`
`~ancer
`
`hemotherapy and
`harmacology
`© Springer-Verlag 1990
`
`Cancer Chemother Pharmacol (1990) 25:395-404 ancer hemotherapy and harmacology (cid:14)9 Springer-Verlag 1990 A strategy for the development of two clinically active cisplatin analogs: CBDCA and CHIP Brenda J. Foster 1, Bonnie J. Harding l, Mary K. Wolpert-DeFilippes 2, Lawrence Y. Rubinstein 3, Kathleen Clagett-Carr 1, and Brian Leyland-Jones 1 I Investigational Drug Branch, 2 Developmental Therapeutics Program, and 3 Biometric Research Branch, National Cancer Institute, Bethesda, Maryland, USA Summary. The antitumor agent cisplatin has a broad an- titumor spectrum and has been incorporated into regimens that are curative for some malignant diseases. However, one of the major limitations to its clinical usefulness is the incidence of severe toxicities involving several major organ systems. Therefore, much enthusiasm has been generated for the development of cisplatin analogs that demonstrate an improved therapeutic index in some pre- clinical models. The two most promising analogs are CBDCA (carboplatin) and CHIP (iproplatin). The preclin- ical and early clinical trial results have demonstrated that these two compounds show activity in cisplatin-responsive tumors. The preclinical background providing the ration- ale for the clinical development of these two analogs is described. We suggest a means of screening for each analog's clinical antitumor activity and determining the analogs' utility against specific malignant diseases com- pared with that of the parent compound or standard treat- ment. Introduction A report by Rosenberg et al. [52] describing the antitumor activity of platinum compounds led to wide-scale clinical investigations of these and other platinum coordination complexes. From these clinical studies, a role for cisplatin in the treatment of a variety of neoplasms was established [34]. The severity of the gastrointestinal and renal toxicities associated with cisplatin administration encouraged trials with schedule manipulations, antiemetic regimens, hydra- tion schema with and without diuretics, and renal prophy- laxis such as hypertonic saline and thiosulfate. In addition, interest was stimulated in the development of alternative platinum compounds with a better therapeutic index and a similar or improved antitumor activity spectrum. Preliminary results against L1210 leukemia and sar- coma 180 in mice [52] demonstrated that the most effica- cious platinum compounds had either a cis configuration for the chloride groups [platinum(II) coordinated com- Offprint requests to: Brian Leyland-Jones, National Cancer In- stitute, Cancer Therapy Evaluation Program, Investigational Drug Branch, Executive Plaza North, Room 731, Bethesda, MD 20892, USA plexes] or were platinum (IV) coordinated complexes. The three properties required for platinum compounds to have antitumor activity are: (a) neutrality; (b) possession of a pair of cis leaving groups that have a lability similar to that of the chlorides; and (c) possession of ligands other than the leaving groups [9, 11, 51]. Two cisplatin analogs with these structural characteristics, CBDCA [diammine 1,1 cyclobutane dicarboxylato Pt(II), JM-8, NSC-241240] and CHIP [bis-isopropylamino-trans-dihydroxy-cis-dichloro Pt(IV), JM-9, NSC-256927], are shown in Fig. 1. Both are undergoing clinical trials sponsored by the National Can- cer Institute (NCI). This paper provides a brief review of the preclinical and phase I data on CBDCA and CHIP to present the background for the development of two first- generation platinum coordination complexes and then describes the NCI's planned development of these two agents. Mechanism of action Platinum coordination complexes inhibit tumor growth by their effects on DNA replication. The binding of these complexes to DNA is similar to that of bifunctional alkylating agents and has been shown to correlate with cytotoxicity in intact cells [15, 41, 42, 64]. All platinum(II) analogs (including CBDCA) induce DNA shortening and superhelical conformational changes, whereas plati- num(IV) compounds (including CHIP) produce DNA de- gradation [40]. Guanine residues have been shown to be a site of DNA cross-linking [26, 32, 36, 54]. The kinetics of the cisplatin- DNA cross-link formation in L1210 leukemia, previously reported by Zwelling et al., required 12 h drug incubation for maximal cross-link formation. For the much less cytotoxic trans isomer, maximal cross-linking occurred by the end of 1 h drug incubation [63]. Other investigators have also reported differences in DNA-protein cross-link kinetics between the cis and trans isomers [35, 37, 41, 42, 54]. Although both CBDCA and CHIP have been shown to react with DNA [8, 20, 40], Mong et al. [40] reported dif- ferences in the types of changes induced in PM-2 DNA by these agents. Cisplatin and CBDCA, both platinum(II) compounds, produced alterations in tertiary DNA confor- mations but had little effect on linear PM-2 DNA; indeed, superhelical structure was a prerequisite for their cyto- toxicity. The activity of both compounds was inhibited by
`
`Platinum coordination complexes inhibit tumor growth by
`their effects on DNA replication. The binding of these
`complexes to DNA is similar to that of bifunctional
`alkylating agents and has been shown to correlate with
`cytotoxicity in intact cells [15, 41, 42, 64]. All platinum(I1)
`analogs (including CBDCA) induce DNA shortening and
`superhelical conformational changes, whereas plati(cid:173)
`num(lV) compounds (including CHIP) produce DNA de(cid:173)
`gradation [40].
