Schedule Dependency of Orally Administered Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in Vivo Mark J. McKeage, Lloyd R. Kelland, Frances E. Boxall, et al. Cancer Res 1994;54:4118-4122. Published online August 1, 1994.
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[CANCER RESEARCH54, 4118-4122, August 1, 19941
Schedule Dependency of Orally Administered Bis-acetato-ammine-dichioro cyclohexylamine-platinum(IV) (JM216) in Vivot Mark J. McKeage,2'@ Lloyd R. Kelland, Frances K Boxall, Melanie it Valenti, Mervyn Jones, Phyllis M. Goddard, Jean Gwynne, and Kenneth R. Harrap Drug Development Section@ The Institute ofCancer
Researck
Block E, 15 Cotswold Roa4 Belmonz Suuon@Surrey SM2 5NG, United Kingdom
ABSTRACT JM216 is a novel antitumor platlnum(IV) complex displaying oral activity, dose-limiting myelosuppression, and a lack of nephro- and neu rotoxicity in rodents. It has been selected for clinical evaluation. The schedule dependency of its antitumor action against a murine (ADJ/PC6 plasmacytoma)
and
a human
tumor
model
(PXN1O9T/C
ovarian
carci
noma xenograft) was studied in vivo. Single dose (q2ld), once a day dosing for 5 consecutive days (q2ld or q2Sd), and once a day dosing indefinitely (chronic
daily dosing) administration
schedules
were compared.
Against
the murine ADJ/PC6 plasmacytoma, daily xS administration improved the tolerance, antitumor potency, and therapeutic index of oral JM216, compared
to single dose administration,
whereas no advantage
was found
for fractionating cisplatin dosages. Against the PXN1O9T/Chuman ovar ian carcinoma xenograft, oral JM216, given at dose levels delivering a equivalent mg/kg/day
total dose on single dose (200 mg/kg q2ld), daily x5 (40 q2ld) and chronic daily dosing (9.5 mgfkaJd) schedules,
showed superior tumor growth delays (55 ±15 days; P < 0.05) and maximal tumor regression (10 ± 11% of initial tumor volume; P < 0.001) with the daily xS schedule. Gastrointestinal toxicity (P < 0.05) and mild nephrotoxicity (P < 0.01) complicated the chronic daily dosing schedule, while leukopenia (P < 0.02) and thrombocyto penia (P < 0.01) were dose-limiting for the single dose and daily xS administration, respectively. Peak plasma ultrafiltrate (PUF) platinum levels were below cytotoxic levels (PUF Cmax, 0.11 ±0.066 mg/I) at the maximally tolerable dose for the chronic dosing schedule (9.5 mg/kgJ. Peak PUF platinum levels did not increase significantly with a 5-fold increase in dosage from 40 mg/kg (PUF Cmax 1.5 ±0.11 mg/I) to 200 mg/kg (PUF Cmax, 2.4 ±0.44 mg/I; P > 0.05). In conclusion, these data demonstrate antitumor schedule dependency for oral JM216 in vivo, independently in two tumor model systems, and with nonlinear pharmacokinetics after Its oral administration to mice. Optimal anti
tumor activity, tolerance, and pharmacoidnetics occurred with daily x5 dosing, and this has prompted the clinical evaluation of this administration
schedule.
INTRODUCTION
resistance,
and,
unlike
cisplatin,
displays
marked
Received 11/3/93; accepted 6/1/94. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. work
was
supported
by grants
to the
Institute
of Cancer
Research
by the Cancer
Research Campaign (United Kingdom), the Medical Research Council, The Johnson Matthey Technology Centre, and Bristol Myers Squibb Oncology. 2 To
whom
3 Present
requests address:
for
reprints
Oncology
should
Research
be
addressed.
