ARTICLE
Auteur(s) :, C
Louvet1,*, T André2, E
Gamelin3, M-L Garcia, A Saavedra2, G
Lenaers4, A de Gramont1, D
Méry-Mignard5, S Kalla4
1Service d’oncologie, Hôpital Saint-Antoine, 184, rue
du Faubourg Saint-Antoine, 75012 Paris, France
2Service d’oncologie médicale, Hôpital Tenon, Paris,
France
3Centre Paul-Papin, Angers, France
4AstraZeneca, Rueil-Malmaison, France
5Aventis Pharma, Paris, France
Colorectal cancer (CRC) is one of the most common malignancies in
the western world [6]. In France, more than 35,000 new cases occur
each year [7]. Up to 50 % of all affected patients will develop
metastatic disease or metastatic recurrence and are candidates for
palliative treatment. For over decades the treatment of CRC has
been exclusively based on fluorouracil (5FU) regimens. More
recently, the combination of irinotecan with 5FU-folinic acid (FA)
has been proven to be significantly more active than 5FU alone in
terms of response rate, time to progression and median survival,
and was approved both in Europe and the United States for the
first-line treatment of metastatic CRC patients [8, 9].Irinotecan
(CPT11) is also registered as an active second-line treatment after
failure to 5FU [10, 11]. However the response rate (RR) of
CPT11-5FU combination remains poor after 5FU-oxaliplatin failure
[7] and many efforts should be done to improve the efficacy
parameters of combined treatment used either as first or second
line.ZD9331 is the gamma-tetrazole analogue of
2-desamino-2,7-dimethyl-N10-propargyl-2’fluoro-5,8-dideaza folate
(ZM214888). It is a potent, thymidylate synthase (TS) inhibitor
intended for the treatment of solid human tumors, including
colorectal cancer. In contrast to other direct inhibitors, ZD9331
does not need to be polyglutamated to be active, avoiding a
frequent cause of tumor cell resistance. ZD91131 is mainly
eliminated through the liver pathway. Phase I and II trials
involving so far approximately 500 patients with advanced cancer,
showed that ZD9331 was relatively well tolerated, the main toxicity
observed being myelosuppression with neutropenia and
thrombocytopenia. In terms of efficacy, ZD9331 has demonstrated
anti-tumor activity across the four phase I trials performed to
determine the dose and regimen to be used. Recommended dose in
monotherapy is 130 mg/m2 on day 1 and 8 every 3 weeks.
Approximately one in four of all patients recruited to one of these
trials received four or more cycles of treatment without
progression of disease [13-15].Preliminary studies in human colon
cancer cells with concomitant exposure of cells to ZD9331 and SN38,
the active metabolite of CPT11, have demonstrated a synergistic
effect at low concentrations and an additive effect at higher
concentrations. This synergistic effect was more potent with
sequential exposure of drugs (SN38 then ZD9331, or ZD9331 then
SN38) rather than with the concomitant exposure (SN38 + ZD9331)
[16]. Given this synergy/additivity between SN38 and ZD9331, the
present open, intra-patient, dose-escalating trial was designed to
assess ZD9331 in combination with CPT11 in patients with metastatic
colorectal cancer who had failed first-line therapy with 5FU with
or without oxaliplatin based therapy.The aims of the study were to
determine the dose of the ZD9331 and CPT11 combination to recommend
for further studies and to assess the toxicity profile of ZD9331 in
combination with CPT11 when given as a two-week schedule. Other
objectives were to determine the pharmacokinetics (PK) of CPT11
when combined with ZD 9331.
Patients and methods
Patients eligibility criteria
Patients were eligible if they had a metastatic colorectal cancer
histologically confirmed, and had failed the first-line
chemotherapy with 5FU with or without oxaliplatin (L-OHP), or had
relapsed within six months after the end of adjuvant therapy with
5FU with or without oxaliplatin. They were to be aged 18 years or
more, and to have a life-expectancy of at least 12 weeks. World
Health Organization performance status (WHO PS) was to be 0 or 1,
and the patients had adequate bone marrow function (corresponding
to neutrophils ≥ 1.5 x 109/L and platelets ≥ 100 x
109/L). The patients presented with measurable disease,
i.e. lesions that could be accurately measured in at least one
dimension (longest diameter to be recorded) as ≥ 20 mm with
conventional techniques or as ≥ 10 mm with spiral CT scan.