`Guanine residues have been shown to be a site of DNA
`cross-linking [26, 32, 36, 54]. The kinetics of the cisplatin(cid:173)
`DNA cross-link formation in LI210 leukemia, previously
`reported by Zwelling et aI., required 12 h drug incubation
`for maximal cross-link formation. For the much less
`cytotoxic trans isomer, maximal cross-linking occurred by
`the end of 1 h drug incubation [63]. Other investigators
`have also reported differences in DNA-protein cross-link
`kinetics between the cis and trans isomers [35, 37, 41,
`42, 54].
`Although both CBDCA and CHIP have been shown to
`react with DNA [8, 20, 40], Mong et ai. [40] reported dif(cid:173)
`ferences in the types of changes induced in PM-2 DNA by
`these agents. Cisplatin and CBDCA, both platinum(II)
`compounds, produced alterations in tertiary DNA confor(cid:173)
`mations but had little effect on linear PM-2 DNA; indeed,
`superhelical structure was a prerequisite for their cyto(cid:173)
`toxicity. The activity of both compounds was inhibited by
`
`A strategy for the development of two clinically
`active cisplatin analogs: CBDCA and CHIP
`
`Brenda J. Foster., Bonnie J. Harding., Mary K. Wolpert-DeFilippes2, Lawrence Y. Rubinstein3
`
`
`and Brian Leyland-Jones!
`
`, Kathleen Clagett-Carr',
`
`I Investigational Drug Branch, 2 Developmental Therapeutics Program, and 3 Biometric Research Branch, National Cancer Institute,
`Bethesda, Maryland, USA
`
`Summary. The antitumor agent cisplatin has a broad an(cid:173)
`titumor spectrum and has been incorporated into regimens
`that are curative for some malignant diseases. However,
`one of the major limitations to its clinical usefulness is the
`incidence of severe toxicities involving several major
`organ systems. Therefore, much enthusiasm has been
`generated for the development of cisplatin analogs that
`demonstrate an improved therapeutic index in some pre(cid:173)
`clinical models. The two most promising analogs are
`CBDCA (carboplatin) and CHIP (iproplatin). The preclin(cid:173)
`ical and early clinical trial results have demonstrated that
`these two compounds show activity in cisplatin-responsive
`tumors. The preclinical background providing the ration(cid:173)
`ale for the clinical development of these two analogs is
`described. We suggest a means of screening for each
`analog's clinical antitumor activity and determining the
`analogs' utility against specific malignant diseases com(cid:173)
`pared with that of the parent compound or standard treat(cid:173)
`ment.
`
`plexes] or were platinum (IV) coordinated complexes. The
`three properties required for platinum compounds to have
`antitumor activity are: (a) neutrality; (b) possession of a
`pair of cis leaving groups that have a lability similar to that
`of the chlorides; and (c) possession of ligands other than
`the leaving groups [9, 11,51]. Two cisplatin analogs with
`these structural characteristics, CBDCA [diammine 1,1
`cyclobutane dicarboxylato Pt(I1), JM-8, NSC-241240] and
`CHIP
`[bis-isopropylamino- trans-dihydroxy- cis-dichloro
`Pt(IV), JM-9, NSC-256927], are shown in Fig. 1. Both are
`undergoing clinical trials sponsored by the National Can(cid:173)
`cer Institute (NCI). This paper provides a brief review of
`the preclinical and phase I data on CBDCA and CHIP to
`present the background for the development of two first(cid:173)
`generation platinum coordination complexes and then
`describes the NCI's planned development of these two
`agents.
`
`Mechanism of action
`
`Introduction
`A report by Rosenberg et ai. [52] describing the antitumor
`activity of platinum compounds led to wide-scale clinical
`investigations of these and other platinum coordination
`complexes. From these clinical studies, a role for cisplatin
`in the treatment of a variety of neoplasms was established
`[34]. The severity of the gastrointestinal and renal toxicities
`associated with cisplatin administration encouraged trials
`with schedule manipulations, antiemetic regimens, hydra(cid:173)
`tion schema with and without diuretics, and renal prophy(cid:173)
`laxis such as hypertonic saline and thiosulfate. In addition,
`interest was stimulated in the development of alternative
`platinum compounds with a better therapeutic index and a
`similar or improved antitumor activity spectrum.