Centre,
Institute
of
Oncology,
The
Prince
of
Wales Hospital, High Street, Randwick, Sydney NSW 2031, Australia. 4 The abbreviations used are: JM216,
days results in improved
tumor
response rates (from 10 to 89%) with changes in neither the incidence nor severity of toxicity (8). Continuous protracted i.v. infusions of the antimetabolite 5-fluorouracil results in improved response rates in advanced colorectal carcinoma and also reduced hematological and gastrointestinal toxicity, in comparison antitumor action of the existing clinical
to bolus schedules (9). The platinum drags do not appear
dependent upon administration schedule (10), while their toxic effects are schedule
dependent
since the myelosuppression
and neurotoxicity
of cisplatin is more prominent with daily X5 administration (11, 12), whereas its nephrotoxicity and emesis are worse with single dose administration (12—is). This paper describes antitumor schedule dependence for oral JM216 against a murine and a human tumor model in vivo. A cisplatin..responsive human ovarian carcinoma xenograft, PXN1O9T/ C (16), was used which would be expected to be sensitive to changes in dosage and schedule of administration. Single dose administration was compared to two divided dose schedules in which oral JM2i6 was given either once a day for 5 consecutive days or once a day continuously. The schedule dependency of antitumor activity was related to plasma pharmacokinetics at equivalent total dose levels for the three administration schedules. The effect of schedule on hema tological toxicity and renal function at equitoxic doses was also investigated. Additionally, the comparative antitumor effects of i.p. given as either a single dose or once daily for
5 consecutive days against the solid murine AD/PC6 plasmacytoma was investigated.
time
dependency of its in vitro cytotoxic action (1). JM216 has oral antitumor activity and bioavailabiity in mice bearing murine and human tumors (1, 2). Rodent toxiciological studies have shown dose
1 ibis
once a day doses for 5 consecutive
cisplatin and oral JM2i6
JM2164 is a lipophilic platinum(IV) complex with in vitro activity against human tumor cell lines both sensitive and resistant to cisplatin (1). It shows a partial lack of cross-resistance to cisplatin in models of acquired
limiting rnyelosuppression, a lack of nephro- and neurotoxicity, and less gastrointestinal toxicity than i.v. cisplatin and i.v. carboplatin (3—5).JM216 has been selected for clinical testing as an orally administered platinum drug (6, 7). The optimal administration sched ule has not yet been identified. The marked time-dependence of its in vitro activity prompted this in vivo comparison of single dose and fractionated administration schedules. Schedule is an important factor influencing the efficacy and toler ance of cancer chemotherapy. In small cell lung cancer, fractionation of the single daily dose of the topoisomerase inhibitor etoposide into
bis-acetato-ammine-dichloro-cyclohexylamine
platinum(IV); M'fD, maximally tolerable dose; ED,.,, 90% of the effective dose; LD@, 50% of lethal dose; AUC, area under the concentration-time curve; cisplatin, cis-diam
minedichloroplatinum(II); Cmax, peak plasma concentration; Pt, platinum; PUF, plasma ultrafiltrate.
MATERIALS AND METhODS Drug Administration.
JM216 was synthesized and supplied by the John
son Matthey Technology Centre, Blount's Court, Sonning Common, Reading, Berkshire RG4 9NH, United Kingdom. 1M216 was suspended in arachis oil (10 mgfkg) by sonication (MSE 150 Watt Ultrasonic Disintegrator, 15 @m for 15 s) immediately
before being given by oral gavage.
JM216
was administered
either as a single dose repeated once every 21 days (single dose q2ld), once a day for 5 consecutive days repeated once every 21 or 28 days (daily X5 q2ld or daily X5 q28d), or once a day indefinitely (chronic daily dosing). Cisplatin was dissolved in sterile sodium chloride (0.9% w/v) by sonication (MSE 150 watt Ultrasonic Disintegrator,
15 ,.@mfor 15 s) and given i.p. as a single dose
or once a day for 5 consecutive days. Assessment of Antitumor Activity. A human ovarian carcinoma xc nograft (PXN1O9T/C),whose biological properties have been described pre viously, was used for this work (16). This xenograft has been established from a cell line, which in turn was raised from an ascites sample taken from a patient
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SCHEDULE DEPENDENCY OF ORAL JM216
with poorly differentiated papillary adenocarcinoma of the ovary. The patient had a history of clinical responses to cisplatin and carboplatin prior to the collection of the sample. The xenografted tumor has been shown previously to be of human karyotype, histologically similar to the original explant, and sensitive to cisplatin, carboplatin, and iproplatin. Its doubling time has been estimated to be 8.4 days (16). under halothane anaesthesia using a 2-mm2fragment. Animals were housed in negative pressure flexible film isolators and maintained on Labsure 21% protein diet (irradiated at 2.5 Mrads) with access to autoclaved tapwater ad libitum. Mice bearing comparably sized tumors were randomized into treat ment or control groups (6—10mice). JM216 was given orally on single dose
q2ld, daily X5 q2ld, daily X5 q28 day, and chronic daily dosing adminis Control animals were
treated with the oral drug vehicle according to the respective schedule. Tumor diameters, (a) and (b), were measured with a slide calliper, where (a) is the
longest diameter and (b) is the longest diameter at right angles to (a). Tumor volumes (@Owere calculated according to the equation V a X b2 X ir/6 and were normalized to the volume at the start of treatment. The ratio of mean tumor
volume
of treated
and control
groups
(T:C) was defined
clearance
as previously
described
(18) 96 h after the last dose of oral JM216
given as a single dose, once a day for 5 consecutive days, or once a day
Implants were made s.c. to female nude (nu/nu) mice (aged 6 to 8 weeks)
tration schedules at doses up to an approximate MiD.
