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The clinical evaluation of BRM agents
Cancer 7)eatment Reviewz (1980) 7, 235-238
The clinical evaluation
of BRM agents
S t e p h e n K. C a r t e r Director, JVorlhern California Cancer Program, p . o . Box 10144, Palo Alto, Cal~ornia 94304, U.S.A.
T i l e clinical e w d u a t i o n o f B k M a g e n t s will r e q u i r e a s t r a t e g y w h i c h involves P h a s e I, II a n d I l l testing m o d i f i e d from the classic a p p r o a c h e s d e v e l o p e d for c a n c e r c h e m o t h e r a p y . F a i l u r e to e v o l v e a clinical e v a l u a t i o n s t r a t e g y for B R . M a g e n t s r u n s the risk o f failing to test effectively these i m p o r t a n t n e w agents. W h e n used for c a n c e r c h e m o t h e r a p y the t h r e e p h a s e s o f clinical trial c a n b e d e s c r i b e d
as (1): P h a s e I: Clinical p h a r m a c o l o g y , P h a s e l I : Efficacy screen, Phase I I I : Role delineations.
Phase I study T h e e n d p o i n t s for a P h a s e 1 s t u d y w i t h a c y t o t o x l c d r u g a r e e l u c i d a t i o n o f the m a x i m a l l y t o l e r a t e d dose ( M T D ) a n d tile p a r a m e t e r s o f toxicity. I n a d d i t i o n a P h a s e I trial is a t h e r a p e u t i c i n t e n t trial a l t h o u g h l]ailure to o b s e r v e clinical efficacy is n o t c o n s i d e r e d a c o n t r a i n d l c a t i o n to the h~titiatlon o f P h a s e I I s t u d y . W i t h a BRtk4 a g e n t it m a y well b e t r u e t h a t t h e M T D m a y n o t b e t h e o p t i m a l d o s e tbr a c h i e v i n g t h e h o p e d for t h e r a p e u t i c gain. Dc.~pite this it w o u l d a p p e a r to b e p r u d e n t to establish the M T D so as to u l t i m a t e l y relate t h e m a x i m a l l y effective close to t h e dose r e s p o n s e effect for toxicity. It m u s t be a s s u m e d t h a t t h e r e w~ll be a d o s e level w h i c h will a c h i e v e o p t i m a l m o d i f i c a t i o n o f host b i o l o g i c r e s p o n s e to the t u m o r . T h i s c o u l d b e called the m a x i m a l l y effective d o s e ( M E D ) . D e p e n d i n g u p o n t h e toxicity p o t e n t i a l o f the B R M a g e n t a n d its m e c h a n i s m o f a c t i o n it m a y b e t h a t t h e M E D a n d M T D will b e identical as it is tbr m o s t e h e n l o t h e r a p e u t i c agents, T h i s c o u l d occ~ar for o n e o f t w o basic reasons. T h e first w o u l d b e if the toxicity o c c u r s at r e l a t i v e l y t o w dose levels b e f o r e the a b s o l u t e M E D c a n b e r e a c h e d . T h e s e c o n d r e a s o n , w h i c h is r e l a t e d , w o u l d b e if t h e r e is a v e r y w i d e d o s e - r e s p o n s e effect w h i c h e x t e n d s u p to v e r y high doses. I t is h a r d 0305-7372/80/040235 + 0,t 802.00]0
~ 1980 Academic Press Inc. (London) Ltd. 235
236
,S. 1,2. t:..\RTI:;R
to i m a g i n e t h a t a n y biohJgicalty activt: l:mterial w o u l d n~t c a u s e c[llzcts o n n o r m a l celJs ;tt sorne dose level. 