- Email: [email protected]
II trial
Cancer TreatmentReviews(1983) I0 (S~bplementA), 167-I 73
High-dose ifosfamlde and mesna as continuous infusion over five days--a phase I/H trial H. O. K l e i n , * e . D i a s W i c k r a m a n a y a k e , * a n d N. B r o c k ~
C1. C o e r p e r , * E. C h r i s t i a n , * J. P o h l ~
*Medical Clinic, University o f Cologne, 5000 KO'ln 41, F.R.G. t Asta-Werke, A.G., Artur-Ladebeck Str., D 4800 Bielefeld, 14 F.R.G.
Based o n preclinical studies in m i c e ( K l e i n et al., this issue, p. 83) t h a t s u p p o r t the h y p o t h e s i s t h a t c o n t i n u o u s infusion o f c),tostatic d r u g s (e.g. o x a z a p h o s p h o r i n e s ) with relatively l o n g s e r u m half-life m i g h t ' y i e l d b e t t e r tolerability a n d g r e a t e r t h e r a p e u t i c effectiveness t h a n p u s h - i n j e c t i o n , we s t a r t e d a clinical p h a s e I / I I trial. T h e a i m o f this trial was to assess t h e ' m a x l m u m t o l e r a t e d dose ( M T D ) a n d the response rate for a v a r i e t y o f t u m o u r s a n d m a l i g n a n t l y m p h o m a s w h e n ifosfamide~ (IF) a n d m e s n a § w e r e a d m i n i s t e r e d as c o n t i n u o u s infusion.
Materials and methods M o s t p a t i e n t s e n t e r i n g the trial h a d t u m o u r s refractory to c o n v e n t i o n a l c h e m o t f i e r a p y ( T a b l e 4). T h i r t y - e i g h t p a t i e n t s were e n t e r e d into this trial ( K a r n o f s k y range: 6 0 - 9 0 % ; m e d i a n age 52 years). I F together w i t h m e s n a (dose-relationship 1 : 1 on a m g ] k g basis) was a d m i n i s t e r e d i.v. c o n t i n u o u s l y o v e r 5 days. T h e dail.y dose was split into 4 fractions a n d each f r a c t i o n was infused o v e r 6 h ( F i g u r e 1). T h e s t a r t i n g dose was 60 m g ] k g ] 2 4 h × 5. I n T a b l e 1 the different doses o f I F a r e listed a n d relate to t h e n u m f f e r o f p a t i e n t s t r e a t e d as well as to t h e t r e a t m e n t cycles. T h e p h a r m a c o k i n e t i c s o f t h e c y t o c i d a l m e t a b o l i t e 4-hydl:oxy-ifosfamide a n d t h e u r i n a r y e x c r e t i o n of m e s n a a n d active thiol c o m p o u n d s were d e t e r m i n e d in a f u r t h e r 6 patients. T h e free s u l f h y d r y l c o m p o u n d s a n d the thiol c o m p o u n d s , d e t e c t a b l e by r e d u c t i o n o f t h e bisulfide bonds, w e r e assayed p h o t o m e t r i c a l l y at 405 n m by a m o d i f i e d m e t h o d d e v e l o p e d by E l l m a n (2). 4 - h y d r o x y - i f o s f a m i d e was d e t e r m i n e d f l u o r o m e t r i c a l l y (3). Mitoxana® (Boehringer Ingelheim Hospital Division, U.K. and Eire) and Holoxan~ (Asta-Werke"AG, F.R.G.). § Uromitexan® (Boehringer Ingelhcim Hospital Division, U.K. and Eire, and Asta-Werke AG, F.R.G.).
0305-7372/83[10A0167+07 $03.0010
~ 1983 Academic Press Inc. (London) Limited 167
168
H . O . KLEIN E T AL.
Ifosfomide
4 xO°mg/kg/24h
Mesno D
4 x D°m~, Kg/24hx5
Dimenhydrinate
4x2
I. 0
i I
x5
omp./24hx5
I 2
t 3
I. . . . . . . . . . 4
o D = different dos~ occordin 9 1o phase I / n "
t 5 days
study
b dose relationship ifosfomide : menso I:1 (on o rng/k~ basis)
Figure 1. Cytostatic treatment protocol for a phase I/II study. Each fraction of ifosfamidc and mesna (by-pass
administration) was infused over a period of 6 h.
I n all patients pre- a n d p o s t - t h e r a p e u t i c e x a m i n a t i o n s ~ e r e c a r r i e d o u t with ultras o n o g r a p h y , s c i n t i g r a p h y , axial c o m p u t e r - t o m o g r a p h y a n d X-rays. T h e s e e x a m i n a t i o n s w e r e d o n e after e v e r y second t h e r a p y cycle. Full blood counts w e r e also d o n e a n d the W H O response criteria w e r e used.
