een oserved, long-term disese-free survivl fter tretment with cytokines hs not een documented in rndomised fshion (Wirth, 1993). Therefore, the need for new effective nd sfe therpies remins. Interleukin 6 (IL-6) is multifunctionl cytokine (Le nd Vilcek, 1989) tht hs stimultory effects on thromocytopoiesis (Ishishi nd Asno, 1992), B- nd T-cell differentition (Kishimoto nd Hirno, 1988; Houssiu nd Vn Snick, 1992) nd the heptic cute phse response (Guldie et l., 1992), s well s meditory role in the metolic nd endocrinologicl response to inflmmtion (Stouthrd et l., 1994, 1995). Furthermore, experimentl nd preclinicl dt indicte tht IL-6 my hve direct nd indirect nti-tumour ctivity in solid tumours (Revel, 1992; Chen et l., 1988; Mule et l., 199, 1992). Here, we descrie our results of multicentre phse II tril of recominnt humn (rh)il-6 in ptients with metsttic renl cell cncer. This study ws initited fter the oservtion of complete remission of pulmonry metstses in ptient with renl cell crcinom fter 6 week course of dily sucutneous recominnt humn IL-6 (rhil- 6) injections s n experimentl drug for thromocytopeni (A Ginell-Borrdori, personl communiction). Using the sme tretment schedule, we investigted nti-tumour effects, toxicity, hemtologicl nd iochemicl chnges nd the induction of nti-il-6 ntiodies in ptients with metsttic renl cell cncer, oth with nd without previous immunotherpy. Correspondence: JML Stouthrd Received 19 July 1995; revised 19 Octoer 1995; ccepted 27 Octoer 1995 Ptients nd methods Ptient selection Eligile for this study were ll ptients with histologiclly verified dignosis of metsttic renl cell cncer, with idimensionlly mesurle tumour lesions nd who were etween 18 nd 75 yers of ge. Their WHO performnce sttus hd to e or 1, nd their life expectncy t lest 3 months. Ptients were required to hve hemogloin level c5 mmol I`, white lood count >3.x 1l-' nd thromocyte count > 1 x 19 1 I, norml liver function s ssessed y iliruin <25 umol l-1 (in cse of heptic metstses < 5 ymol l-') nd norml renl function (cretinine < 175 imol 1`). Excluded were ptients with nephrectomy, chemotherpy or therpy with ny investigtionl drug within 4 weeks of study entry, ptients with rin metstses, with known HIV, virl heptic or Epstein-Brr virus (EBV) infection, with severe llergic disese, uncontrolled psorisis, severe rheumtoid rthritis, glomerulonephritis or ny other severe utoimmune disese nd those on immunosuppressive therpy (corticosteroids) nd pregnnt women. The study ws pproved y the Medicl Ethicl Committees of ll prticipting centres. All ptients gve written informed consent. Study design This ws n open, non-rndomised multicentre phse II study in which four centres prticipted. All centres included t lest seven ptients. Before the strt of the study complete medicl history, including pst therpy for the renl cncer with record of ll surgicl nd rdiotherpeutic procedures nd therpeutic gents used, ws otined. Ptients were strtified y previous use of immunotherpy (e.g. interleukin 2, interferons or ny other immunomodulting therpy) (group I) or not (group II). The tretment in oth groups ws identicl nd consisted of dily sucutneous (s.c.) injection of 15 Hg of Escherichi coli derived rhil-6 (18 units mg-' protein) for 42 consecutive dys. Before s.c. injection, the rhil-6 vil ws reconstituted in 1 ml of sterile wter. After instructions on injection technique y n

2 79 Interleukin 6 in renl cell cncer JML Stouthrd et l oncology nurse, rhil-6 ws injected in the upper leg on n inptient sis on dys 1-3 nd susequently rhil-6 ws self-dministered upon dischrge home. Acetminophen, with mximum of 3 g per dy, ws prescried for fever or flulike symptoms. RhIL-6 (SDZ ILS 969), provided y Sndoz Phrm. (Bsle, Switzerlnd), ws >99% pure (s ssessed y SDS - PAGE) nd contined <.4 endotoxin units mg- (Limulus moeocyte lysis ssy). Vitl signs nd reports of symptoms or dverse events were recorded nd scored ccording to the Ntionl Cncer Institute of Cnd Clinicl Trils Group Expnded Common Toxicity Criteri (NCIC criteri) (Vntongelen, 1991) on dy 1 nd weekly therefter. On dys 1, 22 nd 42 physicl exmintion ws performed