'l'he initial dose level for a Phase l s t u d y o f a c y t o t o x i c d r u g is dr:rived |i'mit a n i n t a l studies (2). S o m e fi'action ~ f the m i n i m a l l y toxic dose in a l a r g e a n i m a l o r tht: IA)10 in a r ~ d e n t will be used. "l'he o b j e c t i v e o f tttis is to initiate the trial at a n o n - t o x i c dose. W i t h a BI;', M the initial dose will also h a v e b e e n c l m s c n ti'om a n i m a l studies. If the d r u g is s h o w n to be n o n - t o x i c in aninxals o v e r a r a n g e o f doses w h i c h a r e etli,'ctive a ltigtmr dose w h i c h relates to the lowest effective dose m a y be c h o s e n . S i n c e the l l u a n t i m t i v e tc~xicity predicticm li'om a n i n m l to m a n is not a b s o l u u ' l y precise, c a u t i o n s h o u l d be e x e r c i s e d in not s t a r t i n g at too h i g h a dose. i n o r d e r to d e v e l o p a c o r r e l a t i o n o f the dose-response r e l a t i m l s h i p lot a c t i v i t y b e t w e e n species it m i g h t be w o r t h w h i l e to begin w i t h the highest n o n - e f f e c t i v e d o s e in a n i m a l s if the toxicity d o s e - r e s p o n s e c u r v e will a l l o w it w i t h a r e a s o n a b l e e x p e c t a t i o n o f initial saii:ty. T h e d o s e - e s c a l a t i o n p r o c e d u r e w i t h c h e m o t h e r a p y u s u a l l y il~volves initially large steps w i t h the i n c r e m e n t s l~ccoming p r o g r e s s i v e l y smaller. T h i s is d u e to the usual steep dose---response, effi:cts seen tbr r n y e l o s u p p r c s s i v e drugs. C o n t i n u i n g to d o u b l e a dose c o u l d c a u s e at j u m p to o c c u r fi'om a m i n i m a l l y toxic dose to a lethal dose, I f the a l u m a l d o s e - r e s p o n s e curve" t~)r toxicity is s h a l l o w l)~r a BRN1, t h e n l a r g e r e s c a l a t i o n doses m a y be d e e m e d to be r e l a t i v e l y salE. T h i s w o u l d a v o i d tim risk o f a P h a s e I s t u d y t a k i n g a v e r y long t i m e b e c a u s e o f h a v i n g to test a l a r g e n u n l b e r o f dose escalatiotls. T h e e n d p o i n t s fox" a P h a s e t s t u d y o f a B R M ideally o u g h t to i n v o h , e t h e t b l l o w i n g : 1. 2. 3. 4, 5.
E l u c i d a t i o n o f t h e N I T D o n the s c h e d u l e ( s ) c h o s e n ; E l u c i d a t i o n o f t h e m i n i m a l l y toxic dose o n the s c h e d u l e ( s ) c h o s e n ; E l u c i d a t i o n o f t h e initial d o s e level at w h i c h e v i d e n c e o f biologic effimt is o b s e r v e d ; E h m i d a t i o n o f the close level(s) at w h i c h o p t i m a l biologic efli:cts is (are) o b s e r v e d ; E l u c i d a t i o n o f t h e toxicity p a r a m e t e r s a n d d e t e r m i n a t i o n if t h e y a r e p r e d i c t a b l e and treatable ; 6. R e c o m m e n d a t i o n o f a d o s a g e s c h e d u l e for Phase I I s t u d y .
Phase ii study T h e P h a s e II s t u d y for a c h e m o t h e r a p e u t i c a g e n t is a n efficacy s c r e e n to d e t e r m i n e w h e t h e r t h e r e is e n o u g h e v i d e n c e o f a n t i t u m o r effect to w a r r a n t l a r g e - s c a l e l~'hase I I I studies. It is k n o w n t h a t the a c t i v i t y , o r lack t h e r e o t , in o n e t u m o r t y p e w i t h cytotoRie drugs will n o t p r e d i c t tbr a n o t h e r type. T h e r e f o r e a series o f disease specific P h a s e I I s t u d i e s a r e u n d e r t a k e n . I d e a l l y o n e s h o u l d d o a P h a s e I I s t u d y in e v e r y t u m o r t y p e in w h i c h it is t h o u g h t t h e n e w d r u g m i g h t be e f f e c t i v e . T h i s is r a r e l y feasible unless a s i g n i f i c a n t a m o u n t o f a n t i t u m o r effect is observed in early Phase II trials. B e c a u s e o f this a p a n e l o f t u m o r types a r e c h o s e n for P h a s e I I s t u d y as a r e a s o n a b l e s c r e e n for a c t i v i t y . T h e a s s u m p t i o n m a d e is t h a t if t h e n e w