`Preliminary results against LI210 leukemia and sar(cid:173)
`coma 180 in mice [52] demonstrated that the most effica(cid:173)
`cious platinum compounds had either a cis configuration
`for the chloride groups [platinum(I1) coordinated com-
`
`Offprint requests to: Brian Leyland-Jones, National Cancer In(cid:173)
`stitute, Cancer Therapy Evaluation Program, Investigational
`Drug Branch, Executive Plaza North, Room 731, Bethesda, MD
`20892, USA
`
`NOVARTIS EXHIBIT 2055
`Par v. Novartis, IPR 2016-01479
`Page 1 of 10
`
`
`
`396
`
`CHEMICAL STRUCTURE
`
`COMMON NAME
`
`NSC #
`
`JM#
`
`Cis Platinum,
`Cisplatin
`
`119875
`
`o
`II
`
`Pt
`
`/O -C>o
`"'-0 - C
`II
`o
`
`CBDCA
`Carboplatin
`
`241240
`
`8
`
`CH 3
`r
`OH
`CH 3 _ CH - NH2~ I /CI
`Pt
`I ~CI
`OH
`
`- CH - NH /
`I
`2
`
`CH
`3
`
`CHIP,
`Iproplatin
`
`256927
`
`9
`
`CH 3
`
`Fig. 1. Structures, names, and NSC numbers of cisplatin and two analogs
`
`Table 1. Antitumor activity of cisplatin, CBDCA, and CHIP against the tumor panel
`
`Tumor system
`
`CBDCA:
`
`Treatment Cisplatin:
`schedule
`(i.p.)
`
`Dose
`range b
`(mg/kg)
`
`T/C±SEa Score c Dose
`(%)
`range
`(mg/kg)
`
`T/C±SE
`(%)
`
`Score
`
`CHIP:
`
`Dose
`range
`(mg/kg)
`
`12.5
`
`50.0
`
`25.0
`
`T/C±SE Score
`(%)
`
`++
`
`++
`
`166
`
`(6)
`
`(46)
`
`12.5-25.0 183± 14 ++
`
`396 CHEMICAL STRUCTURE COMMON NAME NSC # JM# NH~ jct Pt NH3 "j ~ CI Cis Platinum, Cisplatin 119875 NH3~ NH3 / 0 II Pt/o-c ~o c II 0 CBDCA , 241240 Carboplatin CHa I CH 3- CH-- NH2~ OH/CII Pt J l ~c, OH 3 -- CH -- NH2 OH I CH3 CHIP, Iproplatin Fig. 1. Structures, names, and NSC numbers of cisplatin and two analogs 256927 9 Table 1. Antitumor activity of cisplatin, CBDCA, and CHIP against the tumor panel Tumor system Treatment Cisplatin: CBDCA: schedule (i.p.) CHIP: Dose T/C+SE a Score c Dose T/C+SE Score Dose T/C+SE range b (%) range (%) range (%) (mg/kg) (mg/kg) (mg/kg) Score Murine tumors: i.p. B16 qld, 0.2-4.0 178+2 + + 12.5- 25.0 172+ 4 + + 12.5 166 + + melanocarcinoma days 1-9 s.c. CD8 F, q7d, 4.0-12.5 (1 + 1) + + 50.0-100.0 (8) + + 50.0 (6) + + mammary tumor days 1-29 s.c. colon q7d, 2,0-16.0 (38+5) + 100.0-200.0 (33__+11) + 25.0 (46) - 38 tumor days 2,9 i.p. L1210 q7d, 2.0- 4.0 162+2 ++ 25.0- 64.0 148+ 7 + 12.5-25.0 183+14 ++ leukemia days 1-9 i.v. Lewis qld, 0.5- 2.0 153_+6 ++ 6.3- 25.0 119+ 7 - 6.3-12.5 129 - lung-carcinoma days 1-9 Human tumor xenografts : s.c. CX-1 q4d x 3, 2-4 (8l_+8) - 12.5- 50.0 (63) - 25.0 (41) colon tumor days 14- 22 s.c. LX-1 q4d x 3, 2 - 8 (69) - 50.0 (140) - 25.0 (94) lung tumor days 14 s.c. MX-1 q4d x 3, 4-8 (3) + + 25.0 (43) - 25.0 (59) mammary tumor days 14 Optima i.p. dose, days 1-9 1.6 mg/kg 16 mg/kg 14 mg/kg Antitumor activity expressed as the mean optimal T/C (% indicated) (NIH Publication 84 2635) b Dose range for which optimal activity in a dose response was observed. Minimal criteria for activity: % T/C for survival assays - L1210, B16, >~ 125%; Lewis lung, >! 140%; %TC for tumor weight-inhibition assays - CD8 F1, colon 38, ~<42%; CX-I, LX-1, MX-1, ~<20% c DN2 criteria for activity: % T/C for survival assays, I> 150%; % T/C for tumor weight-inhibition assays, < 10% (values in parentheses). + +, Minimal criteria for activity; --, no activity
`
`a Antitumor activity expressed as the mean optimal T/C (% indicated) (NIH Publication 84 2635)
`b Dose range for which optimal activity in a dose response was observed. Minimal criteria for activity: % T/C for survival assays -
`LI2l0, BI6, ;;'125%; Lewis lung, ;;.140%; %TC for tumor weight-inhibition assays - CD 8 Flo colon 38, ';;42%; CX-I, LX-I, MX-I, ';;20%
`c DN2 criteria for activity: % T /C for survival assays, ;;'150%; % T/C for tumor weight-inhibition assays, .;; 10% (values in parentheses).