Results
T h e m a x i m u m tolerated dose ofifosfamide a n d m e s n a is 85 m g / k g / 2 4 h × 5 ( T a b l e 2). T h e dose-limiting side-effects a r c C N S disturbances, c a r d i a c d y s r h y t h m i a s , a n d micro- as well as m a c r o h a e m a t u r i a . T h e overall remission rate is 31 ~/o ( T a b l e 3). T w o patients w e n t into c o m p l e t e remission: o n e female with a r a p i d l y proliferating s q u a m o u s cell c a r c i n o m a of the skin ( i n d u c e d b y extensive r a d i o t h e r a p y ) ; remission d u r a t i o n 4 m o n t h s , a n d a n o t h e r f e m a l e w i t h a r a p i d l y p r o l i f e r a t i n g fibrosarcoma; remission d u r a t i o n 7 m o n t h s . T h e m o s t responsive t u m o u r types a r e m a l i g n a n t l y m p h o m a s , h e a d a n d neck t u m o u r s a n d soft tissue s a r c o m a s ( T a b l e
4). T h e u r i n a r y excretion o f m c s n a with continuous i.v. infusion o f the d r u g is shown in Figures 2, 3 a n d 6. A p p r o x i m a t e l y 3 0 % o f the a d m i n i s t e r e d dose is e x c r e t e d in the u r i n e
Table
Treatment cycles related t o c l o s e f o r a p h a s e I/II study with fractloned ifosfamide dose °
I.
Dose mg/kg/24 h x 5 60 65 30 75 80 85
(4 x (4 × (4 x (4 × (4 x (4x
Total
15) 16.25) 17.5) 18.75) 20) 21.25)
No. of patients
No. of therapy cycles
3 I 4 5 13 12
3 I 5 Il 25 18
38
63
a Each Fraction was infused over 6 Hours.
CONTINUOUS INFUSION OF HIGH-DOSE IF AND MESNA
169
Table 2. Toxicity r e l a t e d t o d o s e f o r a p h a s e I / l I s t u d y w i t h c o n t i n u o u s infusion of ifosfamlde
Dose (mg/kg/24 h x 5) Side-effects
60-65
Nausea Vomiting Loss ofappetite Diarrhoez Leucocytes < 1000/pl Thrombocytes < 100,000/pl Hb < 10.0 g% Alopecia Cardiac dysrhythrnla CNS-disturbances Microhematuria Macrohematuria
70
75
80
85
414 4/4 5/5 13/13 12l 12 4/4 4/4 5/5 13l 13 12/12 4/4 414 5/5 13113 12112 0/4 0/4 0/5 0] 13 0/12 0/4 0/4 1/5 3[13 4t12 014 0/4 0/5 0/13 0112 0/4 0/4 0/5 0/13 0]12 Pretreated patients had already alopecia 014 0/4. 0/5 0/13 2/12 0/4 0/4 0/5 0]13 3112 014 0/4 015 3/13 9/12 0]4 014 0/5 0/13 1112
d u r i n g 3 hours. O v e r the whole period of 4 days the excretion o f t h e active thiol c o m p o u n d s is in a steady state. As c a n be seen in patients A, B a n d C (Figures 2 a n d 3) after the end of i n f u s i o n - - d u e to the short h a l f life o f m e s n a - - t h e excretion in the urine ends very rapidly. C o m p a r e d with push-injection p r o c e d u r e s (Figure 4) the excretion o f m e s n a a n d its active thiol c o m p o u n d s seems to be higher with the c o n t i n u o u s infusion p r o c e d u r e . T h e total dose administered per d a y is c o m p a r a b l e in all patients. In Figures 4, 5 a n d 6 p r e l i m i n a r y p h a r m a c o k i n e t i c d a t a of 4-hydroxy-ifosfamide the m a j o r cytocidal m e t a b o l i t e ofifosfamide are plotted. I n Figure 4 the serum c o n c e n t r a t i o n s of 4-hydroxy-ifosfamide are shown after daily short term infusions of 1 hour. As can be seen, there are several peak c o n c e n t r a t i o n s of 4-hydroxy-ifosfamide between days 2 a n d 4. O n the other h a n d , with c o n t i n u o u s infusion of ifosfamide the m e t a b o l i t e is in an a p p r o x i m a t e steady state from d a y 1 to 4 (Figure 6). T h e serum profile of 4-hydroxy-ifosfamide d u r i n g a 24 h infusion is s h o w n in Figure 5. Surprisingly, even d u r i n g the infusion the serum c o n c e n t r a t i o n of the m e t a b o l i t e decreases to almost zero a n d rises again after t e r m i n a t i o n of the infusion with a p e a k c o n c e n t r a t i o n at 32 hours. This kinetic profile d u r i n g the first 24 h is also seen in the o t h e r investigations (Figures 4, 5 a n d 6). It m i g h t be explained by distribution of ifosfamide a n d its m e t a b o l i t e in the tissues. After s a t u r a t i o n of these c o m p a r t m e n t s a redistribution of 4-hydroxy-ifosfamide takes place w h i c h ends up with a m o r e or less steady state profile d u r i n g c o n t i n u o u s infusion and an increasing c o n c e n t r a t i o n d u r i n g the push-injection (I h infusion) experiment. T a b l e 3. T r e a t m e n t r e s u l t s f o r a p h a s e I / I I s t u d y a f t e r c o n t i n u o u s i n f u s i o n o f i£osfanaide. T h e r e w e r e 38 p a t i e n t s registered, eligible and adequately treated
Com p~te remtmlon
Partial remimion
No change
Progressive disease
no.