d r u g is n e g a t i v e in t h e e n t i r e p a n e l , it is u n l i k e l y to b e a c t i v e in o t h e r t u m o r types. W i t h a B R M it m u s t b e a s s u m e d , u n t i l p r o v e n o t h e r w i s e , t h a t effectiveness will d i f f e r in d i f f e r e n t t u m o r types. T h i s m a y be c a u s e d b y a n y o n e o f the f o l l o w i n g facts: (1) d i f f e r e n t t u m o r s m a y elicit d i f f e r e n t host response; (2) d i f f e r e n t t u m o r s m a y be m o r e o r less a m e n a b l e to t h e r a p e u t i c b e n e f i t from a B R M effect; (3) d i f f e r e n t i a l t u m o r cell
burdens m a y respond differently to B R M effects; (4) p h a r m a c o l o g i c sanctuaries or
CI,INI(3AL I:;VAI,UATION OF BRlk,I ACI|'.;N't'S
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privileged sites m a y exist tbr I~R.M etR;ct. Because of this it w o u l d be p r u d e n t to design a series of disease-oriented Phase 11 studies tbr B R M agellts. "~/ith c y t o t o x i c drugs tile t h e r a p e u t i c e n d p o i n t for a Phase 1I s t u d y is objective rcgre,lsion o f tunu:,r. VChat is not k n o w n is w h e t h e r this will be feasible tbr BRiXI agel~ls. It was not d e e m e d a p p r o p r i a t e tbr i m m u n e lnodulatiiag agents such as 11C(3, (l. p a r v u m , lcvamisole, etc. It is I)cing used tbr c u r r e n t trials o f h u m a n leukocyte intert~ron. It m a y thercfi:n'c diflkr with dilli:rcnt B R M agents. I f objective regression is o b t a i n a b l e with a t~R.M, then the Phase 11 s t r a t e g y is simple; but if it is not, it will be mort: c o m p l i c a t e d . If object iw: response c a n n o t be used as an t.'ndl~oint tbr l?hase 1I study, there are two b r o a d possibilitics tbr Phase II design. O n e a p p r o a c h w o u l d be to a d d tile B R M to s l a n d a r d thcral~y a n d use as t t m . i u d g n m n t p a r a m e t e r a p r o l o n g a t i o n ot'rest)onse d u r a t i o n or surviwd. This has the d i s a d v a n t a g e o f rt:quirillg a colltrol grout~ R~r c o m p a r i s o n . \Vith iHmaunt~-modulating agents nlally groups a t t e m p t e d to use historical controls w i t h o u t a g r e a t deal o f success. It is dillicult to conlrol for all i m p o r t a n t prognostic variables a n d there arc potential ditl'c,'ences in diagnostic w o r k - u p a n d care delivery which arc very ditticult m control tbr. In a d d i t i o n e a r l y a c t u a r i a l p r o d u c t i o n m a y give one an early thlse positive, since there is a longer tbllow-up tinle tbr the historical control. I f a prospective r a n d o m i z e d control is used, then the p r o b l e m becomes the use ol'a Phase II1 naethodology to give a Phase 1I answer. In such a Phase I1. s t u d y a statisticaliy significant difference in s u r v i v a l m a y not be n e e d e d but just e n o u g h c o m p a r a b i l i t y or suggestion o f superiority to w a r r a n t a Phase 1II study. O b v i o u s l y if such a s t u d y design is used, the r u b r i c o f Phase [ I - I i t s t u d y m i g h t be the most applicable. A n o t h e r a p p r o a c h w o u l d he to look tbr only a consistent m o d u l a t i o n o f host response, which w o u l d be assurned to be intrinsically va!.uable. A r m e d with this consistency of implied biologic response i m p a c t , a p p r o p r i a t e P h a s e 1II studies c o u l d then be c o n s i d e r e d justiIiable. This a p p r o a c h has the a l t r a c l i o n ot' clinical d e c i s i o n - m a k i n g based