- Email: [email protected]
Phase I and II studies of vindesine
Cancer Treatment Reviews (I980) 7 (Supplement), 31-37
Phase I and H studies of vindesine Manuel
Valdivieso
UniversiO, of Texas, M . D. Anderson Hospital and Tumor Institute, Houston, Texas, U.S.A.
Introduction W e h a v e c o n d u c t e d trials w i t h v i n d e s i n e at the M. D. A n d e r s o n H o s p i t a l since 1975. O m e x p e r i e n c e w i t h it has n o w b e e n e x p a n d e d to c o m p a r a t i v e studies w i t h t h e p a r e n t c o m p o u n d , v i n b l a s t i n e sulfate, a n d to v i n d e s i n e c o m b i n a t i o n c h e m o t h e r a p y r e g i m e n s fbr p a t i e n t s w i t h g a s t r o i n t e s t i n a l m a l i g n a n c i e s a n d c a n c e r o f t h e lung. T h i s p a p e r d o c u m e n t s o u r o b s e r v a t i o n s m a d e d u r i n g t h e initial P h a s e I a n d I I studies.
Phase I study S i x t y - e i g h t a d u l t s w i t h a v a r i e t y of h u m a n m a l i g n a n c i e s r e c e i v e d v i n d e s i n e . T h e characteristics o f these p a t i e n t s a r e s h o w n in T a b l e 1. M o s t o f t h e m h a d a c u t e l e u k e m i a , r e n a l cell c a r c i n o m a , colorectal c a n c e r a n d m a l i g n a n t m e l a n o m a . A m o n g the 19 p a t i e n t s w i t h a c u t e l e u k e m i a , t h e r e w e r e 10 w i t h a c u t e m y e l o g e n o u s leukemia, 5 with acute lymphoblastic leukemia, 2 with acute undifferentiated.leukemia a n d 2 w i t h blastic t r a n s f o r m a t i o n o f c h r o n i c m y e l o g e n o u s l e u k e m i a . Overall, 32 p a t i e n t s h a d a history o f p r i o r v i n c r i s t i n e t r e a t m e n t a n d 2 h a d r e c e i v e d vinblastine. V i n d e s i n e was a d m i n i s t e r e d as single i n t r a v e n o u s infusions at 2-week intervals. T h e dose o f v i n d e s i n e r a n g e d f r o m a n initial total dose o f 2 m g to a h i g h o f 12.5 rag. T a b l e 2 shows the n u m b e r o f courses g i v e n initially as well as t h e n u m b e r o f courses g i v e n s u b s e q u e n t l y at e a c h dose. O f 176 c h e m o t h e r a p y courses, m o s t p a t i e n t s w e r e g i v e n a total dose r a n g i n g b e t w e e n 7.5 to 10 rag. A s u m m a r y o f t h e h e m a t o l o g i c toxicities e n c o u n t e r e d d u r i n g t h e s t u d y is s h o w n in T a b l e 3. P a t i e n t s w i t h a c u t e l e u k e m i a w e r e e x c l u d e d f r o m this analysis b e c a u s e o f a b n o r m a l b o n e m a r r o w a n d p e r i p h e r a l b l o o d c o u n t s p r i o r to t h e a d m i n i s t r a t i o n o f v i n d e s i n e . By a n d large, t h e h e m a t o l o g i c toxicity o f v i n d e s i n e consisted p r i m a r i l y o f n e u t r o p e n i a w i t h v e r y little effect o n platelets a n d r e d cells. As s h o w n in t h e m i d d l e p o r t i o n o f T a b l e 3, n e u t r o p e n i a a p p e a r e d d o s e - r e l a t e d a n d m o r e p r o n o u n c e d at t h e 0305-7372/80/S00031
+
1980 Academic Press Inc. (London) Ltd.
07 $02.0010 31
32
M. VAI.DIVI ESO T a b l e 1. P h a s e I s t u d y o f v i n d e . s i n e . Patient characteristics
Number of patients Sex: l:enaale Male Age: Median Range Diagnosis: Acute leukemia M. melanoma Sarcoma
Lynaphonaa Ca: Renal Cblorectal Lung Breast Head-neck ()thcrs*
68 23 45 49 years 16-77 years 19 8 3 2 13 8 5 3 3 4
* I patient each with esophageal, undilTcrcntiated, adenoearcinoma of unknown primary and gallbladder ca. h i g h e r doses. H o w e v e r , a t doses l o w e r t h a n 7.5 rag, 80 to 9 0 % o1" tile f i d l - t r e a t m e n t courses w e r e not associated with significant myelosuppression, with the e x c e p t i o n o f a n occasional p a t i e n t w h o h a d h a d prior c h e m o t h e r a p y a n d w h o b e c a m e m y e l o s u p p r c s s c d a t these doses. In a d d i t i o n , the platelct c o u n t d o u b l e d d u r i n g vindesinc t r e a t m e n t in 3 patients w h o received doses o f 2 a n d 4 rag, a n d in w h o m no m y e l o s u p p r e s s i o n d e v e l o p e d . I n contrast, most o f tile patients t r e a t c d with doses o f 7.5 m g o r m o r e d e v e l o p e d m o d e r a t e n c u t r o p e n i a w h i c h was not c u m u l a t i v e a n d w h i c h was reversible in all instances. M o s t paticnts w h o d e v e l o p e d m y e l o s u p p r e s s