%
no.
%
no.
%
no.
%
2
5
10
26
6
16
20
53
0
T a b l e 4.
Treatment ifosfamide
results
related
to turnout
type after
continuous
infusion
CR
MR
of
Pretreatment Pat. n
yes
Lung cancer alveol, cell small cell s q u a m o u s cell
1 1 1
1 1 1
I 1
Ca. breast
2
2
2
Hodgkin's
3
N - H o d g k i n ' s (high g r a d e )
3
3
Ca. p a n c r e a s
3
2
Melanoma
1
Hypernephroma
1
1
Tumour
Teratoma
1
1
Hairy-cell l e u k a e m i a
I
1
Head and neck carcinoma s q u a m o u s cell tear gl. parotid, gl. s u b m a n d , gl sweat gl.
2 1 1 1
2 1 1 1
S q u a m o u s cell c a r c i n o m a (RT induced)
2
2
Soft tissue sarcoma fibrosarcoma myxofihrosarcoma liposarcoma hemangioperieytoma synovial sarcoma
3 1 2 1 1
3 1 2
Mesothelioma
2
Chondrosareoma
1
N e u r o b l a s t o m a o f olfactory n e r v e
no
PR
PD
1
1
I
2
2
l
20 End of infusion
Onset of infusion 0
\ "6 E
I0
0
0
.
-0
O ~
- 0 ~
2 tl
1
I
24 8
I
24
..............
I T2
I,
48
~0
--0 . . . . . . . .
I
96100104
~ 0
o__o
120 I 2 8
Hours ki'gure 2. U r i n a r 3 ' e x c r e t i o n of S M - g r o u p s of p a t i e n t B d u r i n g a n d after a 4 - d a y c o n t i n u o u s infusion o f m e s n a ( 0 m e s n a as active thiol c o m p o u n d ; Q m e s n a + m e s n a d i s u l p h i d e ; m e s n a - - 4 × 15 m g / k g / 2 4 h x 4).
CONTINUOUS INFUSION OF HIGH-DOSE IF AND MESNA 20
171
(a) Onset of infusion
End of infusion
E 0
E
I0 0 / 2
).0~ I
246
0 1
24
...........
48
72
96100104
120 I;28
70 O
(b)
60 50 E "6 E
4O 30 20 I0 5 .=46
24
48
72
9 6 I00104
,044 120 128
Hours
Figure 3. Urinary excretion SM-groups of (a) patient A and (b) patient C during and after a 4-day continuous infusion of rneslaa (O mesna as active thiol compound; Q mesna+mesna disulphide; mesna--4 × 20 mg]kg] 24 hx4).
Discussion Ifosfamide has a long s e r u m h a l f life o f a p p r o x i m a t e l y 15-16 hours for the b e t a - p h a s e (1). This was the reason w h y w e tried to a d m i n i s t e r ifosfamide with c o n t i n u o u s infusion. F r o m the p r e l i m i n a r y p h a r m a c o k i n e t i c d a t a it can be d e d u c e d t h a t c o n t i n u o u s infusion gives a b e t t e r s t e a d y state profile o f s e r u m c o n c e n t r a t i o n o f 4 - h y d r o x y - i f o s f a m i d e c o m p a r e d with the .single push-injection (t h infusion). A n o t h e r point o f interest is t h a t 24 h after t e r m i n a t i o n o f ifosfamide infusion t h e r e are still considerable c o n c e n t r a t i o n s o f the m e t a b o l i t e in the serum. O n the o t h e r h a n d , excretion o f m e s n a slows d o w n very r a p i d l y after t e r m i n a t i o n o f m e s n a infusion. N o d e t e c t a b l e a m o u n t s o f the d r u g can be f o u n d in the u r i n e 24 h after the e n d o f the m e s n a infusion. D u r i n g the infusion period no p a t i e n t showed micro- or m a c r o h a e m a t u r i a . H o w e v e r , some d e v e l o p e d h a e m a t u r i a 1 to 2 d a y s after the e n d o f t r e a t m e n t . F r o m o u r p h a r m a c o k i n e t i c studies a n d the u r i n a r y excretion investigations w e c o n c l u d e t h a t considerable a m o u n t s o f 4 - h y d r o x y - i f o s f a m i d e a r e in the s e r u m a n d e x c r e t e d into the u r i n e 24~ 48 h after the e n d o f i f o s f a m i d e infusion w h e r e a s at this time no d e t e c t a b l e a m o u n t s o f m e s n a a n d its active thiol c o m p o u n d s c a n be m e a s u r e d . T h e s e findings could a c c o u n t for the d e l a y e d h a e m a t u r i a . T h e tolerability o f ifosfamide a n d m e s n a a d m i n i s t e r e d as c o n t i n u o u s infusion over 5 d a y s - - w h e r e the daily dose is given in 4 e q u a l fi-actionsmis good. T h e M T D is 85 mg]kg] 24 h × .5, i.e. an increase b y a factor o f 1.42 c o m p a r e d with the usual dose o f IF. T h e high remission rate o f 4 2 % (5112 pts) in soft tissue s a r c o m a s w a r r a n t s f u r t h e r trials. T h e s a m e holds true for l y m p h o m a s a n d h e a d a n d neck tumours.
