Note: Descriptions are shown in the official language in which they were submitted.
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COMBINATION CHEMOTHERAPY
FIELD OF THE INVENTION
The invention concerns a method for treating tumors utilizing a
combination of known oncolytic agents. The use of the agents together provides
unexpectedly greater efficacy than employing the single agents alone.
BACKGROUND OF THE INVENTION
Cancer chemotherapy has advanced dramatically in recent years. Many
tumors can be effectively treated utilizing compounds which are either
naturally
occurring products or synthetic agents. Cancer chemotherapy often entails use
of a
combination of agents, generally as a means of providing greater therapeutic
effects and reducing the toxic effects that are often encountered with the
individual agents when used alone.
We have now discovered a unique combination of known oncolytic agents
which exhibits a dramatic synergistic effect. The combination utilizes the
agent
acetyldinaline, together with paclitaxel and/or carboplatin. The combination
is
especially effective in treating patients with solid tumors, especially
nonsmall cell
lung cancer and other advanced solid tumors.
Acetyldinaline is 4-acetylamino-N-(2'-aminophenyl)-benzamide. It is also
known as CI-994. It is described in U.S. Patent No. 5,137,918, which is
incorporated herein by reference for its teaching of how to make
acetyldinaline,
how to formulate it into dosage forms, and how to use it for treating cancers
such
as colon cancer and adenocarcinomas. Acetyldinaline is also described in U.S.
Patent No. 5,795,909 as a possible conjugate for cancer treatment.
Paclitaxel is a natural product mitotic inhibitor. It is an antimicrotubule
agent that promotes the assembly of microtubules from tubulin dimers and
stabilizes microtubules by preventing depolymerization. This stability results
in
the inhibition of the normal dynamic reorganization of the microtubule network
that is essential for vital interphase and mitotic cellular functions. In
addition,
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paclitaxel induces abnormal arrays or bundles of microtubules throughout the
cell
cycle and multiple asters of microtubules during mitosis. Paclitaxel is
indicated
primarily for ovarian carcinoma and breast cancer, although it is useful in
treating
other cancers as well. Use of paclitaxel is generally accompanied by
undesirable
side effects, including hypersensitivity reactions, hypotension, bradycardia,
hypertension, nausea and vomiting, and injection site reactions. Paclitaxel is
commercially available as Taxol~ (Bristol-Myers Squibb).
Carboplatin is a bicyclic compound having platinum as a ring atom. The
compound is routinely used clinically as a cancer chemotherapeutic agent,
especially for ovarian carcinoma, as well as nonsmall cell lung cancer
(NSCLC).
Carboplatin generally is used in combination with other antineoplastic agents,
and
the combination use of carboplatin and paclitaxel has become widely used for
treating patients with advanced NSCLC, ovarian cancer, and other serious
cancers
(see Calvert et al., J. Clin. Oncol., 1989;7:1748-1756). Carboplatin is
available
commercially as Paraplatin~ (Bristol-Myers Squibb). The product is supplied as
a
crystalline white powder in vials containing 50, 150, and 450 mg, and the
powder
is reconstituted with either Sterile Water for Injection, 5% Dextrose in
Water, or
0.9% Sodium Chloride for Injection
An object of this invention is to provide a method for treating cancers,
especially advanced solid tumors, with a combination comprising acetyldinaline
together with paclitaxel or carboplatin, or a combination comprising
acetyldinaline, paclitaxel, and carboplatin. A further object is to provide a
composition comprising synergistic amounts of acetyldinaline and paclitaxel,
acetyldinaline and carboplatin, and acetyldinaline and both paclitaxel and
carboplatin.
SUMMARY OF THE INVENTION
This invention relates to a synergistic combination of antineoplastic
agents, and to a method for treating tumors comprising administering the
combination. The invention more particularly provides a composition
comprising,
as a first component, acetyldinaline, and as a second component, paclitaxel or
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carboplatin. The invention also provides a composition comprising all three
agents
together.