nd performnce sttus recorded. Tumour mesurements y rdiologicl or clinil evlution were performed just efore the strt of the study, t the end of the tretment, fter 4 weeks follow-up nd, when possile, every 2 months therefter. Lortory investigtions Complete lood counts, prothromin time, iochemistry [iliruin, cretinine, sodium, potssium, lnine-mino trnsferse, sprtte-mino trnsferse, lkline phosphtse (AP), gmm-glutmyltrnsferse (y-gt), cute phse rectnts (erythrocyte sedimenttion rte (ESR), C-rective protein (CRP), firinogen) nd urinlysis] were otined weekly, eginning t dy 1. On dy 1, efore the first rhil-6 dministrtion, lood ws otined for the mesurement of seline IL-6 concentrtions (Quntikine, R&D Systems, Minnepolis, MN, USA; detection limit.3 ng ml'). On dys 1, 22 nd 42 lood ws smpled for qulittive nd, if positive, quntittive nlysis of nti-rhil-6 ntiodies. For the qulittive nlysis of nti-il-6 ntiodies 'screen ELISA' ws used. In short, microtitre pltes, coted with SDZ ILS 969 in coting uffer, were incuted with positive nd negtive ntiody controls nd with het-inctivted ptient serum in triplicte. After incution lkline phosphtse-conjugted got nti-humn IgG + IgM + IgA ws dded. After ddition of p-nitrophenyl phosphte in diethnolmine opticl density ws red using n UVmx microtitre plte reder t nm. An opticl density of,.35 ws found in 95% of norml individuls, nd considered the cut-off for eing ntiody-negtive for SDZ ILS 969. If higher vlue ws found, quntittive nlysis of nti-il-6 ntiodies ws performed, using ELISA. Microtitre pltes were coted s descried ove, either with coting uffer lone or with coting uffer contining SDZ ILS 969. Serum smples nd controls were dded in 3- fold seril dilutions (strting t 1:1) nd processed s descried. The specific opticl density (OD) ws defined s the OD of the smple in the well tht ws coted with SDZ ILS 969 minus the OD of the smple in the well tht ws coted with coting uffer only. For clim of immunogenecity, ptient hd to hve tretment-specific OD vlue of t lest twice the pretretment specific OD vlue. Vlues of the quntittive nlysis were expressed s positive t given titre. Neutrlising ntiodies to rhil-6 were detected using IL-6 growth-dependent cell line (B13.29), with neutrlising ntiserum otined from got s positive control. A serum smple ws considered s positive for neutrlising ntiodies if it inhiited the prolifertive response to 5 units ml-' rhil-6, nd if the percentge inhiition ws t lest twice the percentge inhiition of the pretretment serum smple t the equivlent dilution. Response criteri Only ptients who completed the 6 week tretment period were included in the evlution. A complete response ws defined s the totl disppernce of ll detectle mlignnt disese for t lest 4 weeks. A prtil response ws defined s >5% reduction of (the sum of) the product(s) of the longest dimeter nd the gretest perpendiculr dimeter of given lesion(s) (dimeter product), nd no ppernce of new lesions for t lest 4 weeks. A minor response ws defined s reduction of >25% ut <5% y the sme definitions. Stle disese ws noted when the (sum of the) dimeter product(s) decresed <5% or incresed <25%. Progressive disese ws defined s n increse >25% of the dimeter product(s) of mesurle lesion, in the sum of the products of individul lesions or in cse of the ppernce of new lesions. Tumour sttus t entry ws defined y the sme criteri using mesurements otined in the 3 months preceding study entry, whenever ville. Sttistics To ssess nti-tumour ctivity, n Optiml Two-Stge Erly Rejection Design (Simon, 1987) ws used: ssuming 2% response rte would indicte tretment effectiveness, 12 ptients were to e recruited in ech group in the first stge. If one or more responses were oserved, the tril would enter second stge nd totl (per group) of 37 ptients would e recruited. All lortory dt re presented s men + s.e.m. Chnges in ny lortory prmeter during the rhil-6 tretment were evluted using nlysis of vrince, nd, where pproprite, y Newmn-Keul's test for multiple comprisons. Differences etween groups were evluted y Mnn-Whitney's t-test for unmtched smples. A P-vlue <.5 (two-tiled) ws considered to