the treatment course (16% body weight loss, day 17), necessitating cessation of treatment. Blood was collected for the determination of peripheral blood counts from an axillary incision during terminal halothane anesthesia into tubes containing EDTA (1 mg) from three mice each at 0, 2, 4, 7, 10, 14, 17, 21, 31, and 35 days. The glomerular filtration rate was determined by inulin
as the ratio of
continuously for 21 days at the MTD with six mice at each data point. Pharmacokinetics. Pharmacokinetic studies were undertaken in female BALB/c mice aged 8 to 10 weeks after single oral doses of JM216 at 9.5
mg/kg, 40 mg/kg, and 200 mg/kg and on the fifth day of a daily X5 treatment course at 40 mg/kg/day X5. Blood was collected under terminal halothane anaesthesia from three mice after oral JM216 at 0, 10, 20, 30, and 60 mm and 2, 3, 4, 6, and 8 h after drug ingestion into tubes containing heparin (10 units) for plasma total platinum and plasma ultrafiltrate platinum analysis. Blood samples were centrifuged (2000 X g for 5 mm at 4°C)immediately after collection to prepare plasma. A aliquot was set aside on ice for plasma total
platinum analysis. An ultrafiltrate sample was prepared immediately from the remaining plasma using an Amicon Centrifree Filter (M130,000 cutoff; Ami con, Beverly, MA). The filters were centrifuged at 2000 X g for 20 mm at 4°C.
the mean relative tumor volume in treated and control groups and was calcu lated at 28 days, since this was an acceptable duration for survival for untreated
Platinum analysis was undertaken by flameless atomic absorption spectrome try using a Perkin Elmer Spectrometer (Models 1100B and HGA700; Perkin
control animals bearing this xenografted tumor. Maximum tumor regression was defined as the smallest relative tumor volume achieved throughout a
Elmer, Ueberlingen, Federal Republic of Germany). Absorption was measured at 265.9 nm. Platinum concentrations were calculated by an external standard
treatment course. The growth delay was the difference in time required for the tumor to double in volume. The growth and assessment of antitumor activity of the solid ADJIPC6 plasmacytoma was as previously described (1, 17). Briefly, 20 days after s.c
curve.
implantation
of platinum concentration versus time was taken as the absorption rate constant (K,). The mean residence time was estimated by dividing the AUC by the
of i-mm@ tumor
fragments,
animals
bearing
comparably
sized
tumors were randomized (3 per dose level and 10 vehicle controls). Cisplatin and JM216 were administered as a single dose or daily for 5 consecutive days. Ten days later, tumors were dissected out, and the weights of control and treated groups were compared. Antitumor activity was defined in terms of a “therapeuticindex,―the ratio of the 50% lethal dose to ED@.
Toxicology Studies. Female BALB/c mice aged 8 to 10 weeks were used. The MTD was defined as a dose causing significant and reversible body weight loss (5 to 20%) but no moribundity that was 25% below a dose causing moribundity. The MTD for oral JM216 given on a single dose administration schedule was as defined previously (200 mg/kg; Ref. 3). The MTD for oral JM216 given once a day for 5 consecutive days was 55 mg/kg/day, since this caused reversible body weight loss (13.4%) but no moribundity, while mon bundity
was observed
at higher
dose
levels
of this schedule
(frequency
of
moribundity: 60 mg/kg day X5, 1 of6; 70 mg/kg day X5, 4 of 6; 80 mg/kg day
x5, 6 of 6). The MTD for oral JM216 given once a day continuously was 15 mg/kg/day, since a higher dose level (20 mg/mg/day) was associated with progressive loss of body weight and deterioration in general condition early in
The
area
under
the
platinum
concentration
versus
time
increasing and by the logarithmic trapezoid rule when successive values were decreasing, up to 8 h. The slope of the input phase on a semilogarithmic plot
AUMC and corrected for the mean absorption time by subtracting the inverse
of the absorption rate constant. The free plasma platinum fraction was assessed by dividing the free plasma platinum AUC by the total plasma platinum AUC and expressing
the fraction
Statistics.