on pre.s u m e d meclaanisnas o f action, but has the d r a w b a c k o f not a t t e m p t i n g to d e m o n s t r a t e evidence o f t r u e biologic i m p a c t prior to c o m n a i t m e n t o f large-scale clinical trial resources. l f a BR.M a g e n t ' s effect c a n only be m e a s u r e d b y a positive inlluence on survival this s t r a t e g y m a y be the only one it is fe.asible to c o n t e m p l a t e . I f the Phase 11 c o n c e p t fbr a B R M is indirecl m e a s u r e m e n t ot" host response t h r o u g h some l a b o r a t o r y or clinical e x a m i n a t i o n , then a c o n t r o l l e d design seems to be essential. \,Vhat has been s h o w n with m e a s u r e m e n t o f i m m u n e reactivity, such as skin lests, l y m p h o c y t e btastogenesis assays, etc., is a high d e g r e e of intrinsic biologic variability. A d o u b l e - b l i n d s t u d y at: the N/[ayo Clinic o f two do.~e levels o f m e t h a n o l ex~k~action residue of BGO (N'IER) with placebo r e v e a l e d C o m p a r a b l e e n h a n c e d irnmum%logic~"' r e a c t i v i t y with both d r n g a n d plncebo (.'3). S u c h c o u l d be the case wilh a BRg'I. A Phase II design could involve a doul)le-l~lind e v a l u a t i o n of the B R M a n d a p l a c e b o with the e u d p o i n t b e i n g i m p a c t on a g r o u p o f clinical a n d l a b o r a t o r y assays p r e s u m e d to be indications o f m o d u l a t e d host biologic response to the ttnnor, l f a d i f f e r e n c e t h a t Favored the B R M was o b s e r v e d large-scale a d j u v a n t or Phase I I I trials w o u l d be justified. This w o u l d involve a Phase I1 s t u d y that was both m o r e c o m p l e x in design a n d m o r e expensive t h a n a classic Phase I I s t u d y with a cytotoxic c o m p o u n d , q.?his w o u l d be w o r t h w h i l e , however, if it c o u l d efl]zctively screen for the potential v a l u e o f a l o n g - t e r m a n d highly expensive a d j u v a n t trial. In addition, the P h a s e I I c o n c e p t Should be flexible e n o u g h to e n c o m p a s s a wMe r a n g e of biological materials.
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References 1. Carter, S, K. (1977) Clinical trials in cancer chemotherapy. Cancer 40: 554-557. 2. Goldsmith, M. A., Slavik, M. & Carter, S. K. (1975) Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res. 35: 1354-1364. 3. O'ConneIl, M . J . , Moertel, C.J., Rifts, R. E.,Jr., Frytak, S. & Reitemeir, R . J . (1979) A comparative clinical and immunological assessment of methanol extraction residue of Bacillus Calmette-Guerin vs. placebo in patients with advanced cancer. Cancer Res. 39: 3720-3724.
The clinical evaluation
of BRM agents
S t e p h e n K. C a r t e r Director, JVorlhern California Cancer Program, p . o . Box 10144, Palo Alto, Cal~ornia 94304, U.S.A.
T i l e clinical e w d u a t i o n o f B k M a g e n t s will r e q u i r e a s t r a t e g y w h i c h involves P h a s e I, II a n d I l l testing m o d i f i e d from the classic a p p r o a c h e s d e v e l o p e d for c a n c e r c h e m o t h e r a p y . F a i l u r e to e v o l v e a clinical e v a l u a t i o n s t r a t e g y for B R . M a g e n t s r u n s the risk o f failing to test effectively these i m p o r t a n t n e w agents. W h e n used for c a n c e r c h e m o t h e r a p y the t h r e e p h a s e s o f clinical trial c a n b e d e s c r i b e d
as (1): P h a s e I: Clinical p h a r m a c o l o g y , P h a s e l I : Efficacy screen, Phase I I I : Role delineations.