i o n h a d thcir lowest blood counts after 8 to l0 days o f t r e a t m e n t . A s u m m a r y o f o t h e r toxicitics e n c o u n t e r e d d u r i n g this study, in relation to the doses o f vindcsine a d m i n i s t e r e d , is s h o w n in T a b l e 4. Gastrointestinal a n d n e u r o l o g i c side effects, p r i m a r i l y in the f o r m o f n a u s e a , v o m i t i n g , constipation, paresthcsias, a n d w e a k ness, w e r e observed. T h e f r e q u e n c y a n d severity o f these m a n i f e s t a t i o n s a p p e a r e d to be dose-related, being m o r e p r o n o u n c e d at the highest doses. O f p a r t i c u l a r i m p o r t a n c e was the d e v e l o p m e n t o f t r a n s i e n t p a r a l y t i c ileus in 6 p a t i e n t s ( a p p r o x i m a t e l y 8 % ) at doses o f 4 rag, 7.5 rag, a n d 12.5 mg. T h e neurologic toxicities w e r e a l m o s t twice as c o m m o n in p a t i e n t s w i t h p r i o r v i n c a alkaloid t r e a t m e n t . W e d i d not observe significant a l t e r a t i o n s in b i o c h e m i c a l p a r T a b l e 2. P h a s e I s t u d y o f v l n d e s i n e . N u m b e r o f c o u r s e s g i v e n at e a c h d o s e l e v e l o f vindesine Total dose (nag) 2 4
5-6
Initially
Subsequently
5 9
5 15
4
25
7.5 9-10 12.5
36 14 0
81 47 3
Total
68
176
P H A S E 1 A N D I1 S T U D I E S O F V I N D E S I N E T a b l e 3. P h a s e I s t u d y o f v i n d e s i n e . toxicities
33
Myelosuppressive
Total vindcsine d .'e (rag)
l.eukocytes
Neulrophils
Platclcts
Day
2 4 5-6 7.5 10-12.'3
4.5 5.5 4.0 2.9 2.8
4.5 3.2 2.:3 1.4 1.3
196 150 200 203 229
7 7 8 8 10
tvledian lowest counts × 10a
a m e t c r s o f r e n a l a n d h e p a t i c functions, or o f s c r u m electrolytes, t h a t c o u l d be a t t r i b u t e d to v i n d e s i n e t r e a t m e n t . O f t h e 68 p a t i e n t s , t h e a n t i t u m o r activity o f v i n d e s i n e was e v a l u a b l c in 60 w h o w e r e a b l e to receive a set.ond c o u r s e o f c h e m o t h c r a p y . O f the r e m a i n i n g 8, 5 d i e d w i t h r a p i d t u m o r p r o g r e s s i o n before d a y 15, a n d 3 p a t i e n t s refused a s e c o n d t r e a t m e n t . T w o o u t o f 15 c v a l u a b l c p a t i e n t s w i t h a c u t e Ieuken~ia (one e a c h w i t h l y m p h o b l a s t i c a n d u n d i f f e r e n t i a t e d typcs) a e h i e v c d a p a r t i a l r e m i s s i o n in spite o f extensive p r i o r c h e m o t h e r a p y , w h i c h i n c l u d e d vincristine in all p a t i e n t s ( T a b l e 5). Less t h a n p a r t i a l remissions w c r c o b s e r v e d in 2 o f 13 p a t i e n t s w i t h r e n a l cell c a r c i n o m a s , 1 o u t o f 4 s:ith s q u a m o u s cell l u n g c a n c e r , a n d 1 o u t of 1 w i t h c s o p h a g e a l c a r c i n o m a . R e s p o n s e s w e r e b r i e f a n d h a d a m e d i a n d u r a t i o n o f 12 wecks. I n a n overall assessment o f t h e P h a s e I s t u d y , we d e t e r m i n e d t h a t p a t i e n t s t o l e r a t e d doses o f 7.5 to 10 m g r e p e a t e d at 2-week intervals. T h e m e a n b o d y surface a r c a o f o u r cases w a s 1.85 n f ' . W c c o n c l u d e d t h a t f u t u r e clinical trials w i t h v i n d e s i n e s h o u l d be c o n d u c t e d at doses o f 4 to 5 m g / m z r e p e a t e d at 2 - w e e k i n t e r v a l s in t h o s e w i t h a d e q u a t e b o n e marroxv reserves, a n d t h a t this dose be r e d u c e d to a p p r o x i m a t e l y 3 m g / m Z for p a t i e n t s w i t h extensive p r i o r m y e l o s u p p r e s s i v e c h e m o t h e r a p y .
Phase II study W i t h t h e a b o v e g u i d e l i n e s , a b r o a d P h a s e I I s t u d y o f v i n d e s i n e was i n i t i a t e d in 79 adults. T h e i r c h a r a c t e r i s t i c s a r e s h o w n in T a b l e 6. M o s t p a t i e n t s h a d a d e n o c a r c i n o m a s T a b l e 4. P h a s e I s t u d y o f v i n d e s i n e . O t h e r t o x i c i t l e s 2-6 mg
7.5 m g
10-12.5 mg
58 39 8 2 12 2 6 4 2 14 ~
70 43 16 4 15 4 12 5 7 16 6
97 70 30 2 27 21 19 19 14 13 8
(%)
Patients with toxicity Courses with toxicity Constipation Paralytic ileus Nausea, vomiting and diarrhea Chills and fever Paresthesias Weakness Alopecia Phlebitis and cellulitis Others*
(%)
(%)
* 5 episodes ofarthralgias, 2 ofconfusion and lethargy, 2 of'heartburn" and 1 each of anorexia, jaw pain and hallucinations.