The significance
as a percentage. of differences
between
means
were
assessed
using a t test. P < 0.05 was regarded as significant.
RESULTS The antitumor activity of oral JM216 and i.v. cisplatin given as either a single dose or once daily for five consecutive days was compared in the murine ADJIPC6 plasmacytoma model. Neither the toxicity, antitumor potency, nor the therapeutic index changed when i.v. cisplatin was given as a fractionated rather than a single dose (cisplatin single dose: LD50, 11.5 mg/kg; ED@, 0.88 mg/kg; TI 13;
Table 1ovarianScheduleDose Antitumor activityof oral JM216 given eitheras a singledose, once a day for 5 cousecutive days, or once a do indefinitelyto nude mice bearinghuman carcinoma xenografts (PXNJO9T/C)y
T:C ratio― dose q21 days100 0/6Daily
regression
Day 28
F' P > 0.02) or daily X5 dosing (6.2 ± 3.7% loss of body weight compared to controls; 0.02 > P > 0.01). In BALB/c mice, hemato logical toxicity occurred with all administration schedules at the The severity
regimens,
0
Total
AUCn@ h
(mg/hr/l @‘) (h)
of leukopenia
was greater
with single dose JM216
[nadir, peripheral WBC count: 1.2 ±0.4 (lO9Iliter); day 2] than with daily X5 dosing [nadir, peripheral WBC count: 2.7 ±0.1 (10@Il);day 12; P < 0.02]. Conversely, the severity of thrombocytopenia was worse with the daily X5 regimen [nadir, platelet count: 159 ±39 (109/liters); day 14] than with single dose administration (nadir, platelet count: 541 ±92; day 10; P < 0.01). No significant reduction in [‘4C]inulinclearance was recorded with the single dose or daily X5
@‘600
I:
1
3200 5
MTh. 800
40, or 260
were also studied on day 5 ofa 40 mg/kg/day X5 treatment
? 40 da@
80
l@ days
but a small
reduction
occurred
with chronic
daily dosing
(—11% of control; P < 0.01). Plasma total and ultrafiltrate platinum pharmacokinetics were stud led in mice after JM216 orally at 9.5, 40, and 200 mg/kg (Table 2; Fig. 2), doses corresponding to the delivery of a equivalent total dose of 200 mg/kg per 21 days for the three administration schedules. Peak ultrafiltrate platinum levels increased by over 10-fold with only a 4-fold increase in dose from 9.5 mg/kg (PUP Cmax, 0.11 ±0.066 mg/i) to 40 mg/kg (PUF Cmax, 1.5 ±0.11 mg/I; P < 0.01) but then did not significantly increase (1.6-fold) with a further 5-fold increase in dose from 40 to 200 mg/kg (PUF Cmax, 2.4 ±0.44 mg/I; P > 0.05). Similarly, peak total platinum levels increased by over 8-fold with only a 4-fold increase in dose from 9.5 mg/kg (Total Cmax, 0.37 ±0.15 mgfl) to 40 mg/kg (Total Cmax, 3.0 ± 0.31 mg/l; P < 0.001) but then did not significantly increase (2.4-fold) with a further
5-fold
increase
in dose from 40 to 200 mg/kg
(Total
Cmax,
5.7 ±0.44 mg/l; P > 0.05). Total and ultrafilterable plasma platinum AUCS also increased disproportionately by about 10-fold with only a 4-fold increase in dosage from 9.5 mg/kg (AUC0_8 h: total 1.3 mghF1; PUF 0.18 mg.h.l1) to 40 mg/kg (AUCO.8 1,: total 14 mg@hl@; PUF 1.7 mg.h.l@) but then increased less than proportion ately (2-fold) with a further 5-fold increase in dose from 40 to 200 days days mg/kg (AUCIJ_8 h: total 25 mgh1'; PUF 3.5 mghl'). Tmax, Fig. 1. Tumor growth curves of a human ovarian carcinoma xenografted tumor MRT, and