Patients were excluded if they had inadequate liver function
(corresponding to serum bilirubin > 1.25 x upper normal value
(UNV), or alanine aminotransferase > 5 x UNV, or aspartate
aminotransferase > 5 x UNV, or alkaline phosphatase > 5 x
UNV, or lactate dehydrogenase > 5 x UNV), or inadequate renal
function (corresponding to plasma creatinine > 1.25 x UNV or
creatinine clearance of < 60 ml/min). Pregnant or breast-feeding
women were excluded from treatment, as were patients with severe or
uncontrolled systemic disease, or severe concurrent condition.
Prior therapy with irinotecan, topotecan, raltitrexed or ZD9331 was
not permitted.
The study was performed in accordance with the principles of the
Declaration of Helsinki and Good Clinical Practice Guidelines.
Treatment and dose escalation criteria
CPT-11 was given at a fixed dose of 180 mg/m2 as a
90-minute intravenous infusion on day 1 followed on day 2 by ZD9331
administered as a 30-minute intravenous infusion. Treatment was
repeated every two weeks (Day 1 - Day 15). We choose an
intra-patient escalation dose schedule in order to establish the
optimal individual dose of ZD9331 in combination with CPT-11 : dose
level I (90 mg/m2, corresponding to 50% of the
recommended dose-intensity), dose level II (120 mg/m2),
and dose level III (150 mg/m2). ZD9331 dose escalation
was permitted on the basis of safety evaluation of the previous two
cycles.
Fifteen patients were enrolled into the dose-finding part of the
study, in order to establish the dose-limiting toxicity (DLT) of
ZD9331 with this combination. All patients received 90
mg/m2 for the first two cycles. In case of grade 3-4
toxicity, dose adaptation was 75 mg/m2 for the following
courses. In absence of grade 3-4 toxicity during the first two
cycles, ZD dose was increased to 120 mg/m2 for the two
following courses, and then to 150 mg/m2 for the further
cycles. At any dose and any cycle, ZD was reduced to previous level
in case of grade 4 or repeated grade 3 toxicity. When a dose
reduction was performed, no further dose escalation was permitted.
The patient was considered to have reached the DLT if a dose
reduction was necessary or if re-dosing criteria were not met at
the end of the first cycle at a new dose level for that patient. At
the end of the dose escalation part of the trial, the patient’s
individual DLT were reviewed to determine the recommended dose
(RD), which correspond to the DLT observed in at least half of this
initial cohort of patients. Once the provisional RD had been
established, a further six patients were treated to confirm the
RD.
Redosing criteria, delay, dose reduction
Both drugs were given as a two-week schedule unless treatment was
delayed. Up to two-week delay between cycles was permitted. If
re-dosing criteria were not met at the end of this period the
patient was to be withdrawn. Patients showing no objective disease
progression (assessed every four cycles) could continue treatment
until such time that a withdrawal criterion was met.
Tolerability and safety
Safety evaluation included adverse events recording during the
study, vital signs (systolic blood pressure, diastolic blood
pressure, and heart rate) collected prior to each chemotherapy
administration and at withdrawal from study, and WHO PS assessed
prior to each cycle and at withdrawal from study. Toxicity
(hematological and non-hematological toxicities) was evaluated for
each treatment cycle according to NCI-CTC. For each dose level as
for pooled dose levels, the results were expressed as the highest
CTC grade evaluated during the treatment period.
