Be­yond tra­di­tion: re­defin­ing FIH on­col­o­gy small mol­e­cule tri­als with healthy vol­un­teers

First-in-hu­man (FIH) Phase I stud­ies are de­signed to es­tab­lish ear­ly safe­ty and tol­er­a­bil­i­ty pro­files of an In­ves­ti­ga­tion­al Med­i­c­i­nal Prod­uct (IMP), with the ma­jor­i­ty of Phase I tri­als con­duct­ed in healthy vol­un­teers. But on­col­o­gy FIH stud­ies typ­i­cal­ly en­roll pa­tients with can­cer, for whom there is no oth­er ther­a­peu­tic op­tion.

Are you ready to con­sid­er an al­ter­na­tive ap­proach to your on­col­o­gy study? The use of healthy vol­un­teers in FIH tri­als with on­col­o­gy small mol­e­cules may ex­pe­dite clin­i­cal de­vel­op­ment and ul­ti­mate­ly ben­e­fit pa­tients.

Fortrea has been nav­i­gat­ing the in­tri­ca­cies of FIH tri­als, backed by a 30-year her­itage as part of Co­v­ance and Lab­corp Drug De­vel­op­ment. With an ex­ten­sive on­col­o­gy port­fo­lio – and a team of about 60 on­col­o­gists – we’ve col­lab­o­rat­ed with our spon­sors to in­ves­ti­gate the pros and cons of in­clud­ing healthy vol­un­teers in on­col­o­gy stud­ies. Here’s what we’ve found:

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What con­di­tions de­ter­mine whether FIH on­col­o­gy can start in HVs or can­cer pa­tients?

De­cid­ing whether healthy vol­un­teers or can­cer pa­tients are most suit­able for an on­col­o­gy FIH tri­al is a com­plex process. It in­volves weigh­ing tox­i­col­o­gy find­ings, a phar­ma­co­ki­net­ics/phar­ma­co­dy­nam­ic pro­file, the mech­a­nism of ac­tion, plus the cost and time re­quire­ments.

For ex­am­ple, a drug with ge­net­ic or epi­ge­net­ic tar­get would not be ap­proved by the reg­u­la­tors to be dosed in healthy vol­un­teers. Sim­i­lar­ly, a drug with re­port­ed ir­re­versible tox­i­col­o­gy or ad­verse ef­fects that can­not be read­i­ly mon­i­tored in the clin­ic, or com­pounds that must be ad­min­is­tered would not be ac­cept­able for healthy vol­un­teers.

In fact, the de­ci­sion will be aligned by reg­u­la­to­ry ad­vice and re­quire­ments. For ex­am­ple, there are key reg­u­la­to­ry dif­fer­ences in how FIH tri­als are con­duct­ed when us­ing healthy vol­un­teers or can­cer pa­tients based on da­ta gath­ered from ear­li­er pre­clin­i­cal work in an­i­mal mod­els through to the Phase I tri­al in hu­mans. In par­tic­u­lar, the clin­i­cal process is high­ly de­pen­dent on the ear­li­er stud­ies, and as­pects like cal­cu­lat­ing start­ing clin­i­cal dos­es from ear­li­er an­i­mal mod­el da­ta dif­fer strong­ly be­tween pa­tients and healthy vol­un­teers.

Pa­tient par­tic­i­pat­ing in a phase I tri­al

Ad­van­tages of healthy vol­un­teer re­cruit­ment:

1. Rapid sub­ject ac­cru­al: It’s much quick­er and eas­i­er to re­cruit healthy vol­un­teers in the ear­ly start­up of the pro­gram, takes less time com­pared to pa­tients and dose es­ca­la­tion can pro­ceed more rapid­ly. This can speed up the over­all progress of the Phase 1 tri­al and ul­ti­mate­ly the en­tire clin­i­cal de­vel­op­ment pro­gram. This ef­fi­cien­cy can al­so help re­duce tri­al costs.
2. Ac­cel­er­at­ed time­lines of the clin­i­cal de­vel­op­ment pro­gram: In healthy vol­un­teers, the min­i­mum da­ta re­quired for dose es­ca­la­tion re­view are de­ter­mined on the half-life of the com­pound, which can be rel­a­tive­ly short for small mol­e­cules. In con­trast, dose es­ca­la­tion for tri­als with can­cer pa­tients re­quires a re­view of the safe­ty da­ta from all pa­tients of the co­hort up to the com­ple­tion of the last day of cy­cle 1 to de­ter­mine whether a dose-lim­it­ing tox­i­c­i­ty was en­coun­tered plus the re­view of the phar­ma­co­ki­net­ic and phar­ma­co­dy­nam­ic avail­able da­ta. Each co­hort cy­cle can last up to three to four weeks in tri­als with can­cer pa­tients, mean­ing that the safe­ty re­view process can slow down the clin­i­cal de­vel­op­ment pro­gram.
3. Lim­it un­nec­es­sary ex­po­sure of can­cer pa­tients to low, sub­ther­a­peu­tic dos­es: Dur­ing ear­ly dose es­ca­la­tion, can­cer pa­tients will re­ceive sub­ther­a­peu­tic dos­es, which may pose eth­i­cal con­cerns at the ear­ly first dos­es. In con­trast, ad­min­is­ter­ing sub­ther­a­peu­tic dos­es with on­col­o­gy drugs to healthy vol­un­teers if the non­clin­i­cal pack­age al­lows, is per­mis­si­ble, mean­ing that can­cer pa­tients can be al­lo­cat­ed to high­er dos­es, which may of­fer in­creas­ing ben­e­fit to them.
4. Eval­u­a­tion of the safe­ty and PK pro­file in the ab­sence of co­mor­bid con­di­tions and con­comi­tant med­ica­tions: When test­ing in can­cer pa­tients, the safe­ty and PK/PD pro­file of the drug might be af­fect­ed by fac­tors such as co­mor­bidi­ties and in­ter­ac­tions with drugs that the pa­tient is tak­ing. While these da­ta are im­por­tant for fu­ture stages of the tri­al, it might in­tro­duce con­found­ing fac­tors when eval­u­at­ing the safe­ty of the ther­a­peu­tic in hu­mans for the first time.
5. In­te­gra­tion of sin­gle-dose clin­i­cal stud­ies: Test­ing in hu­man vol­un­teers al­so al­lows ear­ly as­sess­ment of as­pects like food-ef­fect, drug-drug in­ter­ac­tions as well as im­pact of the age, gen­der and eth­nic­i­ty on the PK of the drug. It can be eas­i­er to test these in­ter­ac­tions in healthy vol­un­teers than in can­cer pa­tients due to po­ten­tial con­found­ing fac­tors such as drug-drug in­ter­ac­tions. These da­ta can help guide dose ad­just­ment and dos­ing reg­i­men in larg­er-scale fu­ture tri­als.

Dis­ad­van­tages of healthy vol­un­teer re­cruit­ment:

1. Ab­sence of pathol­o­gy in the healthy tis­sue: Ob­vi­ous­ly, the drug tar­get in the tu­mor is not present in most healthy tis­sue; there­fore, PD and ef­fi­ca­cy can­not be mon­i­tored at the first dose lev­els. Test­ing in healthy vol­un­teers can thus pro­vide on­ly an in­di­ca­tion of ef­fec­tive­ness in can­cer pa­tients for some drugs if the tar­get is present. So, the ad­van­tage of in­clud­ing can­cer pa­tients is that tu­mor biop­sies can be tak­en to mon­i­tor PD ef­fects, how­ev­er this is a sub­stan­tial bur­den and risk to pa­tients so biop­sies sam­pling should be lim­it­ed.
2. Un­cer­tain­ty about trans­lata­bil­i­ty of PK and PD find­ings to can­cer pa­tients: There could al­so be dif­fer­ences in the PK pro­file of a small mol­e­cule drug in can­cer pa­tients ver­sus healthy vol­un­teers, which large­ly de­pends on the dif­fer­ent ex­pres­sion lev­els of the drug tar­get in healthy and tu­mor tis­sue un­der­ly­ing med­ical con­di­tions in can­cer pa­tients. For ex­am­ple, many can­cer pa­tients might have al­tered he­pat­ic meta­bol­ic func­tion due to liv­er ma­lig­nan­cies or he­pa­to­tox­i­c­i­ty from pre­vi­ous­ly ad­min­is­tered chemother­a­pies. (e.g., the an­timetabo­lite flu­o­rodeoxyuri­dine). As such, the liv­er me­tab­o­lism of the drug and ac­tive metabo­lites might dif­fer be­tween healthy vol­un­teers and can­cer pa­tients. Thus, dose ad­just­ments in the pa­tient pop­u­la­tion might be need­ed for drugs test­ed in healthy vol­un­teers, con­sid­er­ing side ef­fects and ef­fi­ca­cy vari­abil­i­ty in can­cer pa­tients.
3. Risk of un­ex­pect­ed se­ri­ous side ef­fects, which may lead to life-threat­en­ing or long-term ad­verse ef­fects: As with any oth­er new in­ves­ti­ga­tion­al drug, some on­col­o­gy small mol­e­cule drugs have ad­verse tox­i­col­o­gy ef­fects that are too risky and po­ten­tial­ly life-threat­en­ing for test­ing on healthy vol­un­teers. For healthy vol­un­teers who stand to gain no ben­e­fit from the treat­ment, the thresh­old of ac­cept­able risk is low­er than it is for can­cer pa­tients. Dosage es­ca­la­tion and test­ing will there­fore be less ex­ten­sive than in can­cer pa­tients.

Weigh­ing the de­ci­sion

Ul­ti­mate­ly, the choice of whether to start an FIH clin­i­cal tri­al for on­col­o­gy small mol­e­cule drugs in healthy vol­un­teers or can­cer pa­tients de­pends on a wide range of as­pects, but the pre­clin­i­cal pack­age and the mech­a­nism of ac­tion are the key de­ci­sion dri­vers. Each study must be judged on a case-by-case ba­sis, as no “one size fits all” ap­proach ex­ists to de­fine healthy vol­un­teers as a pop­u­la­tion for a FIH on­col­o­gy tri­al. Ben­e­fits and risks need to be bal­anced and all the stake­hold­ers in­volved (spon­sor, reg­u­la­tors, in­ves­ti­ga­tors, even CROs) must de­ter­mine the most ap­pro­pri­ate ap­proach.

Ready to ex­plore this op­tion? With more than 1,200 on­col­o­gy tri­als in the last five years (al­most 600 of which were ei­ther Phase I or Phase I-II), our team at Fortrea is a col­lab­o­ra­tive, ex­pe­ri­enced part­ner for your FIH stud­ies.

LEARN MORE at fortrea.com

AU­THOR IN­FOR­MA­TION

Be­goña de las Heras, MD
Be­goña de las Heras, MD, is Se­nior Med­ical Di­rec­tor in On­col­o­gy based in Madrid, Spain. Dr. de las Heras has more than 23 years of na­tion­al and in­ter­na­tion­al clin­i­cal/clin­i­cal re­search on­col­o­gy ex­pe­ri­ence in­clud­ing the phar­ma­ceu­ti­cal and CRO in­dus­try, fo­cused on plan­ning and ex­e­cu­tion of glob­al on­col­o­gy clin­i­cal de­vel­op­ment from FIH to reg­is­tra­tion. Dr. de las Heras’ main area of ex­per­tise is the de­vel­op­ment of ear­ly phase on­col­o­gy pro­grams. She has pro­vid­ed sig­nif­i­cant con­tri­bu­tion to INDs, or­phan drug ap­pli­ca­tions and one NDA sub­mis­sion. She has au­thored/co-au­thored mul­ti­ple pa­pers and book chap­ters in on­col­o­gy and is named as in­ven­tor of two patent ap­pli­ca­tions. Dr. de las Heras earned her med­ical de­gree from the Uni­ver­si­ty Au­tono­ma of Madrid and com­plet­ed her on­col­o­gy res­i­dence at La Paz Hos­pi­tal in Madrid.