`+ +, Minimal criteria for activity; -, no activity
`
`Murine tumors:
`q1d,
`i.p. BI6
`melanocarcinoma days 1-9
`s.c. CDgF,
`q7d,
`mammary tumor
`days 1-29
`q7d,
`s.c. colon
`days 2,9
`38 tumor
`q7d,
`i.p. LI210
`days 1-9
`leukemia
`q1d,
`Lv. Lewis
`days 1-9
`lung-carcinoma
`
`Human tumor xenografts:
`q4dx3,
`s.c. CX-I
`days 14-22
`colon tumor
`q4dx3,
`s.c. LX-1
`days 14
`lung tumor
`q4d x 3,
`s.c. MX-l
`mammary tumor
`days 14
`Optima i.p. dose, days 1-9
`
`0.2-4.0
`
`178±2
`
`4.0-12.5
`
`(I ± 1)
`
`2.0-16.0
`
`(38± 5)
`
`2.0- 4.0 162±2
`
`0.5- 2.0 153±6
`
`++
`
`++
`
`+
`
`++
`
`++
`
`12.5- 25.0 172± 4
`
`50.0-100.0
`
`(8)
`
`100.0 - 200.0
`
`(33± 11)
`
`25.0- 64.0
`
`148± 7
`
`++
`
`++
`
`+
`
`+
`
`6.3- 25.0
`
`119± 7
`
`6.3-12.5 129
`
`2-4
`
`(81 ± 8)
`
`12.5- 50.0
`
`(63)
`
`2-8
`
`(69)
`
`4-8
`
`(3)
`
`++
`
`50.0
`
`25.0
`
`(140)
`
`(43)
`
`25.0
`
`25.0
`
`25.0
`
`(41)
`
`(94)
`
`(59)
`
`1.6 mg/kg
`
`16 mg/kg
`
`14 mg/kg
`
`NOVARTIS EXHIBIT 2055
`Par v. Novartis, IPR 2016-01479
`Page 2 of 10
`
`
`
`397
`
`Reference
`
`Table 2. Comparative activity of cisplatin, CBDCA, and CHIP against mouse leukemias
`
`Tumor
`
`Treatment
`schedule
`
`Ll210
`
`Day I
`Day 1
`Days 1-9
`Days 1-9
`or
`Days 1,5,9
`Ll210/CDDP Day 1
`Ll210
`Day I
`in vivo --+
`in vitro
`P388
`
`Days 1-9
`Days 1,5,9
`
`Cisplatin:
`
`Dose
`(mg/kg)
`
`4-10
`8
`2/day
`
`Activity
`
`CBDCA:
`
`Dose
`(mg/kg)
`
`Activity
`
`CHIP:
`
`Dose
`(mg/kg)
`
`Activity
`
`157%-186% TIC
`164%-229% TIC
`157%-285% TIC
`
`32
`128
`64
`
`171%T/C
`150% TIC
`157% TIC
`
`50
`32
`16/day
`
`137% TIC
`171% TIC
`207% TIC
`
`[2,7,8,41,
`45,46]
`
`1.6-2.4/day
`
`186%-257% TIC
`
`25/day
`
`152% TIC
`
`25/day
`
`191% TIC
`
`4-8
`9
`
`94%-131% TIC
`Surviving
`fraction
`= 50%-
`
`120
`336
`
`25
`
`113% TIC
`Surviving
`fraction
`= 50%-
`152% TIC
`
`32
`135
`
`18
`50
`
`118%T/C
`Surviving
`fraction
`= 50%-
`202% TIC
`154% TIC
`
`[46]
`[27]
`
`[7,8]
`
`Table 2. Comparative activity of cisplatin, CBDCA, and CHIP against mouse leukemias 397 Tumor Treatment Cisplatin: CBDCA: CHIP: Reference schedule Dose Activity Dose Activity Dose Activity (mg/kg) (mg/kg) (mg/kg) L1210 Day 1 4-10 157%- 186% T/C 32 171% T/C 50 137% T/C [2,7,8,41, Day 1 8 164%-229% T/C 128 150% T/C 32 171% T/C 45,46] Days 1-9 2/day 157%-285% T/C 64 157% T/C 16/day 207% T/C Days 1-9 or 1.6-2.4/day 186%-257% T/C 25/day 152% T/C 25/day 191% T/C Days 1, 5, 9 L1210/CDDP Day 1 4-8 94%- 131% T/C 120 113% T/C 32 118% T/C [46] L1210 Day 1 9 Surviving 336 Surviving 135 Surviving [27] in vivo -~ fraction fraction fraction in vitro = 50% ~ = 50% a = 50% a P388 Days 1-9 - - 25 152% T/C 18 202% T/C [7, 8] Days 1, 5, 9 .... 50 154% T/C In vitro colony formation assay. Shown is the dose that caused a 50% reduction in the colony formation of tumor cells in vitro following treatment of tumor-bearing mice. %T/C, Median survival time of drug-treated tumor-bearing mice compared with that of mice treated with vehicle only. Drugs were given i.p. sodium chloride. CHIP, a platinum(IV) compound, caused breakage of covalently closed, circular PM-2 DNA; this breakage was not inhibited by sodium chloride. This suggests involvement of the axial trans bonds