Pharmacokinetics
Blood samples were required in all patients of the dose-finding
stage of the study, in their first cycle of each dose level. To
determine the CPT11 and SN38 plasma profiles, blood samples (5 mL)
on day 1 were collected before infusion, just at the end of
infusion (1.5 hours), and at 2, 4, 8, and 24 hours after the start
of infusion. To determine the plasma profile of ZD9331, blood
samples on day 2 were collected before infusion, just at the end of
infusion (0.5 hours), at 1, 2, 4, 8, 24, 72 and 144 hours after the
start of infusion, and immediately before the next cycle on day 15
(312 hours). Specimen were collected in heparinized tubes and
immediately centrifuged. Plasma was then stored immediately in a
plain tube and frozen at -20°C before transportation. ZD9331 was
assayed by high-performance liquid chromatography (HPLC) with
tandem mass spectrometry detection. CPT11 and SN38 concentrations
were determined by HPLC using fluorometric detection.
Pharmacokinetic parameters of ZD9331, CPT11 and SN38 included the
following: maximum plasma concentration (Cmax), taken
directly from each plasma profile; area under the plasma
concentration versus time curve (AUC), defined as AUCo-t +
(Clast/lz), where AUCo-t was calculated by the trapezoidal rule and
t was the last time point for the determined concentration Clast;
elimination half-life (t1/2), t1/2 being equal to 0.693/lz where lz
was the terminal slope of the semi-logarithmic-time curve; plasma
clearance; and volume of distribution at steady-state (Vss).
Tumor assessments
Objective responses were defined using the WHO Response
Evaluation Criteria in Solid Tumors (RECIST) revised in May 1999
as: complete response (CR), partial response (PR), stable disease
(SD) or progressive disease (PD). Tumors markers, i.e.
carcinoembryonic antigen (CEA), were performed every four cycles.
Time to progression and overall survival were calculated from the
date of study registration until the date on which progression
disease (objective progression or clinical progression based on
investigator’s judgment) was documented or patient death,
respectively.
Statistical considerations
Descriptive statistics were used, to present quantitative (sample
size, mean, standard deviation, median, range), or qualitative
(absolute and relative frequencies) parameters. Results were
presented by dose level and all doses pooled, and by cycle when
appropriate.
Pharmacokinetic data were listed, summarized and plotted by dose
level received. Cmax and AUC data were summarized using
the geometric mean, coefficient of variation (CV), mean, standard
deviation (SD), minimum, maximum and sample size. All other
pharmacokinetic parameters were summarized using the mean, standard
deviation, minimum, maximum and sample size. Progression free
survival (PFS) and survival data were calculated using the
Kaplan-Meier method.
Results
Patients
Between December, 2000 and October, 2001 a total of 21 patients was
entered and treated in three centers. Twenty patients were
assessable for efficacy, and 21 for safety. A summary of baseline
patient characteristics is included in table 1( Table 1 ).
Median age was 59 years (range, 34 to 78 years), 57 % of
patients were men, with 38 % PS 0 and 62 % PS1. There were 15
patients with colon cancer and six patients with rectal cancer. The
median time from diagnosis to the first administration of the study
treatment was 14.3 months (range, 3.5 to 78.4 months). The number
of involved organs (metastatic or local advanced disease) was two
in 43 % of patients and three or more in 19 %, the most frequent
sites of involvement being liver (67 %) and lung (38 %). All the
patients had prior surgery, and chemotherapy consisted of 5FU for
all patients, combined with oxaliplatin (L-OHP) for 76 % of
them.
Table 1 Patient characteristics
|
Characteristics
|
Number
|
%
|
|
Total number of patients entered
|
21
|
100
|
|
Assessable for efficacy
|
20a
|
|
|
Assessable for safety
|
21
|
|
|
Male/female
|
12/9
|
57/43
|
|
Age, years
|
|
|
|
Median
|
59
|
|
|
Range
|
34-78
|
|
|
Performance status, WHO criteria
|
|
|
|
0
|
8
|
38
|
|
1
|
13
|
62
|
|
Primary tumor site
|
|
|
|
Colon
|
15
|
71
|
|
Rectum
|
6
|
29
|
|
Prior chemotherapy
|
|
|
|
5FU alone
|
7
|
33
|
|
5FU + L-OHP
|
14
|
67
|
|
Number of organs involved
|
|
|
|
1
|
8
|
38
|
|
2
|
9
|
43
|
|
≥ 3
|
4
|
19
|
|
Sites of involvement (number of patients) b
|
|
|
|
Liver
|
14
|
67
|
|
Lung
|
8
|
38
|
|
Other c
|
11
|
52
|
aOne non-evaluable patient due to early death
(myocardial infarction).