M. VALDIVIESO
34
T a b l e 5. P h a s e I s t u d y o f v i n d e s i n e . R e s p o n s e to v i n d e s i n e t h e r a p y
Duration of response (weeks)*
l~lalignancy
Evaluable patients
Partial remissions
Disease stabilization
Disease progression
Acute leukemia Renal cell b,I. melanoma Colorectal Lung Breast Head and neck Lymphoma Sarcoma Esophageal Others'["
15 13 8 6 4 3 3 2 2 1 3
2
2 4 (2 < PR)
11 9 8 4 3 3 3 2 2
9, 12, 14, 8 20, 21, 25, 32
I
9, 12
2 I (I
1 (< PR) 2
10, 12, 29 5
1
* It includes remissions and disease stabilization. t 1 patient each with adeno, uriknown, l °, gallbladder ca and undifferentiated ca.
o f t h e r e c t u m a n d b r e a s t , w i t h o t h e r d i a g n o s e s b e i n g less f r e q u e n t . W i t h t h e e x c e p t i o n o f I 2 p a t i e n t s - - 7 w i t h r e n a l c a r c i n o m a s a n d 5 w i t h s q u a m o u s cell c a r c i n o m a o f t h e e s o p h a g u s - - t h e r e m a i n i n g 67 p a t i e n t s h a d r e c e i v e d e x t e n s i v e p r i o r c h e m o t h e r a p y w h i c h i n c l u d e d v i n c r i s t i n e s u l f a t e in 24 a n d v i n b l a s t i n e in 1. S e v e n t y - o n e p a t i e n t s r e c e i v e d m o r e t h a n o n e c o u r s e o f v i n d e s i n e c h e m o t h e r a p y a n d , w e r e t h e r e f o r e e v a l u a b l e for response. O v e r a l l , t h e r e w e r e 5 c o m p l e t e a n d p a r t i a l remissions, p l u s 6 a d d i t i o n a l r e s p o n s e s w h i c h w e r e less t h a n p a r t i a l ( ' F a b l e 7) i F i v e ,of t h e s e 11 r e s p o n d i n g p a t i e n t s h a d r e c e i v e d p r i o r v i n c r i s t i n e t r e a t m e n t . R e s p o n s e s w e r e s e e n m o s t o f t e n in p a t i e n t s w i t h m e t a s t a t i c c o l o r e c t a l c a n c e r w h e r e , o f 36 e v a l u a b l e p a t i e n t s , t h e r e w a s 1 c o m p l e t e , 1 p a r t i a l , a n d 6 less t h a n p a r t i a l r e m i s s i o n s . T h e o c c u r r e n c e o f p a r t i a l r e m i s s i o n s in p a t i e n t s w i t h esophageal carcinoma, malignant melanoma, and poorly undifferentiated lymphoma w a s also e n c o u r a g i n g .
T a b l e 6. P h a s e h s t u d y o f v l n d e s i n e . P a t i e n t c h a r a c teristics
Number of patients Sex: Female Male Age: Median Range Diagnosis: C:a: Colorectal Breast Renal Squamous, lung esophagus bladder head and neck Malignant melanoma Lymphoma Others*
79 37 42 57 years 15-75 years 36 10 7 6 5 2 2 4 2 5
* I patient each with lymphoepithelioma, endometrial ca, adenocystic ca of palate, adrenal ca arid acute myeloblastic leukemia.
PHASE I AND II STUDIES OF VINDEISEN
35
T a b l e 7, P h a s e II s t u d y o f v i n d e s i n e . R e s p o n s e in e v a l u a b l e p a t i e n t s
Malignancy Colorectal Breast Renal Squamous lung Squamous esophagus M. melanoma Lymphoma Squamous head and neck Others Total
Number of patients 36 9 6 5 4 4 2 2 3 71
Complete remission
Partial remission
Disease stabilization
Disease progression
1
1
14 (6 < PR) 4 3
1 1 1
2
20 5 3 5 1 3 1
Duration of response (weeks) 28+, 32+
12 2 32
2 1
4
3 26 (6 < PR)
40
T h e a n t i t u m o r activity o f vindesine d u r i n g o u r initial Phase I a n d I I studies has b e e n c o m b i n e d a n d s u m m a r i z e d in T a b l e 8. R e m i s s i o n s c o m p l e t e , p a r t i a l , o r less t h a n p a r t i a l - - w e r e o b s e r v e d in a v a r i e t y o f h u m a n t u m o r s , i n c l u d i n g c o l o r e c t a l c a n c e r , a c u t e l e u k e m i a , r e n a l c a r c i n o m a , m a l i g n a n t m e l a n o m a , a n d s q u a m o u s cell c a r c i n o m a s of the lung and esophagus. N i n e o f 17 p a t i e n t s w h o a c h i e v e d a n o b j e c t i v e t u m o r r e s p o n s e w i t h v i n d e s i n e h a d p r i o r e x p o s u r e to v i n c r i s t i n e s u l f a t e , i n d i c a t i n g t h e possible l a c k o f c r o s s - r e s i s t a n c e b e t w e e n these c o m p o u n d s . U n f o r t u n a t e W, w e w e r e u n a b l e to i n v e s t i g a t e t h e c l i n i c a l e f f i c a c y o f v i n d e s i n e in p a t i e n t s w i t h t e s t i c u l a r t u m o r s a n d l y m p h o m a s o f t h e H o d g k i n v a r i e t y , w h e r e t h e p a r e n t c o m p o u n d , v i n b l a s t i n e s u l f a t e , h a s p r o v e d to h a v e s i g n i f i c a n t antitumor activity. T h e h e m a t o l o g i c toxicities e n c o u n t e r e d in t h e P h a s e I I s t u d y o f v i n d e s i n e ( T a b l e 9) w e r e q u i t e s i m i l a r to t h o s e o b s e r v e d in t h e i n i t i a l P h a s e I s t u d y a n d c o n s i s t e d p r i m a r i l y of a moderate degree of neutropenia, which was more significant by approximately D a y 10 o f t r e a t m e n t . N e u t r o p e n i a , o f less t h a n 1000 n e u t r o p h i l s / m l 3, w a s i n f r e q u e n t , as was thrombocytopenia.