Ka showed no dose related changes. A comparison of (PXN1O9T/C) in nude mice treated with oral JM216 as a single dose (q2ld) [A: 0, pharmacokinetics on days 1 and 5 of a 40 mg/kg/day X5 regimen control; @,100 mg/kg; •,200 mg/kg; arrows@ time of treatment], once a day dosing for showed no change in total plasma platinum Cmax (day 1, 3.0 ±0.31 5 consecutive days (q2ld) [B: 0, control; 0, 20 mg/kg/day; t@,40 mg/kg/day; •,60 mg/k&Jday;solid bars, time of treatment], once a day dosing for 5 consecutive days (q28d) mg/l; day 5, 2.9 ±0.60 mg/I; P > 0.05) or AUC (day 1, 14 mghF1; [C: 0, control; 0, 20 mg/kg/thy; @, 40 mg/kg/day; •,60 mg/kg/day; solid bars, time of day 5, 14 mgh1@). However, decreases in ultrafilterable plasma treatmenti, or once a day doses indefinitely (chronic daily dosing), [D: 0, control; 0, 9.5 mg/kg/day; @,14.3 mg/kg/day; •,20 mg/kg/day; solid bar, period of treatment]. platinum Cmax (day 1, 1.5 ±0.11 mgfl; day 5, 0.59 ±0.099 mgfl; 4120
a
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Downloaded from cancerres.aacrjournals.org on July 14, 2011 Copyright © 1994 American Association for Cancer Research
SCHEDULE DEPENDENCY OF ORAL JM216
peak plasma ultrafiltrate levels were 0.62 ,.LM,whereas the IC50 (2-h)
Total plasma
for JM216 0
@
a
20
4'
C •UC)
0.
10
x 0 a
in the cell line from which
chronic dosing schedule
xenograft
is due to plasma drug levels failing to reach
cytotoxic concentrations for an adequate time. Nonlinear pharmacokinetic behavior is characterized by dispropor
C)
tionate changes 00
50
100 150 dose (mg/kg)
Plasma
200
Following
in drag levels and AUC with changes
oral JM216
at 9.5 and 40 mg/kg,
t@traf1ltrate
4,
increase
0.
Cmax
in dose from 40 mg/kg
to 200 mg/kg
(the MTD
for single
dose administration) was accompanied by less than proportionate (about 2-fold) increases in plasma platinum Cmax and AUC, consist
@1.7 I,
ent with a dose-related
a
0
100
in dosage (20).
plasma platinum
and AUCS in mice increased by 10-fold and out of proportion to this 4-fold increase in dosage. This effect may be due to a dose-related increase in the extent of oral absorption. Platinum drugs effect gas trointestinal mobility and transient time6 and such phenomena could be a basis for an apparent dose-related enhancement of oral absorp tion, such as seen in this dose range. .Conversely, a further 5-fold
0
150
dose (mg/kg) Fig. 2. Dose-relationship ofCmax(•)and AUCQ_8 h(O)for total plasma platinum (A)
and ultrafiltrateplasmaplatinum(B) in mice treatedwith oralJM216 [predictedincrease in (i) Cmax (dashed line) and (ii) AUC (dotted line)].
fall in the extent of drag absorption.
A Phase
I study of oral JM216 made a similar finding of an apparent reduction in the extent of drug absorption and less than proportionate increases in Cmax and AUC with dose escalation above 200 mg/rn2 (6). We hypothesize that this finding may relate to the poor aqueous solubility of JM216, trointestinal
limiting
dissolution
from its dosage
tract and availability
for absorption
form within the gas as dosages
exceed
its
P < 0.001), AUC (day 1, 1.7 mghl'; day 5, 0.97 mghr') and free plasma fraction (PUF AUC0.8 @,fFotalAUC0...8 h: day 1; 12% : day 5; 6.9%) were recorded on day 5 compared to day 1.
