Adap­tive De­sign Meth­ods Of­fer Rapid, Seam­less Tran­si­tion Be­tween Study Phas­es in Rare Can­cer Tri­als

Rare can­cers ac­count for 22 per­cent of can­cer di­ag­noses world­wide, yet there is no uni­ver­sal­ly ac­cept­ed de­f­i­n­i­tion for a “rare” can­cer. More­over, with the evo­lu­tion of ge­nomics and as­so­ci­at­ed changes in cat­e­go­riz­ing tu­mors, some com­mon can­cers are now char­ac­ter­ized in­to groups of rare can­cers, each with a unique im­pli­ca­tion for pa­tient man­age­ment and ther­a­py.

Adap­tive de­signs, which al­low for prospec­tive­ly planned mod­i­fi­ca­tions to study de­sign based on ac­cu­mu­lat­ing da­ta from sub­jects in the tri­al, can be used to op­ti­mize rare on­col­o­gy tri­als (see Fig­ure 1). Adap­tive de­sign stud­ies may in­clude mul­ti­ple co­horts and mul­ti­ple tu­mor types. In ad­di­tion, nu­mer­ous adap­ta­tion meth­ods may be used in a sin­gle tri­al and may fa­cil­i­tate a more rapid, seam­less tran­si­tion be­tween study phas­es.

Fig­ure 1. Com­mon adap­tive de­signs for rare on­col­o­gy tri­als

Um­brel­la and bas­ket de­signs are ex­am­ples of mas­ter pro­to­cols that uti­lize ge­nom­ic test­ing to op­er­ate mul­ti­ple pan­el stud­ies un­der one over­ar­ch­ing pro­to­col, which in­creas­es ef­fi­cien­cy and flex­i­bil­i­ty.

Us­ing bio­mark­ers in on­col­o­gy clin­i­cal tri­als

The use of bio­mark­ers in on­col­o­gy clin­i­cal tri­als, par­tic­u­lar­ly for pa­tient se­lec­tion and mon­i­tor­ing of treat­ment re­sponse, has in­creased dra­mat­i­cal­ly over the past five years. Sig­nif­i­cant­ly, re­search has shown that stud­ies that use bio­mark­ers for pa­tient se­lec­tion are not on­ly more like­ly to pro­ceed to the next stage of de­vel­op­ment but al­so more like­ly to ob­tain mar­ket ap­proval (see Fig­ure 2).

Fig­ure 2. On­col­o­gy tri­al suc­cess with or with­out bio­mark­er1

Bio­mark­er test­ing method­olo­gies range from sim­ple tests that de­tect sin­gle mu­ta­tions to com­plex ones that can de­tect a va­ri­ety of gene al­ter­ations, in­clud­ing sub­sti­tu­tions, dele­tions, du­pli­ca­tions, and struc­ture vari­ance. In this uni­verse of test­ing, next-gen­er­a­tion se­quenc­ing (NGS) has been a game-chang­er. NGS en­ables the si­mul­ta­ne­ous analy­sis of a broad spec­trum of ge­nom­ic al­ter­ations. This tech­nol­o­gy can be ap­plied to a pre-spec­i­fied group of genes or gene pan­els, a whole ex­ome, or even the whole genome. Cou­pled with dra­mat­ic de­creas­es in the cost of se­quenc­ing and ef­fi­cien­cies in time- and tis­sue-sav­ing, NGS analy­sis rep­re­sents a par­a­digm shift that is dri­ving both bio­mark­er dis­cov­ery and tar­get­ed drug de­vel­op­ment.