T a b l e 8. R e s p o n s e trials*
to v i n d e s i n e d u r i n g P h a s e I a n d II s t u d i e s in p a t i e n t s r e c e i v i n g a d e q u a t e
Malignancy
Number of patients
Colorectal Acute leukemia Renal M. melanoma Breast Lung Esophageal Head and neck Lymphoma Others t
39 14 18 I0 lI 8 5 4 2 7
Complete remission
Partial remission
Disease stabilization
Disease progression
1
1 2
16 (6< PR) 2 7 (2
21 10 II 9 7 7 1 4 1 2
1 1
4 1 (1 < PR) 3 (1 < PR)
1 5
Duration of response (weeks) 2 8 + , 32+ 9, 12 2 12 32
* Patients receiving ~ 2 courses of therapy at doses ~ 3 mg/m 2. t 1 patient each with lelomyosarcoma, adeno, ca of unknown 1°, gallbladder ca, undifferentiated ca, endometrial adeno: ca, squamous bladder ca and lymphoepithelioma.
36
M. VAI.I) IV I ESO T a b l e 9. P h a s e II s t u d y o f v i n d e s i n e . H e m a t o l o g i c toxicity
Numbt.'r evalt~able courses Lowest neutrophil counts × 10a I~led ian Day ()~,~ I000 /,, ~ ,)00 l.owt'st platclet cotmt × 10u Median Day O/ /~ ~<100,000 o/ / 0 ~ 50,000
104 1.8 I0 25 10 200 7 15
4
A m o n g o t h e r side effects ('Fable 10), different degrees o f paresthesias in u p p e r a n d l o w e r extremities, as well as constipation, n a u s e a a n d v o m i t i n g , weakness a n d fever, w e r e o b s e r v e d in a p p r o x i m a t e l y o n e - t h i r d o f the patients. T h e d e g r e e o f paresthesias was v a r i a b l e a n d it b e c a m e severe in 2 p a t i e m s w h o d e v e l o p e d bilateral foot d r o p afier doses o f 6 m g / m z. E l e c t r o r n y o g r a p h i c cxal~ainations, c o n d u c t e d in 6 p a t i e n t s w h o dev e l o p e d clinical signs of p e r i p h e r a l n e u r o p a t h y , revealed d i f f e r e n t degrees of" d e l a y e d p e r i p h e r a l nerve c o n d u c t i o n . C o n t r a r y to o u r e x p e r i e n c e with v i n c r i s t i n e sulfate, however, paresthesias a p p e a r e d m o r e r a p i d l y reversible in v i n d e s i n e - t r c a t e d patients after d i s c o n t i n u i n g the drug. O t h e r m a n i f e s t a t i o n s o f d r u g t o x i c i t y w e r e less fi-equcnt ( T a b l e 10) a n d i n c l u d e d stomatitis, alopecia, phlebitis, d i a r r h e a , a n d myalgias. T a b l e 10. Phase II study of vindcslnc. Other toxlcities
Patients with toxicitics Paresthesias Constipation Nausea and vomillng Weakness Fever Stomatitis Alopccia Dheblitis Diarrhea l~'lvalgias • •
87°/g 3.)/o 35°i', 35~,~) 300/o 30°~) 22% 17o~ 13% / 4. 0.., 4 o/ /O
Conclusion
T h e s e initial Phase I a n d I I studies i n d i c a t e t h a t vindesine shares s o m e o f the favorable a n d u n f a v o r a b l e features o f the o t h e r two v i n c a alkaloids. T h e o b s e r v e d a n t i t u m o r activity o f v i n d e s i n e in patients w i t h h e m a t o l o g i c a n d nonh e m a t o l o g i c m a l i g n a n c i e s w h o h a d r e c e i v e d p r i o r extensive c h e m o t h e r a p y was noticeable a n d is w o r t h y o f f u r t h e r s t u d y . Like its p a r e n t c o m p o u n d , v i n b l a s t i n e sulfate, vindesine p r o d u c e s t r a n s i e n t doser e l a t e d n e u t r o p e n i a a n d d i f f e r e n t d e g r e e s o f gastrointestinal toxicities, w h i c h i n c l u d e constipation, a n d even p a r a l y t i c ileus. Like vincristine sulfate, a n d c o n t r a r y to w h a t was e x p e c t e d f r o m the preclinical studies, the a d m i n i s t r a t i o n o f v i n d e s i n e was associated
PHASE I AND 1I STUDIES OF VINDESINE
37
with clinical manitlzstations of peripheral neuropathy. However, even when these manil?2slations of drug toxicity became dose-limiting, it appeared to us that they were milder in con,parison with the other two vinca alkaloids. We were particularly impressed by the efficacy of vindesine in patients with longterm exposure to vincristine sulfate, which suggests lack of cross-resistance between these compounds and adds to the potential importance of this newer vinca alkaloid derivative.