bOne patient could have had more than one site of
involvement.
c“Other” included: bone, pleural effusion, lymph
nodes, abdominal local recurrence, ascites, and any other site.
Extent of exposure
A total of 185 cycles of ZD9331-CPT11 combination regimen was
administered during the study, with a median per patient of 10
cycles (range, 1 to 16 cycles).
All the patients started with 90 mg/m2 dose level of
ZD9331. On the basis of safety data, 11 patients received escalated
dose 120 mg/m2 and only 2 patients received 150
mg/m2. Dose reductions from 90 to 75 mg/m2
were implemented for three patients, including one dose level
decreased at the second cycle for one patient (due to grade 3
diarrhea).
The total number of cycles according to dose level were: 104
cycles at 90 mg/m2, 51 cycles at 120 mg/m2,
21 cycles at 75 mg/m2, and nine cycles at 150
mg/m2. One cycle was delayed in three patients due to
toxicity, two cycles were delayed in three patients, and three
cycles in one patient, which gave a 7 % rate of delayed cycles
(12/185) during the study.
Dose intensity
The absolute median dose-intensity was 11.78
mg/m2/day (range, 10.39 to 12.86 mg/m2/day)
for CPT11 (92 % of the theoretical fixed dose), and 6.43
mg/m2/day in median (range, 5.19 to 9.23
mg/m2/day) for ZD9331 (96 mg/m2 per ZD
cycle).
Tolerability and safety
The primary reasons for discontinuation from the study were disease
progression (10 patients, 48 %), and investigator’s discretion
(eight patients, 38 %).
There were 11/21 (52 %) patients with grade 3-4 neutropenia at
90 mg/m2 ZD9331 dose level, 4/11 (36 %) patients at
120-mg/m2, and 1/2 (50%) at 150 mg/m2, which
corresponded to a 67 % rate of grade 3-4 neutropenia whatever the
treatment dose. No febrile neutropenia was observed, nor grade 3-4
thrombocytopenia whatever the ZD9331 dose. Non-hematological severe
toxicity was uncommon (one grade 3 diarrhea at level I, two grade 3
nausea-vomiting at levels 1 and II). One early death occurred due
to a massive cardiac infarction occurred at day 8 of the first
cycle in a patient with a past history of heart disease. The
relation of this event to the trial remains uncertain. Drug related
serious adverse events (SAEs) were observed in three additional
patients (14 %), and consisted of grade 3 anemia + grade 3 icterus
(onset at dose level 1), grade 3 arrhythmia (onset at dose level
1), and grade 3 vomiting (onset at dose level 2). A summary of
tolerability/safety data according to ZD9331 dose level is shown in
table 2( Table 2 ).
Dose-limiting toxicity, maximum-tolerated dose, and recommended
dose of ZD 9331
For the first 15 patients of the dose-finding part of the study,
the dose-limiting toxicity (DLT) for ZD9331 was achieved at 120
mg/m2 in 7 patients (47 %), 90 mg/m2 in 6
patients (40 %), and 150 mg/m2 in 2 patients (13 %). For
these first 15 patients the maximum-tolerated dose (MTD) for ZD9331
was achieved at 90 mg/m2 in 8 patients (53 %), 120
mg/m2 in 4 patients (27 %), 150 mg/m2 in 2
patients (13 %), and 75 mg/m2 in 1 patient (7 %).
Thus, the recommended dose (RD) in this ZD9331 and CPT11
combination was established at 90 mg/m2 ZD9331 dose.