Im­por­tant­ly, the vol­ume of da­ta gen­er­at­ed by NGS has made the in­ter­pre­ta­tion of ge­nom­ic da­ta more crit­i­cal than ever. Giv­en that not all ge­nom­ic in­for­ma­tion from NGS is clin­i­cal­ly rel­e­vant, it is im­por­tant to sift through the “noise” to as­sess the clin­i­cal sig­nif­i­cance of this da­ta. To help in the in­ter­pre­ta­tion of ge­nom­ic da­ta, some or­ga­ni­za­tions have cre­at­ed pre­ci­sion med­i­cine de­ci­sion teams or mol­e­c­u­lar tu­mor boards. There are al­so in­creas­ing num­bers of on­line ge­nom­ic knowl­edge bases, al­though knowl­edge in rare can­cer types is still dis­parate.

Liq­uid biop­sies are al­so emerg­ing as im­por­tant bio­mark­er tools. Liq­uid biop­sies — which may be blood, plas­ma, or oth­er body flu­ids — ad­dress some of the chal­lenges as­so­ci­at­ed with tis­sue biop­sies, in­clud­ing avail­abil­i­ty of tis­sue, in­va­sive­ness, and abil­i­ty to per­form re­peat or mul­ti­ple as­sess­ments. With liq­uid biop­sies, it is pos­si­ble to per­form cost-ef­fec­tive se­r­i­al sam­pling, to pro­vide dy­nam­ic and lon­gi­tu­di­nal as­sess­ment, and to per­form down­stream analy­sis of tu­mor mar­kets for greater in­sight in­to the ge­nom­ic land­scape.

On Au­gust 7, 2020, Guardant360 re­ceived FDA ap­proval for the first com­pan­ion di­ag­nos­tic to com­bine NGS and liq­uid biop­sy to iden­ti­fy pa­tients with spe­cif­ic epi­der­mal growth fac­tor re­cep­tor gene mu­ta­tions in metasta­t­ic non-small cell lung can­cer.

Em­pow­er­ing pa­tient in­volve­ment

Rare dis­eases re­quire strong pa­tient ad­vo­ca­cy and en­gage­ment. In the ear­ly 2000s, ima­tinib was a his­toric il­lus­tra­tion of the pow­er of the in­ter­net, and the in­flu­ence pa­tient ac­tivism can have on drug de­vel­op­ment. News of re­mis­sion with ima­tinib treat­ment in a Phase 1 tri­al led to a pa­tient-dri­ven in­crease in clin­i­cal tri­al par­tic­i­pa­tion, which even­tu­al­ly led to a Phase 2 tri­al and sub­se­quent ap­provals.

To­day, tech­nol­o­gy has in­creased pa­tient in­volve­ment by sev­er­al or­ders of mag­ni­tude. So­cial me­dia plat­forms such as Face­book and Twit­ter en­able vir­tu­al pa­tient knowl­edge-shar­ing on a large scale. There are Face­book groups for a ma­jor­i­ty of rare can­cer types, many of which in­clude more than 1,000 mem­bers. There are al­so non­prof­it or­ga­ni­za­tions such as Count Me In, which bring pa­tients and re­searchers to­geth­er to ac­cel­er­ate dis­cov­ery and sup­port the de­vel­op­ment of new treat­ment strate­gies.

Key take­aways

The field of on­col­o­gy has changed dra­mat­i­cal­ly over the last two decades. The con­flu­ence of new tech­nol­o­gy to iden­ti­fy rare can­cers, flex­i­ble tri­al de­signs, evolv­ing reg­u­la­to­ry process­es, and in­creased pa­tient ac­tivism is ad­vanc­ing our un­der­stand­ing of can­cer and ac­cel­er­at­ing the dis­cov­ery of nov­el ther­a­pies. Pre­mier Re­search of­fers a full spec­trum of clin­i­cal re­search, de­vel­op­ment, and con­sult­ing ser­vices to help you op­ti­mize your rare on­col­o­gy drug de­vel­op­ment. To sched­ule a con­ver­sa­tion with one of our ex­perts, click here.


1Adapt­ed from Wong CH, Siah KW, Lo AW. Es­ti­ma­tion of clin­i­cal tri­al suc­cess rates and re­lat­ed pa­ra­me­ters. Bio­sta­tis­tics 2019;20(2):273-286.

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