Phase I and H studies of vindesine Manuel
Valdivieso
UniversiO, of Texas, M . D. Anderson Hospital and Tumor Institute, Houston, Texas, U.S.A.
Introduction W e h a v e c o n d u c t e d trials w i t h v i n d e s i n e at the M. D. A n d e r s o n H o s p i t a l since 1975. O m e x p e r i e n c e w i t h it has n o w b e e n e x p a n d e d to c o m p a r a t i v e studies w i t h t h e p a r e n t c o m p o u n d , v i n b l a s t i n e sulfate, a n d to v i n d e s i n e c o m b i n a t i o n c h e m o t h e r a p y r e g i m e n s fbr p a t i e n t s w i t h g a s t r o i n t e s t i n a l m a l i g n a n c i e s a n d c a n c e r o f t h e lung. T h i s p a p e r d o c u m e n t s o u r o b s e r v a t i o n s m a d e d u r i n g t h e initial P h a s e I a n d I I studies.
Phase I study S i x t y - e i g h t a d u l t s w i t h a v a r i e t y of h u m a n m a l i g n a n c i e s r e c e i v e d v i n d e s i n e . T h e characteristics o f these p a t i e n t s a r e s h o w n in T a b l e 1. M o s t o f t h e m h a d a c u t e l e u k e m i a , r e n a l cell c a r c i n o m a , colorectal c a n c e r a n d m a l i g n a n t m e l a n o m a . A m o n g the 19 p a t i e n t s w i t h a c u t e l e u k e m i a , t h e r e w e r e 10 w i t h a c u t e m y e l o g e n o u s leukemia, 5 with acute lymphoblastic leukemia, 2 with acute undifferentiated.leukemia a n d 2 w i t h blastic t r a n s f o r m a t i o n o f c h r o n i c m y e l o g e n o u s l e u k e m i a . Overall, 32 p a t i e n t s h a d a history o f p r i o r v i n c r i s t i n e t r e a t m e n t a n d 2 h a d r e c e i v e d vinblastine. V i n d e s i n e was a d m i n i s t e r e d as single i n t r a v e n o u s infusions at 2-week intervals. T h e dose o f v i n d e s i n e r a n g e d f r o m a n initial total dose o f 2 m g to a h i g h o f 12.5 rag. T a b l e 2 shows the n u m b e r o f courses g i v e n initially as well as t h e n u m b e r o f courses g i v e n s u b s e q u e n t l y at e a c h dose. O f 176 c h e m o t h e r a p y courses, m o s t p a t i e n t s w e r e g i v e n a total dose r a n g i n g b e t w e e n 7.5 to 10 rag. A s u m m a r y o f t h e h e m a t o l o g i c toxicities e n c o u n t e r e d d u r i n g t h e s t u d y is s h o w n in T a b l e 3. P a t i e n t s w i t h a c u t e l e u k e m i a w e r e e x c l u d e d f r o m this analysis b e c a u s e o f a b n o r m a l b o n e m a r r o w a n d p e r i p h e r a l b l o o d c o u n t s p r i o r to t h e a d m i n i s t r a t i o n o f v i n d e s i n e . By a n d large, t h e h e m a t o l o g i c toxicity o f v i n d e s i n e consisted p r i m a r i l y o f n e u t r o p e n i a w i t h v e r y little effect o n platelets a n d r e d cells. As s h o w n in t h e m i d d l e p o r t i o n o f T a b l e 3, n e u t r o p e n i a a p p e a r e d d o s e - r e l a t e d a n d m o r e p r o n o u n c e d at t h e 0305-7372/80/S00031
+
1980 Academic Press Inc. (London) Ltd.
07 $02.0010 31
32
M. VAI.DIVI ESO T a b l e 1. P h a s e I s t u d y o f v i n d e . s i n e . Patient characteristics
Number of patients Sex: l:enaale Male Age: Median Range Diagnosis: Acute leukemia M. melanoma Sarcoma
Lynaphonaa Ca: Renal Cblorectal Lung Breast Head-neck ()thcrs*
68 23 45 49 years 16-77 years 19 8 3 2 13 8 5 3 3 4
* I patient each with esophageal, undilTcrcntiated, adenoearcinoma of unknown primary and gallbladder ca. h i g h e r doses. H o w e v e r , a t doses l o w e r t h a n 7.5 rag, 80 to 9 0 % o1" tile f i d l - t r e a t m e n t courses w e r e not associated with significant myelosuppression, with the e x c e p t i o n o f a n occasional p a t i e n t w h o h a d h a d prior c h e m o t h e r a p y a n d w h o b e c a m e m y e l o s u p p r c s s c d a t these doses. In a d d i t i o n , the platelct c o u n t d o u b l e d d u r i n g vindesinc t r e a t m e n t in 3 patients w h o received doses o f 2 a n d 4 rag, a n d in w h o m no m y e l o s u p p r e s s i o n d e v e l o p e d . I n contrast, most o f tile patients t r e a t c d with doses o f 7.5 m g o r m o r e d e v e l o p e d m o d e r a t e n c u t r o p e n i a w h i c h was not c u m u l a t i v e a n d w h i c h was reversible in all instances. M o s t paticnts w h o d e v e l o p e d m y e l o s u p p r e s s i o n h a d thcir lowest blood counts after 8 to l0 days o