H. O. K L E I N E T AL.
172
(o) 20 .infusion E "6 t= f,.
Infusion
,0 .o
\/
I I1 I c,
4
2,
8
0
E
C:
IJl
o
1 I
1 II
4~ 4e 5o ~e ~2
I
1
1 1
69 7~ 80 72 7'6
Day 2
~3~ .,oo.
Day 3
Doy 4
(b)
t
I0 10
2s 32 2,4 28
Day I
@
20
Infusion / \
o,O,
L,
30
Infusion
L
,,
o
•
•
-,,o
• ..o-o% ~ -
I
l
0"0
24
8
21242832
.,o/t.
~ o f~~ o o.-..._~ \11 X O.O..L.-....----.---~L;'*O ,.| 0
454852
l
l
Ooyl
56
0"0"0
69727680
9 3 9 6 IOOh
|
Doy 2
"e
,,,
I
Day 3
Day 4
Figure 4. For patient B, (a) serum concentration of 4-hydroxy-ifosfamide and (b) u r i n a r y excretion of mesna as function oftime after 1 h infusion ofifosfami,ae a n d mesna for 4 days. I n (b), I F - - 2 4 0 0 mg]mZ]24 h × 4; m ~ n a - - ½ h after IF 800 mg/m 2, 4 h after I F 800 mg]m 2, 8 h after 1F 800 mg/mZ; O mesna as active thiol compound, O mesna + active thiol compound.
20
2°I0 nset of infu.
End of infusion
(o)
n
o -6 E r-
-6 E ¢,,,
I 0 ~:).o_ o
i
!
X
o/° ~
! _ I ~ . - - 0 0 " 4
8
!
2t2426
28
!
Doy I
32
ot~
: !~ 4548h
I0
/Ji
(b)
-
o° 24
a\ 8
21 2 4 I
28
32
45
48h !
!
Doy 2
Doyl
Ooy2
Figure 5. For patient C, (a) serum concentration of 4-hydroxy-ifosfamide and (b) u r i n a r y excretion o f m e s n a as a function of time after continuous infusion over 24.h ofifosfamide and mesna. I n (a), each fraction was infused over 6 h; IF: 4 x 600 mg]mZ/24 h; mesna: 4 × 600 mg/ma/24 h. I n (b), O mesna as active thio[ c o m p o u n d ; Q mesna + active thiol compound.
CONTINUOUS INFUSION OF HIGH-DOSE IF AND MESNA
so _ E
sj.~. .o. z,~
20 ;riser of i infusion
0
E r-
,o -/\ ?\ k,,,l I.. 4 8
fl /
(o) End of infusion
O~
i01
? \oo
/ /
.I III
I
~o
I
/ o o
_
45 49 56 48 5E
I
l
Doy I
Doy 2
-
i,°\
/
,,o/
I III
21 25 32 E428
173
I II I I
69 73 80 7E 76
/\l
\
o
]_ I I. lOOh
93
96
I
I
Doy :5
i
Day4
(b)
.-./
•
"6 E
I0
~" i~ i _ 24 8
\,,,/
k~, ~ / ~ , o "
ll~l
JY'T'T ......
2l :~428 32 i
Doy I
45485256 t
Doy 2
. o.O°
J';'l
J
69727680 i
Doy .3
iJ"o 939S lOOh I
Ooy 4
Figure 6. For patient A, (a) serum concentration of 4-hydroxy-ifosfamide and (b) urinary excretion ofmesna as a function of time after continuous infusion over 4 days of ifosfamide and mesna. In (a) each fraction was infused over 6 h; IF: 4 × 600 rag/m2/24 h × 4; mesna: 4 × 600 rag/m2/24 h × 4. In (b) O mesna as active thiol compound; 4P mesna + active thiol compound.
Acknowledgement The support of the Bundesminister f'dr Forschung und Technologic is gratefully acknowledged.
References 1. Allen, L. M., Creaven, P. J. & Nelson, R. L. (1976) Studies on the human pharmacokinetics of isophosphamide (NSC-t 09724). Cancer Treatment Rep. 60 (4): 451. 2. Ellman, GI. (1959) Tissue sulfhydryl groups. Arch. Biochem. Biophys 82: 70-77. 3. Voelcker, G., Haeglsperger, R. & Hohorst, H. J. (1979) Fluorometrische Bcstimmung yon "aktiviertem" Cyclophosphamid und Ifosfamid im Blur. ,7. CancerRes. Clin. OncoL 93: 233-240.