Phase I study T h e e n d p o i n t s for a P h a s e 1 s t u d y w i t h a c y t o t o x l c d r u g a r e e l u c i d a t i o n o f the m a x i m a l l y t o l e r a t e d dose ( M T D ) a n d tile p a r a m e t e r s o f toxicity. I n a d d i t i o n a P h a s e I trial is a t h e r a p e u t i c i n t e n t trial a l t h o u g h l]ailure to o b s e r v e clinical efficacy is n o t c o n s i d e r e d a c o n t r a i n d l c a t i o n to the h~titiatlon o f P h a s e I I s t u d y . W i t h a BRtk4 a g e n t it m a y well b e t r u e t h a t t h e M T D m a y n o t b e t h e o p t i m a l d o s e tbr a c h i e v i n g t h e h o p e d for t h e r a p e u t i c gain. Dc.~pite this it w o u l d a p p e a r to b e p r u d e n t to establish the M T D so as to u l t i m a t e l y relate t h e m a x i m a l l y effective close to t h e dose r e s p o n s e effect for toxicity. It m u s t be a s s u m e d t h a t t h e r e w~ll be a d o s e level w h i c h will a c h i e v e o p t i m a l m o d i f i c a t i o n o f host b i o l o g i c r e s p o n s e to the t u m o r . T h i s c o u l d b e called the m a x i m a l l y effective d o s e ( M E D ) . D e p e n d i n g u p o n t h e toxicity p o t e n t i a l o f the B R M a g e n t a n d its m e c h a n i s m o f a c t i o n it m a y b e t h a t t h e M E D a n d M T D will b e identical as it is tbr m o s t e h e n l o t h e r a p e u t i c agents, T h i s c o u l d occ~ar for o n e o f t w o basic reasons. T h e first w o u l d b e if the toxicity o c c u r s at r e l a t i v e l y t o w dose levels b e f o r e the a b s o l u t e M E D c a n b e r e a c h e d . T h e s e c o n d r e a s o n , w h i c h is r e l a t e d , w o u l d b e if t h e r e is a v e r y w i d e d o s e - r e s p o n s e effect w h i c h e x t e n d s u p to v e r y high doses. I t is h a r d 0305-7372/80/040235 + 0,t 802.00]0
~ 1980 Academic Press Inc. (London) Ltd. 235
236
,S. 1,2. t:..\RTI:;R
to i m a g i n e t h a t a n y biohJgicalty activt: l:mterial w o u l d n~t c a u s e c[llzcts o n n o r m a l celJs ;tt sorne dose level. 'l'he initial dose level for a Phase l s t u d y o f a c y t o t o x i c d r u g is dr:rived |i'mit a n i n t a l studies (2). S o m e fi'action ~ f the m i n i m a l l y toxic dose in a l a r g e a n i m a l o r tht: IA)10 in a r ~ d e n t will be used. "l'he o b j e c t i v e o f tttis is to initiate the trial at a n o n - t o x i c dose. W i t h a BI;', M the initial dose will also h a v e b e e n c l m s c n ti'om a n i m a l studies. If the d r u g is s h o w n to be n o n - t o x i c in aninxals o v e r a r a n g e o f doses w h i c h a r e etli,'ctive a ltigtmr dose w h i c h relates to the lowest effective dose m a y be c h o s e n . S i n c e the l l u a n t i m t i v e tc~xicity predicticm li'om a n i n m l to m a n is not a b s o l u u ' l y precise, c a u t i o n s h o u l d be e x e r c i s e d in not s t a r t i n g at too h i g h a dose. i n o r d e r to d e v e l o p a c o r r e l a t i o n o f the dose-response r e l a t i m l s h i p lot a c t i v i t y b e t w e e n species it m i g h t be w o r t h w h i l e to begin w i t h the highest n o n - e f f e c t i v e d o s e in a n i m a l s if the toxicity d o s e - r e s p o n s e c u r v e will a l l o w it w i t h a r e a s o n a b l e e x p e c t a t i o n o f initial saii:ty. T h e d o s e - e s c a l a t i o n p r o c e d u r e w i t h c h e m o t h e r a p y u s u a l l y il~volves initially large steps w i t h the i n c r e m e n t s l~ccoming p r o g r e s s i v e l y smaller. T h i s is d u e to the usual steep dose---response, effi:cts seen tbr r n y e l o s u p p r c s s i v e drugs. C o n t i n u i n g to d o u b l e a dose c o u l d c a u s e at j u m p to o c c u r fi'om a m i n i m a l l y toxic dose to a lethal dose, I f the a l u m a l d o s e - r e s p o n s e curve" t~)r toxicity is s h a l l o w l)~r a BRN1, t h e n l a r g e r e s c a l a t i o n doses m a y be d e e m e d to be r e l a t i v e l y salE. T h i s w o u l d a v o i d tim risk o f a P h a s e I s t u d y t a k i n g a v e r y long t i m e b e c a u s e o f h a v i n g to test a l a r g e n u n l b e r o f dose escalatiotls. T h e e n d p o i n t s fox" a P h a s e t s t u d y o f a B R M ideally o u g h t to i n v o h , e t h e t b l l o w i n g : 1. 2. 3. 4, 5.