limit of solubility. Interestingly, a similar pattern of nonlinear phar macokinetic behavior has been reported for etoposide, an oral anti cancer agent with schedule-dependent properties and poor aqueous solubility (21). The complex nonlinear pharmacokinetic behavior of oral JM216 in mice meant that optimal plasma pharmacokinetics occurred at dosages used in the daily X5 administration schedules and
DISCUSSION
may be the basis for the in vivo antitumor schedule
We have demonstrated the dependence upon administration sched ule of the antitumor activity of a novel oral platinum agent (JM216) independently in two in vivo tumor models. Against the murine ADJ/PC6 plasmacytoma, daily X5 administration of oral JM216 resulted in improved tolerance, antitumor potency, and therapeutic index compared to single dose administration. Against a human ovar ian carcinoma
xenograft,
antitumor
activity
was best for daily
be daily X5 dosing, since this schedule showed the best activity and tolerance in these preclinical model systems. Further experiments addressed the pharmacokinetics of oral JM216 and the possible mechanistic basis of its in vivo antitumor schedule dependency. At the MTD for the chronic dosing schedule (9.5 mg/kg),
dependancy
of the
drug in these model systems. A further pharmacokinetic comparison in mice treated with oral JM216 found falls in ultrafilterable plasma platinum Cmax, AUC, and free fraction on the fifth compared to the first day of a daily X5 ad ministration
schedule.
This finding did not appear due to a reduction
in oral absorption since there were no changes in total plasma plati num Cmax
X5
administration compared to single dose or once daily dosing indefi nitely administration schedules, both at their respective MTDs and at dose levels delivering an equivalent amount of total drug. In contrast, antitumor schedule dependency is not a well recognized property of either the existing clinical platinum drugs (10) or alkylating agents (19). In keeping with this, we found no advantage for a fractionated schedule (daily X5) of cisplatin compared to its single dose admin istration in the murine ADJIPC6 plasmacytoma. Small functional differences in toxicity were found with the different schedules of oral JM216, such as mild nephrotoxicity and greater body weight loss, suggestive of more severe gastrointestinal toxicity with chronic daily dosing and more severe thrombocytopema and less leukopenia with daily X5 dosing. These data show that oral JM216 has antitumor schedule dependent properties in vivo, which is an unusual feature for this class of agent, and suggest that the optimal clinical protocol may
@
the PXN1O9T/C
tumor was established is 2.7 P.M.5 Previous work has demonstrated that the cytotoxicity of JM216 is highly time dependent, with optimal in vitro activity occurring with drug exposure durations of 24 to 96 h (1). This suggests that the poor in vivo antitumor activity of the
or AUC
over
a 5-day
treatment
period.
JM216
is a
platinum(IV) complex, and such complexes are thought to require activation by reduction to platinum(II) species as a prelude to inter actions with biological macromolecules (22). In keeping with this, metabolism studies have found very little parent JM216 after its oral administration in rodent or human plasma but a series of platinum(II) metabolites
including
ammine-dichloro-cyclohexylamine-platinum
(II) (JM1 18) (23). This suggests that JM216 is a pro-drug and that the time-dependent changes in plasma ultrafiltrable platinum pharmaco kinetics may relate to the induction of its activation to platinum(II) metabolites.
In summary, oral JM216 displays antiturnor schedule dependency in vivo in preclinical tumor model systems and nonlinear pharmaco kinetics after its oral administration to mice. Its schedule-dependent properties
appear to relate to dose-related
changes
in the extent of
absorption. Optimal antitumor activity, tolerance, and pharmacokinet ics occurred with daily X5 dosing, and these findings have prompted the clinical
evaluation
of a daily X5 administration
5 L
R. Kelland,
unpublished
6
E. Morgan,
personal
data.
communication.
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Downloaded from cancerres.aacrjournals.org on July 14, 2011 Copyright © 1994 American Association for Cancer Research
schedule
(7).
5CHEDULE DEPENDENCY OF ORAL JM216
ACKNOWLEDGMENTS
10. Delaflor-Weiss, E., Uziely, B., and Muggia, F. M. Protacted drug infusions in cancer treatment: an appraisal of 5-fluorouradil, doxorubicin and platinums. Ann. OncoL, 4: 723—733,1993. 11. Gandara, D. R., Crowley, J., Livingstone, R. B., Perez, E. A., Taylor, C. W., Weiss,
Thanks are due to the Royal Marsden Hospital Hematology for processing
the blood counts.
G., Neefe, J. R, Hutchins,L F., Roach,R. W., Grunberg,S. M., Braun,T. J., Natale, R. B., and Balcerzak, S. P. Evaluation of cisplatin intensity in metastatic non-small cell lung cancer: a phase III study of the Southwest oncology group. J. Clin. Oncol.,
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11: 873—878,1993. 12. Blumenreich, M. S., Woodcock, T. M., Jones, M., Richman, S. P., Gentile, P. S.,
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13. Kovach, J. S., Moertel, C. G., Schutt, A. J., Reitemeier, R. G., and Hahn, R. G. Phase
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