High-dose ifosfamlde and mesna as continuous infusion over five days--a phase I/H trial H. O. K l e i n , * e . D i a s W i c k r a m a n a y a k e , * a n d N. B r o c k ~
C1. C o e r p e r , * E. C h r i s t i a n , * J. P o h l ~
*Medical Clinic, University o f Cologne, 5000 KO'ln 41, F.R.G. t Asta-Werke, A.G., Artur-Ladebeck Str., D 4800 Bielefeld, 14 F.R.G.
Based o n preclinical studies in m i c e ( K l e i n et al., this issue, p. 83) t h a t s u p p o r t the h y p o t h e s i s t h a t c o n t i n u o u s infusion o f c),tostatic d r u g s (e.g. o x a z a p h o s p h o r i n e s ) with relatively l o n g s e r u m half-life m i g h t ' y i e l d b e t t e r tolerability a n d g r e a t e r t h e r a p e u t i c effectiveness t h a n p u s h - i n j e c t i o n , we s t a r t e d a clinical p h a s e I / I I trial. T h e a i m o f this trial was to assess t h e ' m a x l m u m t o l e r a t e d dose ( M T D ) a n d the response rate for a v a r i e t y o f t u m o u r s a n d m a l i g n a n t l y m p h o m a s w h e n ifosfamide~ (IF) a n d m e s n a § w e r e a d m i n i s t e r e d as c o n t i n u o u s infusion.
Materials and methods M o s t p a t i e n t s e n t e r i n g the trial h a d t u m o u r s refractory to c o n v e n t i o n a l c h e m o t f i e r a p y ( T a b l e 4). T h i r t y - e i g h t p a t i e n t s were e n t e r e d into this trial ( K a r n o f s k y range: 6 0 - 9 0 % ; m e d i a n age 52 years). I F together w i t h m e s n a (dose-relationship 1 : 1 on a m g ] k g basis) was a d m i n i s t e r e d i.v. c o n t i n u o u s l y o v e r 5 days. T h e dail.y dose was split into 4 fractions a n d each f r a c t i o n was infused o v e r 6 h ( F i g u r e 1). T h e s t a r t i n g dose was 60 m g ] k g ] 2 4 h × 5. I n T a b l e 1 the different doses o f I F a r e listed a n d relate to t h e n u m f f e r o f p a t i e n t s t r e a t e d as well as to t h e t r e a t m e n t cycles. T h e p h a r m a c o k i n e t i c s o f t h e c y t o c i d a l m e t a b o l i t e 4-hydl:oxy-ifosfamide a n d t h e u r i n a r y e x c r e t i o n of m e s n a a n d active thiol c o m p o u n d s were d e t e r m i n e d in a f u r t h e r 6 patients. T h e free s u l f h y d r y l c o m p o u n d s a n d the thiol c o m p o u n d s , d e t e c t a b l e by r e d u c t i o n o f t h e bisulfide bonds, w e r e assayed p h o t o m e t r i c a l l y at 405 n m by a m o d i f i e d m e t h o d d e v e l o p e d by E l l m a n (2). 4 - h y d r o x y - i f o s f a m i d e was d e t e r m i n e d f l u o r o m e t r i c a l l y (3). Mitoxana® (Boehringer Ingelheim Hospital Division, U.K. and Eire) and Holoxan~ (Asta-Werke"AG, F.R.G.). § Uromitexan® (Boehringer Ingelhcim Hospital Division, U.K. and Eire, and Asta-Werke AG, F.R.G.).
0305-7372/83[10A0167+07 $03.0010
~ 1983 Academic Press Inc. (London) Limited 167
168
H . O . KLEIN E T AL.
Ifosfomide
4 xO°mg/kg/24h
Mesno D
4 x D°m~, Kg/24hx5
Dimenhydrinate
4x2
I. 0
i I
x5
omp./24hx5
I 2
t 3
I. . . . . . . . . . 4
o D = different dos~ occordin 9 1o phase I / n "
t 5 days
study
b dose relationship ifosfomide : menso I:1 (on o rng/k~ basis)
Figure 1. Cytostatic treatment protocol for a phase I/II study. Each fraction of ifosfamidc and mesna (by-pass
administration) was infused over a period of 6 h.
I n all patients pre- a n d p o s t - t h e r a p e u t i c e x a m i n a t i o n s ~ e r e c a r r i e d o u t with ultras o n o g r a p h y , s c i n t i g r a p h y , axial c o m p u t e r - t o m o g r a p h y a n d X-rays. T h e s e e x a m i n a t i o n s w e r e d o n e after e v e r y second t h e r a p y cycle. Full blood counts w e r e also d o n e a n d the W H O response criteria w e r e used.