E l u c i d a t i o n o f t h e N I T D o n the s c h e d u l e ( s ) c h o s e n ; E l u c i d a t i o n o f t h e m i n i m a l l y toxic dose o n the s c h e d u l e ( s ) c h o s e n ; E l u c i d a t i o n o f t h e initial d o s e level at w h i c h e v i d e n c e o f biologic effimt is o b s e r v e d ; E h m i d a t i o n o f the close level(s) at w h i c h o p t i m a l biologic efli:cts is (are) o b s e r v e d ; E l u c i d a t i o n o f t h e toxicity p a r a m e t e r s a n d d e t e r m i n a t i o n if t h e y a r e p r e d i c t a b l e and treatable ; 6. R e c o m m e n d a t i o n o f a d o s a g e s c h e d u l e for Phase I I s t u d y .
Phase ii study T h e P h a s e II s t u d y for a c h e m o t h e r a p e u t i c a g e n t is a n efficacy s c r e e n to d e t e r m i n e w h e t h e r t h e r e is e n o u g h e v i d e n c e o f a n t i t u m o r effect to w a r r a n t l a r g e - s c a l e l~'hase I I I studies. It is k n o w n t h a t the a c t i v i t y , o r lack t h e r e o t , in o n e t u m o r t y p e w i t h cytotoRie drugs will n o t p r e d i c t tbr a n o t h e r type. T h e r e f o r e a series o f disease specific P h a s e I I s t u d i e s a r e u n d e r t a k e n . I d e a l l y o n e s h o u l d d o a P h a s e I I s t u d y in e v e r y t u m o r t y p e in w h i c h it is t h o u g h t t h e n e w d r u g m i g h t be e f f e c t i v e . T h i s is r a r e l y feasible unless a s i g n i f i c a n t a m o u n t o f a n t i t u m o r effect is observed in early Phase II trials. B e c a u s e o f this a p a n e l o f t u m o r types a r e c h o s e n for P h a s e I I s t u d y as a r e a s o n a b l e s c r e e n for a c t i v i t y . T h e a s s u m p t i o n m a d e is t h a t if t h e n e w d r u g is n e g a t i v e in t h e e n t i r e p a n e l , it is u n l i k e l y to b e a c t i v e in o t h e r t u m o r types. W i t h a B R M it m u s t b e a s s u m e d , u n t i l p r o v e n o t h e r w i s e , t h a t effectiveness will d i f f e r in d i f f e r e n t t u m o r types. T h i s m a y be c a u s e d b y a n y o n e o f the f o l l o w i n g facts: (1) d i f f e r e n t t u m o r s m a y elicit d i f f e r e n t host response; (2) d i f f e r e n t t u m o r s m a y be m o r e o r less a m e n a b l e to t h e r a p e u t i c b e n e f i t from a B R M effect; (3) d i f f e r e n t i a l t u m o r cell
burdens m a y respond differently to B R M effects; (4) p h a r m a c o l o g i c sanctuaries or
CI,INI(3AL I:;VAI,UATION OF BRlk,I ACI|'.;N't'S
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privileged sites m a y exist tbr I~R.M etR;ct. Because of this it w o u l d be p r u d e n t to design a series of disease-oriented Phase 11 studies tbr B R M agellts. "~/ith c y t o t o x i c drugs tile t h e r a p e u t i c e n d p o i n t for a Phase 1I s t u d y is objective rcgre,lsion o f tunu:,r. VChat is not k n o w n is w h e t h e r this will be feasible tbr BRiXI agel~ls. It was not d e e m e d a p p r o p r i a t e tbr i m m u n e lnodulatiiag agents such as 11C(3, (l. p a r v u m , lcvamisole, etc. It is I)cing used tbr c u r r e n t trials o f h u m a n leukocyte intert~ron. It m a y thercfi:n'c diflkr with dilli:rcnt B R M agents. I f objective regression is o b t a i n a b l e with a t~R.M, then the Phase 11 s t r a t e g y is simple; but if it is not, it will be mort: c o m p l i c a t e d . If object iw: response c a n n o t be used as an t.'ndl~oint tbr l?hase 1I study, there are two b r o a d possibilitics tbr Phase II design. O n e a p p r o a c h w o u l d be to a d d tile B R M to s l a n d a r d thcral~y a n d use as t t m . i u d g n m n t p a r a m e t e r a p r o l o n g a t i o n ot'rest)onse d u r a t i o n or surviwd. This has the d i s a d v a n t a g e o f rt:quirillg a colltrol grout~ R~r c o m p a r i s o n . \Vith iHmaunt~-modulating agents nlally groups a t t e m p t e d to use historical controls w i t h o u t a g r e a t deal o f success. It is dillicult