represent sttisticlly significnt difference. Results Ptient chrcteristics The demogrphic nd disese chrcteristics of the ptients re given in Tle I. A totl of 49 ptients ws included; 12 ptients with, nd 37 ptients without previous immunotherpy. There were no significnt differences etween the two groups. Of the previously treted ptients, five received IL-2, four IL-2 + -interferon (-IFN) + lymphokine-ctivted killer cells, nd three received oc-ifn. The medin intervl until strt of the IL-6 tretment ws 8 (rnge 3-32) months. Two ptients hd prtil remission, wheres none of the others responded. Tumour responses The responses to rhil-6 tretment re given in Tle II. In the group tht hd hd previous immunotherpy, 1 out of 12 ptients were evlule for response. There were no minor, prtil or complete responses oserved. Stle disese ws noted in five ptients. Of the five ptients who hd stle Tle I Ptient chrcterisitcs P-vlue I II I vs II Numer of ptients Age (yers) 59± NS Sex (mle/femle) 8/4 29/8 NS Time from dignosis to tretment 27 ± NS (months) Tumour sttus (stle/progressive) 5/4 11/15 NS Performnce (/1) 5/7 21/16 NS Metsttic sites Lung 8 25 NS Bone 1 7 NS Other 7 15 NS Nephrectomy 6 24 NS Previous rdiotherpy 5 1 NS Previous chemotherpy 2 8 NS Dt not ville for ll ptients. Totl numer my exceed numer of ptients owing to multiple metsttic sites in some ptients. NS, not significnt.

3 Tle II Tumour response fter 6 weeks of rhil-6 tretment in ptients with (I) nd without (II) prior immunotherpy I II Complete remission - - Prtil remission - 2 Stle disese 5 12 Progressive disese 5 16 disese t entry, three remined stle. Two of the four ptients with progressive disese t entry hd stle disese t the end of the tretment. In the group without prior immunotherpy, two prtil responses were noted. One prtil response occurred in 66 yer-old mle with pulmonry nd liver metstses tht progressed on chemotherpy with fluorodeoxyuridine, dministered until 2 months efore rhil-6 tretment. A rdicl nephrectomy hd een performed 36 months efore. The ptient noticed considerle improvement in well-eing while on rhil-6 tretment. At the end of the 6 week rhil-6 tretment course n pproximtely 6% tumour reduction ws noted, with further reduction during the next 1 weeks (totl tumour reduction 8%). A second 6 week rhil-6 tretment, initited 4 months lter ecuse of recurrent disese, unfortuntely filed to reinduce remission. The other prtil response ws oserved in 65-yer-old mle who underwent rdicl nephrectomy 36 months efore, nd who hd pr-ortic lymph node metstses tht were progressive t study entry. After 6 weeks of rhil-6 tretment stle disese ws noted. Three months lter, without ny susequent tretment, prtil remission ws found on the sis of 55% reduction in dimeter product, tht lsted 2 months. Of the other 35 ptients in this group, 28 were evlule for tumour response; 12 hd stle disese, 16 hd progressive disese. There were no minor responses. Seven of the 11 ptients who hd stle disese t entry, remined stle. Of the 15 ptients who hd progressive disese t the strt of the rhil-6 tretment, one hd prtil response (see ove) nd four were stle throughout the tretment period. Interleukin 6 in renl cell cncer JML Stouthrd et l (63%) nd y-gt (61%). Two ptients developed hyperclcemi during rhil-6 tretment. One ptient hd rpid progression of this disese. The other ptient hd stle disese. After institution of iphosphonte therpy his plsm clcium levels normlised. Finlly, ll ptients hd locl erythem t the injection site, which susided within 48 h. All toxicity reversed within 4 weeks fter discontinution of the rhil-6 tretment. Nine ptients hd to discontinue rhil-6 tretment premturely, i.e. fter men of 31 weeks: two ptients in group I nd seven in group II. The resons for discontinuing rhil-6 tretment were ftigue, leding to semi permnent edrest, in two ptients, ccompnied y severe mentl depression in one; deteriortion of their generl condition due to tumour progression in three ptients; gross hemturi due to hemorrhge from the primry tumour in the kidney, with susequent urosepsis, in one ptient; hemipresis due to tumour progression, for which rdition