However, considering that dose escalation was possible in patients
able to receive it, we could escalate the dose to 120
mg/m2 on the basis of safety evaluation for the six
additional patients.
Table 2 Safety (hematological and non-hematological
toxicities) by dose level
|
ZD9331 dose level (mg/m2)a
|
|
90 (n = 21)
|
120 (n = 11)
|
150 (n = 2)
|
|
NCI/CTC grade
|
|
G1 + 2
|
G 3 + 4
|
G 1 + 2
|
G 3 + 4
|
G 1 + 2
|
G 3 + 4
|
|
|
No.
|
%
|
No.
|
%
|
No.
|
%
|
No.
|
%
|
No.
|
%
|
No.
|
%
|
|
Hematological toxicities
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Anemia
|
19b
|
90
|
1
|
5
|
11c
|
100
|
0
|
-
|
2d
|
100
|
0
|
-
|
|
Neutropenia
|
4
|
19
|
11
|
52
|
4
|
36
|
4
|
36
|
0
|
-
|
1
|
50
|
|
Thrombocytopenia
|
8
|
38
|
0
|
-
|
0
|
-
|
0
|
-
|
0
|
-
|
0
|
-
|
|
Non-hematological toxicities
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Nausea
|
15
|
71
|
1
|
5
|
7
|
64
|
2
|
18
|
2
|
100
|
0
|
-
|
|
Vomiting
|
9
|
43
|
2
|
10
|
5
|
46
|
2
|
18
|
1
|
50
|
0
|
-
|
|
Diarrhea
|
13
|
62
|
1
|
5
|
5
|
46
|
0
|
-
|
1
|
50
|
0
|
-
|
|
Asthenia
|
14
|
67
|
0
|
-
|
10
|
91
|
0
|
-
|
2
|
100
|
0
|
-
|
|
Arrhythmia
|
0
|
-
|
1
|
5
|
0
|
-
|
0
|
-
|
0
|
-
|
0
|
-
|
|
SGOT/AST – SGPT/ALT
|
9
|
45
|
0
|
-
|
2
|
18
|
0
|
-
|
1
|
50
|
0
|
-
|
|
|
7
|
35
|
0
|
-
|
2
|
18
|
1
|
9
|
0
|
-
|
0
|
-
|
aThree patients had the ZD9331 dose decreased to 75
mg/m2: one patient at cycle 2, one patient at cycle 7, and one
patient at cycle 11.
bAt baseline, three patients had anemia (no toxicity
assessment was to be performed before the first cycle of
treatment).
cTen patients had grade 1-2 anemia at the 90 mg/m2
ZD9331 dose level before to go to level 120.
dThese two patients had grade 1 anemia at the 90 or
120 mg/m2 ZD9331 dose level before to go to level 150.
Pharmacokinetics
The pharmacokinetics of ZD9331 in combination with CPT11 and its
active metabolite SN38 involved 14 patients at the 90
mg/m2 ZD9331 dose, and 8 patients at the 120
mg/m2 ZD9331 dose. Only 2 patients had dose escalation
to the 150 mg/m2 ZD9331 dose level.
Taking into account patient variability and the relatively
limited amount of data, there was unlikely to be significant
difference in exposure to ZD9331, CPT11 and SN38, when dosed in
combination. The mean half-life was about 40 hours for ZD9331 and
approximately five hours for CPT11. The main pharmacokinetic
parameters for ZD9331, CPT11 and SN38 are displayed in table 3(
Table 3 ).