rather than the equatorial cis bonds [40]. In addition, the con- centration of CHIP required to produce DNA damage was higher than that required for cytotoxicity [401, suggesting that DNA breakage may not be the primary mechanism of cytotoxicity. Antitumor activity CBDCA and CHIP have been tested for antitumor activity against many in vitro and in vivo tumor models, including human tumor xenografts. Comparative results obtained with the analogs and cisplatin at optimal doses against tumors used in a preclinical screen at the NCI are shown in Table 1 [60, 61]. These data are the results of screening carried out under the auspices of the Developmental Therapeutics Program (Division of Cancer Treatment, NCI, Bethesda, Md). Cisplatin showed the broadest ac- Table 3. Toxicity of cisplatin, CBDCA, and CHIP after a single i.v. dose in male F344 rats Cisplatin CBDCA CHIP mg/kg (rag/m2) mg/kg (rag/m2) mg/kg (rag/m2) LD 10 LDs0 LDs0 a LDt0 LD 50 b LDs0 6 (36) 52.5 (313.2) 33.4 (200.4) 8 (48) 60.9 (365.4) 39.0 (234.0) 1.3 1.2 1.2 7.6 4.9 LD 10 or LDs0 is the dose that produced lethality in 10% or 50%, respectively, of the rats treated (data from [58]) a LDso compound in mg/kg LD to compound in mg/kg = toxicity quotient b LDs0 analog in mg/kg LDs0 cisplatin in mg/kg = potency ratio Table 4. (a) Comparative toxicity of cisplatin, CBDCA, and CHIP after a single i.v. injection in male F344 rats Parameter Cisplatin CBDCA CHIP Hematocrit 1 3 2 WBC 3 2 3 BUN 3 1 1 Creatinine 3 1 1 SGPT 1 1 1 Body weight loss 3 1 2 Histopathology: Renal 4 1 3 Lymphatic 4 1 4 Hematopoietic 3 4 3 Gastrointestinal 4 1 1 Total score: 30 16 21 (b) Scoring used for comparative toxicity of platinum compounds after single-dose administration Parameter Scoring system and definitions Hematocrit, 1 WBC 2 3 BUN, creatinine, 1 SGPT 2 3 Body weight loss I 2 3 Histopathology 1 2 3 4 = <20% decrease = 20%-50% decrease = > 50% decrease = < 50% decrease = 50%- 200% increase = > 200% increase = no weight loss (maybe slowing of growth) = < 10% (or < 15% serial bleeding) weight loss = > 10% (or > 15% serial bleeding) weight loss = no lesions = mild lesions in few animals = lesions of moderate to marked severity = lesions of marked to extreme severity WBC, leukocyte count; BUN, blood urea nitrogen; SGPT, glu- tamic pyruvic transaminase Data from [58]
`
`Antitumor activity
`CBDCA and CHIP have been tested for antitumor activity
`against many in vitro and in vivo tumor models, including
`human tumor xenografts. Comparative results obtained
`with the analogs and cisplatin at optimal doses against
`tumors used in a preclinical screen at the NCI are shown
`in Table 1 [60, 61]. These data are the results of screening
`carried out under the auspices of the Developmental
`Therapeutics Program (Division of Cancer Treatment,
`NCI, Bethesda, Md). Cisplatin showed the broadest ac-
`
`a In vitro colony formation assay. Shown is the dose that caused a 50% reduction in the colony formation of tumor cells in vitro following
`treatment of tumor-bearing mice. % TIC, Median survival time of drug-treated tumor-bearing mice compared with that of mice treated
`with vehicle only. Drugs were given i.p.