f t r e a t m e n t . A s u m m a r y o f o t h e r toxicitics e n c o u n t e r e d d u r i n g this study, in relation to the doses o f vindcsine a d m i n i s t e r e d , is s h o w n in T a b l e 4. Gastrointestinal a n d n e u r o l o g i c side effects, p r i m a r i l y in the f o r m o f n a u s e a , v o m i t i n g , constipation, paresthcsias, a n d w e a k ness, w e r e observed. T h e f r e q u e n c y a n d severity o f these m a n i f e s t a t i o n s a p p e a r e d to be dose-related, being m o r e p r o n o u n c e d at the highest doses. O f p a r t i c u l a r i m p o r t a n c e was the d e v e l o p m e n t o f t r a n s i e n t p a r a l y t i c ileus in 6 p a t i e n t s ( a p p r o x i m a t e l y 8 % ) at doses o f 4 rag, 7.5 rag, a n d 12.5 mg. T h e neurologic toxicities w e r e a l m o s t twice as c o m m o n in p a t i e n t s w i t h p r i o r v i n c a alkaloid t r e a t m e n t . W e d i d not observe significant a l t e r a t i o n s in b i o c h e m i c a l p a r T a b l e 2. P h a s e I s t u d y o f v l n d e s i n e . N u m b e r o f c o u r s e s g i v e n at e a c h d o s e l e v e l o f vindesine Total dose (nag) 2 4
5-6
Initially
Subsequently
5 9
5 15
4
25
7.5 9-10 12.5
36 14 0
81 47 3
Total
68
176
P H A S E 1 A N D I1 S T U D I E S O F V I N D E S I N E T a b l e 3. P h a s e I s t u d y o f v i n d e s i n e . toxicities
33
Myelosuppressive
Total vindcsine d .'e (rag)
l.eukocytes
Neulrophils
Platclcts
Day
2 4 5-6 7.5 10-12.'3
4.5 5.5 4.0 2.9 2.8
4.5 3.2 2.:3 1.4 1.3
196 150 200 203 229
7 7 8 8 10
tvledian lowest counts × 10a
a m e t c r s o f r e n a l a n d h e p a t i c functions, or o f s c r u m electrolytes, t h a t c o u l d be a t t r i b u t e d to v i n d e s i n e t r e a t m e n t . O f t h e 68 p a t i e n t s , t h e a n t i t u m o r activity o f v i n d e s i n e was e v a l u a b l c in 60 w h o w e r e a b l e to receive a set.ond c o u r s e o f c h e m o t h c r a p y . O f the r e m a i n i n g 8, 5 d i e d w i t h r a p i d t u m o r p r o g r e s s i o n before d a y 15, a n d 3 p a t i e n t s refused a s e c o n d t r e a t m e n t . T w o o u t o f 15 c v a l u a b l c p a t i e n t s w i t h a c u t e Ieuken~ia (one e a c h w i t h l y m p h o b l a s t i c a n d u n d i f f e r e n t i a t e d typcs) a e h i e v c d a p a r t i a l r e m i s s i o n in spite o f extensive p r i o r c h e m o t h e r a p y , w h i c h i n c l u d e d vincristine in all p a t i e n t s ( T a b l e 5). Less t h a n p a r t i a l remissions w c r c o b s e r v e d in 2 o f 13 p a t i e n t s w i t h r e n a l cell c a r c i n o m a s , 1 o u t o f 4 s:ith s q u a m o u s cell l u n g c a n c e r , a n d 1 o u t of 1 w i t h c s o p h a g e a l c a r c i n o m a . R e s p o n s e s w e r e b r i e f a n d h a d a m e d i a n d u r a t i o n o f 12 wecks. I n a n overall assessment o f t h e P h a s e I s t u d y , we d e t e r m i n e d t h a t p a t i e n t s t o l e r a t e d doses o f 7.5 to 10 m g r e p e a t e d at 2-week intervals. T h e m e a n b o d y surface a r c a o f o u r cases w a s 1.85 n f ' . W c c o n c l u d e d t h a t f u t u r e clinical trials w i t h v i n d e s i n e s h o u l d be c o n d u c t e d at doses o f 4 to 5 m g / m z r e p e a t e d at 2 - w e e k i n t e r v a l s in t h o s e w i t h a d e q u a t e b o n e marroxv reserves, a n d t h a t this dose be r e d u c e d to a p p r o x i m a t e l y 3 m g / m Z for p a t i e n t s w i t h extensive p r i o r m y e l o s u p p r e s s i v e c h e m o t h e r a p y .
Phase II study W i t h t h e a b o v e g u i d e l i n e s , a b r o a d P h a s e I I s t u d y o f v i n d e s i n e was i n i t i a t e d in 79 adults. T h e i r c h a r a c t e r i s t i c s a r e s h o w n in T a b l e 6. M o s t p a t i e n t s h a d a d e n o c a r c i n o m a s T a b l e 4. P h a s e I s t u d y o f v i n d e s i n e . O t h e r t o x i c i t l e s 2-6 mg
7.5 m g
10-12.5 mg
58 39 8 2 12 2 6 4 2 14 ~
70 43 16 4 15 4 12 5 7 16 6
97 70 30 2 27 21 19 19 14 13 8
(%)
Patients with toxicity Courses with toxicity Constipation Paralytic ileus Nausea, vomiting and diarrhea Chills and fever Paresthesias Weakness Alopecia Phlebitis and cellulitis Others*
(%)
(%)
* 5 episodes ofarthralgias, 2 ofconfusion and lethargy, 2 of'heartburn" and 1 each of anorexia, jaw pain and hallucinations.