therpy hd to e instituted, in one ptient; ftl cererl hemorrhge, without evidence of centrl nervous system metstses on CT scnning, ut with history of hypertension, in one ptient; lck of ility to comply with the protocol in one ptient. Hemtology nd cute phse response Figures 1 nd 2 show the time course of the hemtologicl effects of nd the cute phse response to rhil-6 tretment. Anemi ws frequently noted side-effect, necessitting lood trnsfusions in 13 ptients. Hemogloin content progressively declined during the rhil-6 dministrtion y men of pproximtely 19% (from to mmol 1-1, seline vs ndir P<.1). At week 1, i.e. 4 weeks fter discontinution of the rhil-6 tretment, * op 791 Toxicity Side-effects re summrised in Tle III. All ptients were evlule for toxicity, nd since there were no differences in side-effects etween ptients with or without previous immunotherpy, the dt of group I nd II were pooled. The min side-effects were fever (89% of the ptients), fvourly responding to cetminophen in most ptients; flu-like symptoms such s ftigue (22%), hedche (14%) nd mylgi or rthrlgi (12%); nuse (37%); weight loss (37%); nd heptotoxicity, s indicted y increses in AF cn CO 1) -J 7' * Tle HI Toxicity, ccording to NCIC criteri, during rhil-6 tretment. No grde 4 toxicity ws oserved NCIC grde Fever Anemi taf ty-gt Nuse Vomiting Weight loss 17 1 Ftigue Hedche Mylgi/rthrlgi 5 1 Dizziness Mentl depression Stomtitis 3 Dirrhoe Co ) 4 - E 3 L.,)A ZIuu r IL-6 tretment Weeks Figure 1 Chnges in leucocyte () nd thromocyte () counts (in 191-1) (men + s.e.m.) during nd fter rhil-6 tretment. *P<.5 vs seline vlue. I 1

4 Interleukin 6 in renl cell cncer 9 JML Stouthrd et l r- l c ) ). IL r- s ~ OS ~~~~~~mm X SD n= 14. PD n= E 5 ) 15 co 3 25 Lr L. E~ 1 CL c5 5 Weeks Figure 2 Chnges in firinogen () nd (men + s.e.m.) during nd fter rhil-6 seline vlue. CRP () concentrtions tretment. *P<.5 vs men hemogloin content in ptients who did not receive lood trnsfusion ws still lower thn the seline vlue. Administrtion of rhil-6 led to significnt increse in leucocyte count (from x 19 I` t seline to x t week 3, P<.1) (Figure 1), without mjor chnges in differentil counts. A grdul increse of the thromocyte count, reching plteu fter 3 weeks (from to x191-; seline vs week 3, P<.1) ws oserved (Figure 1). At week 1 the thromocyte count ws not different from seline. RhIL-6 lso induced n cute phse response, s indicted y increses in CRP (from 28+5 mg 1-' t seline to mg l-' t week 2, P<.1) nd firinogen (from mg l-' to mg l-l t week 2, P<.1) (Figure 2). ESR incresed prllel to the increses in firinogen (from 47+5mmh - to 15+3mmh t week 2, P<.1). At week 1 CRP nd firinogen concentrtion, ut not ESR, hd returned to seline vlues. IL-6 concentrtions nd immunogenecity Pretretment smples for determintion of IL-6 concentrtions nd pre- nd post-tretment smples for determintion of nti-il-6 ntiodies were received from 41 sujects. At seline the IL-6 concentrtions were elow the detection limit in 17 sujects. Figure 3 shows the individul seline IL-6 concentrtions of the ptients whose tumour sttus t entry ws known. Furthermore, seline IL-6 concentrtions in reltion to tumour response re given. From these dt it cn e concluded tht there ws no sttisticlly significnt difference in IL-6 concentrtions etween those who hd stle or progressive disese t entry, or etween those who did or did not respond to rhil-6 tretment. 1 PR n = 2 P SD n = 16 PD n = 21 Figure 3 Bseline plsm IL-6 concentrtions expressed s function of tumour sttus t study entry () or s function of the response to rhil-6 tretment (). Dotted line indictes detection level of the IL-6 ssy t 3 pgml-1. Anti-IL-6 ntiodies were detected in five ptients in group I nd in 1 ptient in group II. On quntittive nlysis, the nti-il-6 ntiody titres vried from 1:1 to 1:3. Of these ptients, three hd stle disese fter rhil-6 tretment, nd three hd progressive disese. Neutrlising ntiodies were only detectle in the one ptient with nti-il-6 ntiodies in group II. This ptient hd pulmonry metstses tht were stle t study entry, nd his disese progressed during rhil-6 tretment. Discussion This phse II tril