Results
T h e m a x i m u m tolerated dose ofifosfamide a n d m e s n a is 85 m g / k g / 2 4 h × 5 ( T a b l e 2). T h e dose-limiting side-effects a r c C N S disturbances, c a r d i a c d y s r h y t h m i a s , a n d micro- as well as m a c r o h a e m a t u r i a . T h e overall remission rate is 31 ~/o ( T a b l e 3). T w o patients w e n t into c o m p l e t e remission: o n e female with a r a p i d l y proliferating s q u a m o u s cell c a r c i n o m a of the skin ( i n d u c e d b y extensive r a d i o t h e r a p y ) ; remission d u r a t i o n 4 m o n t h s , a n d a n o t h e r f e m a l e w i t h a r a p i d l y p r o l i f e r a t i n g fibrosarcoma; remission d u r a t i o n 7 m o n t h s . T h e m o s t responsive t u m o u r types a r e m a l i g n a n t l y m p h o m a s , h e a d a n d neck t u m o u r s a n d soft tissue s a r c o m a s ( T a b l e
4). T h e u r i n a r y excretion o f m c s n a with continuous i.v. infusion o f the d r u g is shown in Figures 2, 3 a n d 6. A p p r o x i m a t e l y 3 0 % o f the a d m i n i s t e r e d dose is e x c r e t e d in the u r i n e
Table
Treatment cycles related t o c l o s e f o r a p h a s e I/II study with fractloned ifosfamide dose °
I.
Dose mg/kg/24 h x 5 60 65 30 75 80 85
(4 x (4 × (4 x (4 × (4 x (4x
Total
15) 16.25) 17.5) 18.75) 20) 21.25)
No. of patients
No. of therapy cycles
3 I 4 5 13 12
3 I 5 Il 25 18
38
63
a Each Fraction was infused over 6 Hours.
CONTINUOUS INFUSION OF HIGH-DOSE IF AND MESNA
169
Table 2. Toxicity r e l a t e d t o d o s e f o r a p h a s e I / l I s t u d y w i t h c o n t i n u o u s infusion of ifosfamlde
Dose (mg/kg/24 h x 5) Side-effects
60-65
Nausea Vomiting Loss ofappetite Diarrhoez Leucocytes < 1000/pl Thrombocytes < 100,000/pl Hb < 10.0 g% Alopecia Cardiac dysrhythrnla CNS-disturbances Microhematuria Macrohematuria
70
75
80
85
414 4/4 5/5 13/13 12l 12 4/4 4/4 5/5 13l 13 12/12 4/4 414 5/5 13113 12112 0/4 0/4 0/5 0] 13 0/12 0/4 0/4 1/5 3[13 4t12 014 0/4 0/5 0/13 0112 0/4 0/4 0/5 0/13 0]12 Pretreated patients had already alopecia 014 0/4. 0/5 0/13 2/12 0/4 0/4 0/5 0]13 3112 014 0/4 015 3/13 9/12 0]4 014 0/5 0/13 1112
d u r i n g 3 hours. O v e r the whole period of 4 days the excretion o f t h e active thiol c o m p o u n d s is in a steady state. As c a n be seen in patients A, B a n d C (Figures 2 a n d 3) after the end of i n f u s i o n - - d u e to the short h a l f life o f m e s n a - - t h e excretion in the urine ends very rapidly. C o m p a r e d with push-injection p r o c e d u r e s (Figure 4) the excretion o f m e s n a a n d its active thiol c o m p o u n d s seems to be higher with the c o n t i n u o u s infusion p r o c e d u r e . T h e total dose administered per d a y is c o m p a r a b l e in all patients. In Figures 4, 5 a n d 6 p r e l i m i n a r y p h a r m a c o k i n e t i c d a t a of 4-hydroxy-ifosfamide the m a j o r cytocidal m e t a b o l i t e ofifosfamide are plotted. I n Figure 4 the serum c o n c e n t r a t i o n s of 4-hydroxy-ifosfamide are shown after daily short term infusions of 1 hour. As can be seen, there are several peak c o n c e n t r a t i o n s of 4-hydroxy-ifosfamide between days 2 a n d 4. O n the other h a n d , with c o n t i n u o u s infusion of ifosfamide the m e t a b o l i t e is in an a p p r o x i m a t e steady state from d a y 1 to 4 (Figure 6). T h e serum profile of 4-hydroxy-ifosfamide d u r i n g a 24 h infusion is s h o w n in Figure 5. Surprisingly, even d u r i n g the infusion the serum c o n c e n t r a t i o n of the m e t a b o l i t e decreases to almost zero a n d rises again after t e r m i n a t i o n of the infusion with a p e a k c o n c e n t r a t i o n at 32 hours. This kinetic profile d u r i n g the first 24 h is also seen in the o t h e r investigations (Figures 4, 5 a n d 6). It m i g h t be explained by distribution of ifosfamide a n d its m e t a b o l i t e in the tissues. After s a t u r a t i o n of these c o m p a r t m e n t s a redistribution of 4-hydroxy-ifosfamide takes place w h i c h ends up with a m o r e or less steady state profile d u r i n g c o n t i n u o u s infusion and an increasing c o n c e n t r a t i o n d u r i n g the push-injection (I h infusion) experiment. T a b l e 3. T r e a t m e n t r e s u l t s f o r a p h a s e I / I I s t u d y a f t e r c o n t i n u o u s i n f u s i o n o f i£osfanaide. T h e r e w e r e 38 p a t i e n t s registered, eligible and adequately treated
Com p~te remtmlon
Partial remimion
No change
Progressive disease
no.