Table 3 Pharmacokinetics of ZD9331, CPT11 and SN38
|
ZD9331
|
Irinotecan (CPT11)
|
SN38
|
|
ZD9331 dose level (mg/m2)
|
|
90
|
120
|
90
|
120
|
90
|
120
|
|
Number of patients
|
14
|
8
|
14
|
8
|
14
|
8
|
|
Cmax (ng/mL)
|
Geometric mean
|
23190.64
|
26190.35
|
2384.50
|
2220.64
|
38.62
|
32.84
|
|
(CV)
|
(27.58)
|
(24.20)
|
(38.53)
|
(16.97)
|
(40.00)
|
(34.08)
|
|
AUC (ng • h/mL)
|
Geometric mean
|
186454.49
|
163041.87
|
13448.58
|
11862.20
|
441.76
|
329.74
|
|
(CV)
|
(39.89)
|
(51.61)
|
(40.76)
|
(19.34)
|
(80.20)
|
(38.55)
|
|
Elimination half-life (h)
|
Median
|
42.25
|
38.20
|
5.26
|
5.18
|
9.24
|
11.16
|
|
[range]
|
[24.20-52.60]
|
[14.40-72.90]
|
[2.51-8.20]
|
[1.77-19.37]
|
[3.77-21.69]
|
[1.74-18.23]
|
Efficacy results
Efficacy results were expressed as intent-to-treat best overall
responses (RECIST criteria) for the 21 included patients (20
evaluable). Two (9.5 %) partial responses (PR), 12 (57.1 %) stable
diseases (SD), and 6 progressive diseases (PD) + 1 non evaluable
(33.3 %) were observed, resulting in a tumor growth control (PR +
SD) in 14 (66.7 %) patients. Four patients out 7 (2 PR and 2 SD)
had a disease control when previously exposed to 5FU alone, while
10 patients out 14 (0 PR and 10 SD) had a disease control when
previously exposed to both 5FU and oxaliplatin. Efficacy according
to previous treatment is shown in table 4( Table
4 ). Among the 17 patients with abnormal CEA at baseline, 2
patients became normal and 3 patients had a decrease > 50 %.
With a median follow-up time of 14.6 months, the median time to
progression was 6.0 months, 95 % CI (2.9 to 7.0), the median
overall survival was 8.4 months, 95 % CI (8.1 to 14.7) (( figure 1 )), and the
one-year survival rate was 43 %, 95 % CI (20-94 %).
Table 4 Antitumor activity of ZD9331combined with
CPT-11
|
Number of evaluable patients/total number of patients
|
20/21a
|
% (ITT)
|
|
Partial response (PR)
|
2
|
9.5
|
|
Stable disease (SD)
|
12
|
57.1
|
|
Tumor growth control (TGC)
|
14
|
66.7
|
|
Previous exposure to 5FU-FA alone (7 patients)
|
|
PR
|
2
|
28.5
|
|
SD
|
2
|
28.5
|
|
TGC
|
4
|
57.1
|
|
Previous exposure to 5FU-FA-oxaliplatin (14 patients)
|
|
PR
|
0
|
0
|
|
SD
|
10
|
71.4
|
|
TGC
|
10
|
71.4
|
|
Median time to progression (months), (95% CI)
|
6.0 (2.9-7.0)
|
|
|
Median overall survival (months), (95% CI)
|
8.4 (8.1-14.7)
|
|
|
One-year survival rate (%), (95% CI)
|
43.1 (19.8-93.8)
|
|
aOne non-evaluable patient due to early death
(myocardial infarction).
Discussion
Previous trials have demonstrated that the non-polyglutamatable
thymidylate synthase (TS) inhibitor ZD9331 can be administered to
humans at dose levels producing tumor responses [13, 15, 17]. A
synergy/additivity between the active metabolite SN38 of the
topoisomerase I inhibitor irinotecan (CPT11) and ZD9331 was
observed in preclinical studies [16]. Thus, the present open,
intra-patient, dose-escalating trial was designed to assess ZD9331
in combination with CPT11 in patients with metastatic colorectal
cancer who had failed first-line therapy with 5FU with or without
oxaliplatin based therapy.
Given a two-week regimen of CPT11 was shown to produce less
toxicity than the standard three-week regimen [18], the study
design was adapted accordingly. CPT11 was administered at a fixed
dose of 180 mg/m2 as a 90 minute intravenous infusion on
day 1 followed on day 2 by ZD9331 administered as a 30 minute
intravenous infusion, both drugs being given as a two-week schedule
unless treatment was delayed. This fixed 180
mg/m2/two-week CPT11 dose was in accordance with that of
several CPT11-5FU combinations active in metastatic colorectal
cancer [12,19].