investigted the nti-tumour effects of interleukin 6 in metsttic renl cell cncer. Two prtil remissions were noted. Spontneous tumour regression in metsttic renl cell crcinom, especilly shortly fter surgicl removl of the primry tumour, hs een oserved in less thn 1% of ll ptients (Mrston et l., 1989). However, since neither of these two ptients underwent recent nephrectomy, the inhiition of tumour growth my hve een the consequence of the rhil-6 dministrtion. Antitumour effects of IL-6 in experimentl studies my e either direct (Chen et l., 1988) or medited y enhncing cytotoxic T-lymphocytes (Mule et l., 1992; Porgdor et l., 1992) or y other s yet undefined routes. A non-direct nti-tumour effect in our ptients seems more likely, given the perpetution of tumour reduction fter completion of the rhil-6 tretment. This ltency is in ccordnce with previous findings in ptients with renl cell cncer who responded to other immunotherpy (Wirth, 1993). Toxicity, hemtologicl nd iochemicl chnges induced y the sucutneous rhil-6 tretment were lrgely comprle with tht previously reported in humns (Vn Gmeren et l., 1994; Weer et l., 1993). In these previous studies rhil-6 ws dministered during mximum of 7 consecutive dys. Prolonging the tretment period to 42 dys, s in our

5 study, reveled no tchyphylxis for the min side-effects nd lortory chnges, s ws previously documented in niml studies with other cytokines (Tkhshi et l., 1991). Since toxicity ws tolerle without requiring hospitlistion in the mjority of ptients, we conclude tht rhil-6 cn e sfely dministered on n outptient sis. Anti-IL-6 ntiodies during or fter rhil-6 tretment were detected in 15% ofthe ptients. Hlfof these ptients hd stle disese fter rhil-6 tretment, the other hlfprogressive disese. Neutrlising ntiodies were detected in only one ptient. It is therefore concluded tht our results were not ffected y the interference of ntiodies ginst the rhil-6 used. This study ws initited fter oserving tumour response of pulmonry metstses in ptient with renl cell crcinom fter rhil-6 tretment. The role of IL-6 in renl cell crcinom, however, is complex. Prneoplstic symptoms, such s cchexi, fever, elevted erythrocyte sedimenttion rte nd nemi, commonly oserved in renl cell cncer (Wirth, 1993), hve een linked to the presence of elevted plsm concentrtions of IL-6 in these ptients (Bly et l., 1992; Tsukmoto et l., 1992). As source of IL-6 the renl crcinom itself could e ppointed, since oth norml (Gogusev et l., 1993) nd mlignnt renl cells (Tsukmoto et l., 1992; Gogusev et l., 1993) hve een shown to produce nd relese IL-6. Moreover, in vitro dt indicte hml*"i 6 in.ii cd cncer A& Stoutfwd et im tht IL-6 my ct s n utocrine growth fctor in these tumours (Miki et l., 1989; Gruss et l., 1991; Koo et l., 1992). On the other hnd, IL-6 is not n independent predictor of survivl s would e predicted if it were cliniclly importnt utocrine growth fctor (Stdler et l., 1992). In our ptient popultion neither endogenous seline IL-6 concentrtions nor the exogenous IL-6 dministrtion could e relted to tumour ehviour. In two previous, preliminry reports 5-dy continuous infusion of 15-fold higher dosge of rhil-6 (n= 12), or 14 dy course of s.c. rhil-6 dministrtion (n =1) in ptients with metsttic renl cell cncer resulted in no ojective responses (Rvoet et l., 1994; Weiss et l., 1994). We oserved prtil remission in only 2 out of 49 (4%) ptients. The ptient chrcteristics of the responders in our study were not discernile from those of the non-responders. Therefore, t present rhil-6 given s dily s.c. injection for 6 weeks cnnot e dvocted s tretment modlity for metsttic renl cell crcinom. Our dt further indicte, however, tht prolonged tretment with rhil-6 cn e performed sfely on n outptient sis nd is ssocited with moderte, reversile toxicity. Finlly, continuous rhil-6 dministrtion is ccompnied y the development of nonneutrlising nti-il-6 ntiodies in only minority of ptients. 7Q-A References BLAY J-Y, NEGRIER S, COMBARET V, ATTALI S, GOILLOT E, MERROUCHE Y, MERCATELLO A, RAVOULT A AND TOURANI JM. (1992). 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