%
no.
%
no.
%
no.
%
2
5
10
26
6
16
20
53
0
T a b l e 4.
Treatment ifosfamide
results
related
to turnout
type after
continuous
infusion
CR
MR
of
Pretreatment Pat. n
yes
Lung cancer alveol, cell small cell s q u a m o u s cell
1 1 1
1 1 1
I 1
Ca. breast
2
2
2
Hodgkin's
3
N - H o d g k i n ' s (high g r a d e )
3
3
Ca. p a n c r e a s
3
2
Melanoma
1
Hypernephroma
1
1
Tumour
Teratoma
1
1
Hairy-cell l e u k a e m i a
I
1
Head and neck carcinoma s q u a m o u s cell tear gl. parotid, gl. s u b m a n d , gl sweat gl.
2 1 1 1
2 1 1 1
S q u a m o u s cell c a r c i n o m a (RT induced)
2
2
Soft tissue sarcoma fibrosarcoma myxofihrosarcoma liposarcoma hemangioperieytoma synovial sarcoma
3 1 2 1 1
3 1 2
Mesothelioma
2
Chondrosareoma
1
N e u r o b l a s t o m a o f olfactory n e r v e
no
PR
PD
1
1
I
2
2
l
20 End of infusion
Onset of infusion 0
\ "6 E
I0
0
0
.
-0
O ~
- 0 ~
2 tl
1
I
24 8
I
24
..............
I T2
I,
48
~0
--0 . . . . . . . .
I
96100104
~ 0
o__o
120 I 2 8
Hours ki'gure 2. U r i n a r 3 ' e x c r e t i o n of S M - g r o u p s of p a t i e n t B d u r i n g a n d after a 4 - d a y c o n t i n u o u s infusion o f m e s n a ( 0 m e s n a as active thiol c o m p o u n d ; Q m e s n a + m e s n a d i s u l p h i d e ; m e s n a - - 4 × 15 m g / k g / 2 4 h x 4).
CONTINUOUS INFUSION OF HIGH-DOSE IF AND MESNA 20
171
(a) Onset of infusion
End of infusion
E 0
E
I0 0 / 2
).0~ I
246
0 1
24
...........
48
72
96100104
120 I;28
70 O
(b)
60 50 E "6 E
4O 30 20 I0 5 .=46
24
48
72
9 6 I00104
,044 120 128
Hours
Figure 3. Urinary excretion SM-groups of (a) patient A and (b) patient C during and after a 4-day continuous infusion of rneslaa (O mesna as active thiol compound; Q mesna+mesna disulphide; mesna--4 × 20 mg]kg] 24 hx4).
Discussion Ifosfamide has a long s e r u m h a l f life o f a p p r o x i m a t e l y 15-16 hours for the b e t a - p h a s e (1). This was the reason w h y w e tried to a d m i n i s t e r ifosfamide with c o n t i n u o u s infusion. F r o m the p r e l i m i n a r y p h a r m a c o k i n e t i c d a t a it can be d e d u c e d t h a t c o n t i n u o u s infusion gives a b e t t e r s t e a d y state profile o f s e r u m c o n c e n t r a t i o n o f 4 - h y d r o x y - i f o s f a m i d e c o m p a r e d with the .single push-injection (t h infusion). A n o t h e r point o f interest is t h a t 24 h after t e r m i n a t i o n o f ifosfamide infusion t h e r e are still considerable c o n c e n t r a t i o n s o f the m e t a b o l i t e in the serum. O n the o t h e r h a n d , excretion o f m e s n a slows d o w n very r a p i d l y after t e r m i n a t i o n o f m e s n a infusion. N o d e t e c t a b l e a m o u n t s o f the d r u g can be f o u n d in the u r i n e 24 h after the e n d o f the m e s n a infusion. D u r i n g the infusion period no p a t i e n t showed micro- or m a c r o h a e m a t u r i a . H o w e v e r , some d e v e l o p e d h a e m a t u r i a 1 to 2 d a y s after the e n d o f t r e a t m e n t . F r o m o u r p h a r m a c o k i n e t i c studies a n d the u r i n a r y excretion investigations w e c o n c l u d e t h a t considerable a m o u n t s o f 4 - h y d r o x y - i f o s f a m i d e a r e in the s e r u m a n d e x c r e t e d into the u r i n e 24~ 48 h after the e n d o f i f o s f a m i d e infusion w h e r e a s at this time no d e t e c t a b l e a m o u n t s o f m e s n a a n d its active thiol c o m p o u n d s c a n be m e a s u r e d . T h e s e findings could a c c o u n t for the d e l a y e d h a e m a t u r i a . T h e tolerability o f ifosfamide a n d m e s n a a d m i n i s t e r e d as c o n t i n u o u s infusion over 5 d a y s - - w h e r e the daily dose is given in 4 e q u a l fi-actionsmis good. T h e M T D is 85 mg]kg] 24 h × .5, i.e. an increase b y a factor o f 1.42 c o m p a r e d with the usual dose o f IF. T h e high remission rate o f 4 2 % (5112 pts) in soft tissue s a r c o m a s w a r r a n t s f u r t h e r trials. T h e s a m e holds true for l y m p h o m a s a n d h e a d a n d neck tumours.