ZD-CPT11 combination main toxicity was neutropenia. Other side
effects were mild to moderate. No unexpected side effect, nor
related toxic death occurred.
The disposition pharmacokinetics of ZD9331 in combination with
CPT11 involved 14 patients at the 90 mg/m2 ZD9331 dose,
and eight patients at the 120 mg/m2 ZD9331 dose.
Although the human pharmacokinetics of ZD9331 have been shown to be
non-linear, these data have been compared with data of ZD9331 dosed
alone [20] in order to assess whether dosing in combination with
CPT11 affected the pharmacokinetics of ZD9331. Taking into account
patient variability and the relatively limited amount of data,
there is unlikely to be significant difference in exposure to
ZD9331, in terms of AUC (0-t) and Cmax, when dosed in
combination with CPT11. Plasma concentrations at the end of the
infusion period declined generally in a bi-exponential manner with
an early, relatively rapid distribution phase after the end of
infusion followed by a much slower terminal elimination phase with
a mean half-life of about 40 hours. The clearance of ZD9331 from
the systemic circulation and volume of distribution at steady state
are in line with previously obtained results for ZD9331 dosed
alone.
Upon administration of CPT11, plasma concentration data suggest
that the human pharmacokinetics could be best described using an
open two-compartment model. At the end of infusion there was an
initial rapid decline in plasma concentrations followed by a slower
decline with a half-life of approximately 6 hours. These results
have been compared with published CPT11 pharmacokinetics [21,22].
Again, inter-patient variability limits the interpretation of these
data, but exposure (AUC) is in the range quoted. Plasma clearance
and volume of distribution at steady state are also similar to
those previously reported.
CPT11 is extensively metabolized in vivo, and preliminary
hydrolysis yields SN38, an active metabolite. Although levels of
SN38 tend to be 100-1000 fold lower than parent compound, this has
to be balanced with in vitro potency about 100-1000 times parent.
In this study, following administration of CPT11, plasma
concentrations of SN38 were measured, closely following that of
parent with a half-life in line with those previously reported
[21]. Thus, these data suggest similar exposure and variability for
ZD9331, CPT11 and SN38 when dosed in combination.
In conclusion the present study, conducted in patients with
metastatic colorectal cancer who had failed first-line therapy with
5FU with or without oxaliplatin or who had relapsed within six
months after the end of adjuvant therapy with 5FU with or without
oxaliplatin, confirms that the thymidylate synthase inhibitor
ZD9331 in combination with CPT11 can be administered at dose levels
producing tumor growth control in patients previously exposed to
5FU + oxaliplatin combination, as well as responses in patients
previously exposed to 5FU alone. However, taking in account the
small number of patients included in this phase I-II trial, it is
impossible to draw out any conclusion on the ability of this
ZD9331-CPT11 combination to better control disease in 5FU or in 5FU
+ oxaliplatin previously-exposed patients. In the same connection,
the 6.0 months median TTP compares favorably to the 2.5 months
median PFS described by Tournigand in patients treated with Folfiri
after Folfox [7], but the current study was performed in an
heterogeneous group and a small number of patients. The recommended
dose (RD) was established at 90 mg/m2 ZD9331 dose for
the first two cycles, with the possibility to escalate at 120
mg/m2 on the basis of safety evaluation. Taking into
account the relatively limited amount of pharmacokinetic data and
the patient variability, there is probably no significant
difference in exposure to ZD9331, CPT11 and its metabolite SN38,
when dosed in combination.
Uncited references
[1-5].
Acknowledgements
This work was supported by Astrazeneca (1, place Renault, 92844
Rueil-Malmaison Cedex, France), and by Aventis (46, quai de la
Rapée, 75590 Paris Cedex 12, France) for the purchase of CPT11. We
are indebted to Lincoln (38, rue Vauthier, 92774
Boulogne-Billancourt, France), for the statistical analyses and
manuscript preparation.
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