`
`sodium chloride. CHIP, a platinum(IV) compound,
`caused breakage of covalently closed, circular PM-2
`DNA; this breakage was not inhibited by sodium chloride.
`This suggests involvement of the axial trans bonds rather
`than the equatorial cis bonds [40]. In addition, the con(cid:173)
`centration of CHIP required to produce DNA damage was
`higher than that required for cytotoxicity [40], suggesting
`that DNA breakage may not be the primary mechanism of
`cytotoxicity.
`
`Table 3. Toxicity of cisplatin, CBDCA, and CHIP after a single
`i.v. dose in male F344 rats
`
`Cisplatin
`CBDCA
`CHIP
`mg/kg (mg/m 2) mg/kg (mg/m2) mg/kg (mg/m 2)
`
`6 (36)
`8 (48)
`
`1.3
`
`LD lo
`LD50
`LDso"
`LD lo
`LDsOb
`LD50
`
`52.5 (313.2)
`60.9 (365.4)
`
`33.4 (200.4)
`39.0 (234.0)
`
`1.2
`
`7.6
`
`1.2
`
`4.9
`
`LD 10 or LD so is the dose that produced lethality in 10% or 50%,
`respectively, of the rats treated (data from [58])
`a LD 50 compound in mg/kg
`. .
`.
`d .
`toxIcIty quotIent
`Ik
`LD
`10 compoun
`III mg g
`b LD 50 analog in mg/kg
`I . .
`.
`Ik
`LD
`50 CISP atm III mg g
`
`.
`= potency ratIO
`
`=
`
`Table 4. (a) Comparative toxicity of cisplatin, CBDCA, and CHIP
`after a single i.v. injection in male F344 rats
`
`Parameter
`
`Cisplatin
`
`CBDCA
`
`CHIP
`
`Hematocrit
`WBC
`BUN
`Creatinine
`SGPT
`Body weight loss
`Histopathology:
`Renal
`Lymphatic
`Hematopoietic
`Gastrointestinal
`Total score:
`
`I
`3
`3
`3
`I
`3
`
`4
`4
`3
`4
`30
`
`3
`2
`I
`I
`I
`I
`
`I
`I
`4
`I
`16
`
`2
`3
`I
`I
`I
`2
`
`3
`4
`3
`I
`21
`
`(b) Scoring used for comparative toxicity of platinum compounds
`after single-dose administration
`
`Parameter
`
`Scoring system and definitions
`
`Hematocrit,
`WBC
`
`I = < 20% decrease
`2 = 20% - 50% decrease
`3 = > 50% decrease
`BUN, creatinine, I = < 50% decrease
`SGPT
`2 = 50%-200% increase
`3 = > 200% increase
`I = no weight loss (maybe slowing of growth)
`2 = < 10% (or < 15% serial bleeding) weight loss
`3 = 2: 10% (or> 15% serial bleeding) weight loss
`I = no lesions
`2 = mild lesions in few animals
`3 = lesions of moderate to marked severity
`4 = lesions of marked to extreme severity
`
`Body weight loss
`
`Histopathology
`
`WBC, leukocyte count; BUN, blood urea nitrogen; SGPT, glu(cid:173)
`tamic pyruvic transaminase
`Data from [58]
`
`NOVARTIS EXHIBIT 2055
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`Page 3 of 10
`
`
`
`398
`
`tivity spectrum, with significant activity against i. v. Lewis
`lung carcinoma and s. c. human mammary xenograft [60,
`61], neither of which were affected by CBOCA or CHIP.
`Both cisplatin and CBOCA showed a similar level of ac(cid:173)
`tivity against s. c. colon 38, whereas CHIP showed no ac(cid:173)
`tivity. Cisplatin and CHIP showed quantitatively better
`activity against i. p. LI2l0 than did CBOCA [60,61].
`The results of comparative experiments in mouse
`leukemias are summarized in Table 2 [4, 9, 10, 29, 45, 49,
`50, 58]. The LI210 in vivo and in vitro results clearly indi(cid:173)
`cate that cisplatin has the highest potency, followed by
`CHIP, with CBOCA being the least potent [29]. An LI2l0
`line made resistant in vitro to cisplatin (LI2lO/COOP)
`demonstrated cross-resistance to CBOCA and CHIP [49].