to conlrol for all i m p o r t a n t prognostic variables a n d there arc potential ditl'c,'ences in diagnostic w o r k - u p a n d care delivery which arc very ditticult m control tbr. In a d d i t i o n e a r l y a c t u a r i a l p r o d u c t i o n m a y give one an early thlse positive, since there is a longer tbllow-up tinle tbr the historical control. I f a prospective r a n d o m i z e d control is used, then the p r o b l e m becomes the use ol'a Phase II1 naethodology to give a Phase 1I answer. In such a Phase I1. s t u d y a statisticaliy significant difference in s u r v i v a l m a y not be n e e d e d but just e n o u g h c o m p a r a b i l i t y or suggestion o f superiority to w a r r a n t a Phase 1II study. O b v i o u s l y if such a s t u d y design is used, the r u b r i c o f Phase [ I - I i t s t u d y m i g h t be the most applicable. A n o t h e r a p p r o a c h w o u l d he to look tbr only a consistent m o d u l a t i o n o f host response, which w o u l d be assurned to be intrinsically va!.uable. A r m e d with this consistency of implied biologic response i m p a c t , a p p r o p r i a t e P h a s e 1II studies c o u l d then be c o n s i d e r e d justiIiable. This a p p r o a c h has the a l t r a c l i o n ot' clinical d e c i s i o n - m a k i n g based on pre.s u m e d meclaanisnas o f action, but has the d r a w b a c k o f not a t t e m p t i n g to d e m o n s t r a t e evidence o f t r u e biologic i m p a c t prior to c o m n a i t m e n t o f large-scale clinical trial resources. l f a BR.M a g e n t ' s effect c a n only be m e a s u r e d b y a positive inlluence on survival this s t r a t e g y m a y be the only one it is fe.asible to c o n t e m p l a t e . I f the Phase 11 c o n c e p t fbr a B R M is indirecl m e a s u r e m e n t ot" host response t h r o u g h some l a b o r a t o r y or clinical e x a m i n a t i o n , then a c o n t r o l l e d design seems to be essential. \,Vhat has been s h o w n with m e a s u r e m e n t o f i m m u n e reactivity, such as skin lests, l y m p h o c y t e btastogenesis assays, etc., is a high d e g r e e of intrinsic biologic variability. A d o u b l e - b l i n d s t u d y at: the N/[ayo Clinic o f two do.~e levels o f m e t h a n o l ex~k~action residue of BGO (N'IER) with placebo r e v e a l e d C o m p a r a b l e e n h a n c e d irnmum%logic~"' r e a c t i v i t y with both d r n g a n d plncebo (.'3). S u c h c o u l d be the case wilh a BRg'I. A Phase II design could involve a doul)le-l~lind e v a l u a t i o n of the B R M a n d a p l a c e b o with the e u d p o i n t b e i n g i m p a c t on a g r o u p o f clinical a n d l a b o r a t o r y assays p r e s u m e d to be indications o f m o d u l a t e d host biologic response to the ttnnor, l f a d i f f e r e n c e t h a t Favored the B R M was o b s e r v e d large-scale a d j u v a n t or Phase I I I trials w o u l d be justified. This w o u l d involve a Phase I1 s t u d y that was both m o r e c o m p l e x in design a n d m o r e expensive t h a n a classic Phase I I s t u d y with a cytotoxic c o m p o u n d , q.?his w o u l d be w o r t h w h i l e , however, if it c o u l d efl]zctively screen for the potential v a l u e o f a l o n g - t e r m a n d highly expensive a d j u v a n t trial. In addition, the P h a s e I I c o n c e p t Should be flexible e n o u g h to e n c o m p a s s a wMe r a n g e of biological materials.
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References 1. Carter, S, K. (1977) Clinical trials in cancer chemotherapy. Cancer 40: 554-557. 2. Goldsmith, M. A., Slavik, M. & Carter, S. K. (1975) Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. Cancer Res. 35: 1354-1364. 3. O'ConneIl, M . J . , Moertel, C.J., Rifts, R. E.,Jr., Frytak, S. & Reitemeir, R . J . (1979) A comparative clinical and immunological assessment of methanol extraction residue of Bacillus Calmette-Guerin vs. placebo in patients with advanced cancer. Cancer Res. 39: 3720-3724.