M. VALDIVIESO
34
T a b l e 5. P h a s e I s t u d y o f v i n d e s i n e . R e s p o n s e to v i n d e s i n e t h e r a p y
Duration of response (weeks)*
l~lalignancy
Evaluable patients
Partial remissions
Disease stabilization
Disease progression
Acute leukemia Renal cell b,I. melanoma Colorectal Lung Breast Head and neck Lymphoma Sarcoma Esophageal Others'["
15 13 8 6 4 3 3 2 2 1 3
2
2 4 (2 < PR)
11 9 8 4 3 3 3 2 2
9, 12, 14, 8 20, 21, 25, 32
I
9, 12
2 I (I
1 (< PR) 2
10, 12, 29 5
1
* It includes remissions and disease stabilization. t 1 patient each with adeno, uriknown, l °, gallbladder ca and undifferentiated ca.
o f t h e r e c t u m a n d b r e a s t , w i t h o t h e r d i a g n o s e s b e i n g less f r e q u e n t . W i t h t h e e x c e p t i o n o f I 2 p a t i e n t s - - 7 w i t h r e n a l c a r c i n o m a s a n d 5 w i t h s q u a m o u s cell c a r c i n o m a o f t h e e s o p h a g u s - - t h e r e m a i n i n g 67 p a t i e n t s h a d r e c e i v e d e x t e n s i v e p r i o r c h e m o t h e r a p y w h i c h i n c l u d e d v i n c r i s t i n e s u l f a t e in 24 a n d v i n b l a s t i n e in 1. S e v e n t y - o n e p a t i e n t s r e c e i v e d m o r e t h a n o n e c o u r s e o f v i n d e s i n e c h e m o t h e r a p y a n d , w e r e t h e r e f o r e e v a l u a b l e for response. O v e r a l l , t h e r e w e r e 5 c o m p l e t e a n d p a r t i a l remissions, p l u s 6 a d d i t i o n a l r e s p o n s e s w h i c h w e r e less t h a n p a r t i a l ( ' F a b l e 7) i F i v e ,of t h e s e 11 r e s p o n d i n g p a t i e n t s h a d r e c e i v e d p r i o r v i n c r i s t i n e t r e a t m e n t . R e s p o n s e s w e r e s e e n m o s t o f t e n in p a t i e n t s w i t h m e t a s t a t i c c o l o r e c t a l c a n c e r w h e r e , o f 36 e v a l u a b l e p a t i e n t s , t h e r e w a s 1 c o m p l e t e , 1 p a r t i a l , a n d 6 less t h a n p a r t i a l r e m i s s i o n s . T h e o c c u r r e n c e o f p a r t i a l r e m i s s i o n s in p a t i e n t s w i t h esophageal carcinoma, malignant melanoma, and poorly undifferentiated lymphoma w a s also e n c o u r a g i n g .
T a b l e 6. P h a s e h s t u d y o f v l n d e s i n e . P a t i e n t c h a r a c teristics
Number of patients Sex: Female Male Age: Median Range Diagnosis: C:a: Colorectal Breast Renal Squamous, lung esophagus bladder head and neck Malignant melanoma Lymphoma Others*
79 37 42 57 years 15-75 years 36 10 7 6 5 2 2 4 2 5
* I patient each with lymphoepithelioma, endometrial ca, adenocystic ca of palate, adrenal ca arid acute myeloblastic leukemia.
PHASE I AND II STUDIES OF VINDEISEN
35
T a b l e 7, P h a s e II s t u d y o f v i n d e s i n e . R e s p o n s e in e v a l u a b l e p a t i e n t s
Malignancy Colorectal Breast Renal Squamous lung Squamous esophagus M. melanoma Lymphoma Squamous head and neck Others Total
Number of patients 36 9 6 5 4 4 2 2 3 71
Complete remission
Partial remission
Disease stabilization
Disease progression
1
1
14 (6 < PR) 4 3
1 1 1
2
20 5 3 5 1 3 1
Duration of response (weeks) 28+, 32+
12 2 32
2 1
4
3 26 (6 < PR)
40
T h e a n t i t u m o r activity o f vindesine d u r i n g o u r initial Phase I a n d I I studies has b e e n c o m b i n e d a n d s u m m a r i z e d in T a b l e 8. R e m i s s i o n s c o m p l e t e , p a r t i a l , o r less t h a n p a r t i a l - - w e r e o b s e r v e d in a v a r i e t y o f h u m a n t u m o r s , i n c l u d i n g c o l o r e c t a l c a n c e r , a c u t e l e u k e m i a , r e n a l c a r c i n o m a , m a l i g n a n t m e l a n o m a , a n d s q u a m o u s cell c a r c i n o m a s of the lung and esophagus. N i n e o f 17 p a t i e n t s w h o a c h i e v e d a n o b j e c t i v e t u m o r r e s p o n s e w i t h v i n d e s i n e h a d p r i o r e x p o s u r e to v i n c r i s t i n e s u l f a t e , i n d i c a t i n g t h e possible l a c k o f c r o s s - r e s i s t a n c e b e t w e e n these c o m p o u n d s . U n f o r t u n a t e W, w e w e r e u n a b l e to i n v e s t i g a t e t h e c l i n i c a l e f f i c a c y o f v i n d e s i n e in p a t i e n t s w i t h t e s t i c u l a r t u m o r s a n d l y m p h o m a s o f t h e H o d g k i n v a r i e t y , w h e r e t h e p a r e n t c o m p o u n d , v i n b l a s t i n e s u l f a t e , h a s p r o v e d to h a v e s i g n i f i c a n t antitumor activity. T h e h e m a t o l o g i c toxicities e n c o u n t e r e d in t h e P h a s e I I s t u d y o f v i n d e s i n e ( T a b l e 9) w e r e q u i t e s i m i l a r to t h o s e o b s e r v e d in t h e i n i t i a l P h a s e I s t u d y a n d c o n s i s t e d p r i m a r i l y of a moderate degree of neutropenia, which was more significant by approximately D a y 10 o f t r e a t m e n t . N e u t r o p e n i a , o f less t h a n 1000 n e u t r o p h i l s / m l 3, w a s i n f r e q u e n t , as was thrombocytopenia.