`
`Toxicology
`Comparative toxicologic studies showed CBOCA and
`CHIP to be less potent than the parent compound, as
`evidenced by the defined toxic doses shown in Table 3 [58].
`The severity of myelosuppression, nephrotoxicity, and
`gastrointestinal toxicity caused by the parent compound
`was qualitatively different from that observed after treat(cid:173)
`ment with the two analogs, as shown in Table 4 [29, 45, 50,
`58]. Both CBOCA and CHIP produced more hematologic
`toxicity than did cisplatin, but they caused much less renal
`toxicity than the parent drug. Cisplatin produced more
`severe histopathologic lesions in the gastrointestinal tract
`than did either analog.
`In summary, toxicologic studies showed the two
`analogs to be less potent than cisplatin, and, although the
`same organ systems (hematologic, renal, and gastrointes(cid:173)
`tinal) were affected by all three compounds, the patterns
`of toxicity were different. The analogs consistently showed
`less renal and gastrointestinal toxicity but more hema(cid:173)
`topoietic toxicity than did cisplatin.
`
`Clinical studies results
`
`Phase I trials
`
`398 tivity spectrum, with significant activity against i.v. Lewis lung carcinoma and s.c. human mammary xenograft [60, 61], neither of which were affected by CBDCA or CHIP. Both cisplatin and CBDCA showed a similar level of ac- tivity against s.c. colon 38, whereas CHIP showed no ac- tivity. Cisplatin and CHIP showed quantitatively better activity against i.p. LI210 than did CBDCA [60, 61]. The results of comparative experiments in mouse leukemias are summarized in Table 2 [4, 9, 10, 29, 45, 49, 50, 58]. The L1210 in vivo and in vitro results clearly indi- cate that cisplatin has the highest potency, followed by CHIP, with CBDCA being the least potent [29]. An L1210 line made resistant in vitro to cisplatin (L1210/CDDP) demonstrated cross-resistance to CBDCA and CHIP [49]. Toxicology Comparative toxicologic studies showed CBDCA and CHIP to be less potent than the parent compound, as evidenced by the defined toxic doses shown in Table 3 [58]. The severity of myelosuppression, nephrotoxicity, and gastrointestinal toxicity caused by the parent compound was qualitatively different from that observed after treat- ment with the two analogs, as shown in Table 4 [29, 45, 50, 58]. Both CBDCA and CHIP produced more hematologic toxicity than did cisplatin, but they caused much less renal toxicity than the parent drug. Cisplatin produced more severe histopathologic lesions in the gastrointestinal tract than did either analog. In summary, toxicologic studies showed the two analogs to be less potent than cisplatin, and, although the same organ systems (hematologic, renal, and gastrointes- tinal) were affected by all three compounds, the patterns of toxicity were different. The analogs consistently showed less renal and gastrointestinal toxicity but more hema- topoietic toxicity than did cisplatin. Clinical studies results Phase I trials Comparative results from phase I studies of cisplatin, CBDCA, and CHIP in adults are shown in Table 5 [5-7, 12-14, 17, 22, 24, 25, 27, 31, 33, 46, 47, 53, 55, 57, 59]. Based on the total dose (in milligrams) tolerated for each drug, cisplatin is the most potent; CHIP, intermediate; and CBDCA, the least potent. CBDCA and CHIP differed from cisplatin in the relative severity of their gastrointes- tinal, neurologic, renal, and hematologic side effects. Hematologic effects, especially thrombocytopenia, were dose-limiting for CBDCA and CHIP [5, 6, 12, 13, 17, 22, 24, 27, 31, 46, 47, 53, 55, 57, 59], whereas renal, hematologic, and gastrointestinal effects were frequently dose-limiting for cisplatin [12, 22, 53, 57]. Diarrhea was reported from studies of CHIP, but it was not dose-limit- ing [5, 13, 17, 24, 47]. Renal toxic effects observed in studies of CBDCA and CHIP occurred in patients who had preexisting renal disease or a concomitant nephro- toxic event [6, 14, 17, 27, 47]. No new neurologic toxicity was found with administration of the analogs; however, exacerbations of preexisting neurologic defects were ob- served following treatment with CBDCA [6, 14, 27, 55]. Antitumor effects were reported from the phase I trials of each compound, particularly in patients with ovarian car- cinoma. In summary, less renal toxicity was seen with the analogs and hematologic toxic effects were dose-limiting in phase I testing of CBDCA and CHIP, confirming the results seen in preclinical toxicologic studies. Clinical pharmacokinetics The clinical pharmacokinetic parameters of the three com- pounds after i.v. single-dose administration are sum- marized in Table 6. Total and filterable (free, non-protein- bound) platinum values were determined using flameless atomic absorption spectrophotometry [18, 19, 21, 24, 43]. Following CBDCA or CHIP administration, the plot of the plasma levels for either total or filterable