H. O. K L E I N E T AL.
172
(o) 20 .infusion E "6 t= f,.
Infusion
,0 .o
\/
I I1 I c,
4
2,
8
0
E
C:
IJl
o
1 I
1 II
4~ 4e 5o ~e ~2
I
1
1 1
69 7~ 80 72 7'6
Day 2
~3~ .,oo.
Day 3
Doy 4
(b)
t
I0 10
2s 32 2,4 28
Day I
@
20
Infusion / \
o,O,
L,
30
Infusion
L
,,
o
•
•
-,,o
• ..o-o% ~ -
I
l
0"0
24
8
21242832
.,o/t.
~ o f~~ o o.-..._~ \11 X O.O..L.-....----.---~L;'*O ,.| 0
454852
l
l
Ooyl
56
0"0"0
69727680
9 3 9 6 IOOh
|
Doy 2
"e
,,,
I
Day 3
Day 4
Figure 4. For patient B, (a) serum concentration of 4-hydroxy-ifosfamide and (b) u r i n a r y excretion of mesna as function oftime after 1 h infusion ofifosfami,ae a n d mesna for 4 days. I n (b), I F - - 2 4 0 0 mg]mZ]24 h × 4; m ~ n a - - ½ h after IF 800 mg/m 2, 4 h after I F 800 mg]m 2, 8 h after 1F 800 mg/mZ; O mesna as active thiol compound, O mesna + active thiol compound.
20
2°I0 nset of infu.
End of infusion
(o)
n
o -6 E r-
-6 E ¢,,,
I 0 ~:).o_ o
i
!
X
o/° ~
! _ I ~ . - - 0 0 " 4
8
!
2t2426
28
!
Doy I
32
ot~
: !~ 4548h
I0
/Ji
(b)
-
o° 24
a\ 8
21 2 4 I
28
32
45
48h !
!
Doy 2
Doyl
Ooy2
Figure 5. For patient C, (a) serum concentration of 4-hydroxy-ifosfamide and (b) u r i n a r y excretion o f m e s n a as a function of time after continuous infusion over 24.h ofifosfamide and mesna. I n (a), each fraction was infused over 6 h; IF: 4 x 600 mg]mZ/24 h; mesna: 4 × 600 mg/ma/24 h. I n (b), O mesna as active thio[ c o m p o u n d ; Q mesna + active thiol compound.
CONTINUOUS INFUSION OF HIGH-DOSE IF AND MESNA
so _ E
sj.~. .o. z,~
20 ;riser of i infusion
0
E r-
,o -/\ ?\ k,,,l I.. 4 8
fl /
(o) End of infusion
O~
i01
? \oo
/ /
.I III
I
~o
I
/ o o
_
45 49 56 48 5E
I
l
Doy I
Doy 2
-
i,°\
/
,,o/
I III
21 25 32 E428
173
I II I I
69 73 80 7E 76
/\l
\
o
]_ I I. lOOh
93
96
I
I
Doy :5
i
Day4
(b)
.-./
•
"6 E
I0
~" i~ i _ 24 8
\,,,/
k~, ~ / ~ , o "
ll~l
JY'T'T ......
2l :~428 32 i
Doy I
45485256 t
Doy 2
. o.O°
J';'l
J
69727680 i
Doy .3
iJ"o 939S lOOh I
Ooy 4
Figure 6. For patient A, (a) serum concentration of 4-hydroxy-ifosfamide and (b) urinary excretion ofmesna as a function of time after continuous infusion over 4 days of ifosfamide and mesna. In (a) each fraction was infused over 6 h; IF: 4 × 600 rag/m2/24 h × 4; mesna: 4 × 600 rag/m2/24 h × 4. In (b) O mesna as active thiol compound; 4P mesna + active thiol compound.
Acknowledgement The support of the Bundesminister f'dr Forschung und Technologic is gratefully acknowledged.
References 1. Allen, L. M., Creaven, P. J. & Nelson, R. L. (1976) Studies on the human pharmacokinetics of isophosphamide (NSC-t 09724). Cancer Treatment Rep. 60 (4): 451. 2. Ellman, GI. (1959) Tissue sulfhydryl groups. Arch. Biochem. Biophys 82: 70-77. 3. Voelcker, G., Haeglsperger, R. & Hohorst, H. J. (1979) Fluorometrische Bcstimmung yon "aktiviertem" Cyclophosphamid und Ifosfamid im Blur. ,7. CancerRes. Clin. OncoL 93: 233-240.