T a b l e 8. R e s p o n s e trials*
to v i n d e s i n e d u r i n g P h a s e I a n d II s t u d i e s in p a t i e n t s r e c e i v i n g a d e q u a t e
Malignancy
Number of patients
Colorectal Acute leukemia Renal M. melanoma Breast Lung Esophageal Head and neck Lymphoma Others t
39 14 18 I0 lI 8 5 4 2 7
Complete remission
Partial remission
Disease stabilization
Disease progression
1
1 2
16 (6< PR) 2 7 (2
21 10 II 9 7 7 1 4 1 2
1 1
4 1 (1 < PR) 3 (1 < PR)
1 5
Duration of response (weeks) 2 8 + , 32+ 9, 12 2 12 32
* Patients receiving ~ 2 courses of therapy at doses ~ 3 mg/m 2. t 1 patient each with lelomyosarcoma, adeno, ca of unknown 1°, gallbladder ca, undifferentiated ca, endometrial adeno: ca, squamous bladder ca and lymphoepithelioma.
36
M. VAI.I) IV I ESO T a b l e 9. P h a s e II s t u d y o f v i n d e s i n e . H e m a t o l o g i c toxicity
Numbt.'r evalt~able courses Lowest neutrophil counts × 10a I~led ian Day ()~,~ I000 /,, ~ ,)00 l.owt'st platclet cotmt × 10u Median Day O/ /~ ~<100,000 o/ / 0 ~ 50,000
104 1.8 I0 25 10 200 7 15
4
A m o n g o t h e r side effects ('Fable 10), different degrees o f paresthesias in u p p e r a n d l o w e r extremities, as well as constipation, n a u s e a a n d v o m i t i n g , weakness a n d fever, w e r e o b s e r v e d in a p p r o x i m a t e l y o n e - t h i r d o f the patients. T h e d e g r e e o f paresthesias was v a r i a b l e a n d it b e c a m e severe in 2 p a t i e m s w h o d e v e l o p e d bilateral foot d r o p afier doses o f 6 m g / m z. E l e c t r o r n y o g r a p h i c cxal~ainations, c o n d u c t e d in 6 p a t i e n t s w h o dev e l o p e d clinical signs of p e r i p h e r a l n e u r o p a t h y , revealed d i f f e r e n t degrees of" d e l a y e d p e r i p h e r a l nerve c o n d u c t i o n . C o n t r a r y to o u r e x p e r i e n c e with v i n c r i s t i n e sulfate, however, paresthesias a p p e a r e d m o r e r a p i d l y reversible in v i n d e s i n e - t r c a t e d patients after d i s c o n t i n u i n g the drug. O t h e r m a n i f e s t a t i o n s o f d r u g t o x i c i t y w e r e less fi-equcnt ( T a b l e 10) a n d i n c l u d e d stomatitis, alopecia, phlebitis, d i a r r h e a , a n d myalgias. T a b l e 10. Phase II study of vindcslnc. Other toxlcities
Patients with toxicitics Paresthesias Constipation Nausea and vomillng Weakness Fever Stomatitis Alopccia Dheblitis Diarrhea l~'lvalgias • •
87°/g 3.)/o 35°i', 35~,~) 300/o 30°~) 22% 17o~ 13% / 4. 0.., 4 o/ /O
Conclusion
T h e s e initial Phase I a n d I I studies i n d i c a t e t h a t vindesine shares s o m e o f the favorable a n d u n f a v o r a b l e features o f the o t h e r two v i n c a alkaloids. T h e o b s e r v e d a n t i t u m o r activity o f v i n d e s i n e in patients w i t h h e m a t o l o g i c a n d nonh e m a t o l o g i c m a l i g n a n c i e s w h o h a d r e c e i v e d p r i o r extensive c h e m o t h e r a p y was noticeable a n d is w o r t h y o f f u r t h e r s t u d y . Like its p a r e n t c o m p o u n d , v i n b l a s t i n e sulfate, vindesine p r o d u c e s t r a n s i e n t doser e l a t e d n e u t r o p e n i a a n d d i f f e r e n t d e g r e e s o f gastrointestinal toxicities, w h i c h i n c l u d e constipation, a n d even p a r a l y t i c ileus. Like vincristine sulfate, a n d c o n t r a r y to w h a t was e x p e c t e d f r o m the preclinical studies, the a d m i n i s t r a t i o n o f v i n d e s i n e was associated
PHASE I AND 1I STUDIES OF VINDESINE
37
with clinical manitlzstations of peripheral neuropathy. However, even when these manil?2slations of drug toxicity became dose-limiting, it appeared to us that they were milder in con,parison with the other two vinca alkaloids. We were particularly impressed by the efficacy of vindesine in patients with longterm exposure to vincristine sulfate, which suggests lack of cross-resistance between these compounds and adds to the potential importance of this newer vinca alkaloid derivative.