platinum was most often described as biexponential. The initial half-life (h/2) was usually ~1 h, whereas the terminal half-life (h/213) ranged from 7 h to over 5 days. This biexponential pattern was not reported for cisplatin. Thus far, no major phar- macokinetic differences have been observed that explain the differences in clinical potency and toxicity of these three analogs. Developmental plans The simultaneous clinical development of CBDCA and CHIP has stimulated many questions regarding the rela- tive utility of each with respect to the other as well as to cisplatin. The scientific questions center around the rela- tive therapeutic index (antitumor effects vs acute and chronic toxic side effects) of each compound relative to the others. This section describes some of the clinical developmental plans for these two analogs as well as giving specific illustrative examples for each of the three main disease categories. Disease-oriented strategy. To incorporate the concept of relative therapeutic index into the phase II and phase Ill developmental plans, diseases were divided into three major categories according to cisplatin responsiveness and whether or not cisplatin was an important component of currently used standard treatment of the advanced disease. Illustrative examples of these disease categories are given in Table 7 and include the following: A Cisplatin-sensitive diseases, where standard therapy in- corporating cisplatin is curative; examples include germ- cell tumors and epithelial ovarian carcinomas. In this category, it is highly likely that CBDCA and CHIP would have some antitumor activity; in fact, hints of tumor responsiveness were seen in patients with ovarian car- cinoma entered in the phase I trials. In this category, the usefulness of a traditional phase II trial was questioned. A phase II trial entering 30-40 patients would delineate an analog's antitumor activity with such broad confidence limits that it would not be possible to determine the ac- tivity relative to that of the parent compound. Therefore, the plan was to move directly from phase I testing to phase III comparative trials. An illustrative example for this category is provided by a comparative trial of one analog with the parent com- pound. Patients with advanced ovarian carcinoma who had not received prior chemotherapy were randomized to receive a combination of either CBDCA plus cyclophos- phamide or cisplatin plus cyclophosphamide [1]. The cyclophosphamide dose (mg/m 2) was the same in each combination. Preliminary results show equivalent activity;
`
`Comparative results from phase I studies of cisplatin,
`CBOCA, and CHIP in adults are shown in Table 5 [5 - 7,
`12-14, 17, 22, 24, 25, 27, 31, 33, 46, 47, 53, 55, 57, 59].
`Based on the total dose (in milligrams) tolerated for each
`drug, cisplatin is the most potent; CHIP, intermediate;
`and CBOCA, the least potent. CBOCA and CHIP differed
`from cisplatin in the relative severity of their gastrointes(cid:173)
`tinal, neurologic, renal, and hematologic side effects.
`Hematologic effects, especially thrombocytopenia, were
`dose-limiting for CBOCA and CHIP [5, 6, 12, 13, 17, 22,
`24, 27, 31, 46, 47, 53, 55, 57, 59], whereas renal,
`hematologic, and gastrointestinal effects were frequently
`dose-limiting for cisplatin [12, 22, 53, 57]. Oiarrhea was
`reported from studies of CHIP, but it was not dose-limit(cid:173)
`ing [5, 13, 17, 24, 47]. Renal toxic effects observed in
`studies of CBOCA and CHIP occurred in patients who
`had preexisting renal disease or a concomitant nephro(cid:173)
`toxic event [6, 14, 17, 27, 47]. No new neurologic toxicity
`was found with administration of the analogs; however,
`exacerbations of preexisting neurologic defects were ob(cid:173)
`served following treatment with CBOCA [6, 14, 27, 55].
`Antitumor effects were reported from the phase I trials of
`each compound, particularly in patients with ovarian car(cid:173)
`cinoma. In summary, less renal toxicity was seen with the
`
`analogs and hematologic toxic effects were dose-limiting
`in phase I testing of CBOCA and CHIP, confirming the
`results seen in preclinical toxicologic studies.
`
`Clinical pharmacokinetics
`
`The clinical pharmacokinetic parameters of the three com(cid:173)
`pounds after i. v. single-dose administration are sum(cid:173)
`marized in Table 6. Total and filterable (free, non-protein(cid:173)
`bound) platinum values were determined using flameless
`atomic absorption spectrophotometry [18, 19, 21, 24, 43].
`Following CBOCA or CHIP administration, the plot of
`the plasma levels for either total or filterable platinum was
`most often described as biexponential. The initial half-life
`(tId was usually < 1 h, whereas the terminal half-life (t1/2 ~)
`ranged from 7 h to over 5 days. This biexponential pattern
`was not reported for cisplatin. Thus far, no major phar(cid:173)
`macokinetic differe