The compositions of this invention consist essentially of the above active
ingredients, or suitable salts thereof, together with common excipients,
diluents,
and carriers.
In a further embodiment of the invention, we provide a method for treating
cancer comprising administering to an animal in need of treatment an effective
amount of a combination of acetyldinaline with either paclitaxel or
carboplatin, or
a combination of acetyldinaline, paclitaxel, and carboplatin.
A preferred method embraces treatment of solid tumors.
A further preferred method employs an antitumor amount of acetyldinaline
and an effective amount of paclitaxel to treat susceptible cancers, including
NSCLC, breast cancer, ovarian cancer, head and neck cancer, myelomas, prostate
cancer, and pancreatic cancer.
A further preferred method employs an antitumor amount of acetyldinaline
and an effective amount of carboplatin to treat susceptible cancers.
A further preferred method employs an antitumor amount of acetyldinaline
plus an effective amount of paclitaxel plus an effective amount of carboplatin
to
treat susceptible cancers.
Another embodiment of the invention is a kit comprising in one
compartment a dosage of acetyldinaline, and in another compartment a dosage of
paclitaxel.
Another embodiment of the invention is a kit comprising in one
compartment a dosage of acetyldinaline, and in another compartment a dosage of
carboplatin.
Another embodiment of the invention is a kit comprising in one
compartment a dosage of acetyldinaline, and in another compartment a dosage of
paclitaxel, and in a third compartment a dosage of carboplatin.
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DESCRIPTION OF FIGURES
Figure 1 shows the synergy of CI-994 and paclitaxel in mouse colon
cancer cells.
Figure 2 shows the anti-tumor activities of CI-994, paclitaxel and
carboplatin, each alone, and the combination treatment with all three.
DETAILED DESCRIPTION OF THE INVENTION
The compounds to be utilized in the method of this invention will be
administered in doses commonly employed clinically. Such doses will be
calculated in the normal fashion, for example on body surface area.
Acetyldinaline
will be administered, for example, at doses from about 1.0 mg/m2 to about
50 mg/m2, preferably from about 2.0 mg/m2 to about 10.0 mg/m2. Ideally,
acetyldinaline will be administered at a dose which will produce plasma levels
of
about 5 to about 100 ~g/mL. Acetyldinaline typically is administered orally,
for
example, as capsules having active ingredient in the amounts of 2.5, ~, and 25
mg
per capsule. Acetyldinaline will be administered daily at about the same dose
levels throughout a treatment period, typically for 15 to 30 days. Multiple
treatment periods can be practiced, as dictated by the attending medical
practitioner and the particular patient and condition being treated.
Paclitaxel is a cytotoxic anticancer drug, and caution should be exercised
in handling the agent. Paclitaxel typically is provided in vials, and is
diluted prior
to administration by intravenous infusion. Typical diluents include 0.9%
sodium
chloride, 5% dextrose. The final concentration for infusion generally is about
0.3 to about 1.2 mg/mL. Paclitaxel is commercially available in several
concentrations, for instance, 30 mg/5 mL multidose vials, 100 mg/16.7 mL
multidose vials, and 300 mg/50 mL multidose vials. The product generally is
administered, for treatment of ovarian cancer for example, at doses of about
135 mg/m2 to about 225 mg/m2 over 3 hours every 3 weeks, generally in
increments of about 25 mg/m2.
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The agent is an effective treatment for carcinoma of the breast at doses of
175 mg/m2 administered IV over 3 hours every 3 weeks. For treatment of
AIDS-related Kaposi"s sarcoma, paclitaxel generally is given IV at 135 mg/m2
over 3 hours every 3 weeks, or at 100 mg/m2 over 3 hours every 2 weeks. In
general, the dosage intensity of paclitaxel will be about 45 to 50 mg/m2/week.
Carboplatin is administered as an IV infusion over a period of about
30 minutes to about 1 hour. The dosage commonly used will be about 25 mg to
about 500 mg for each treatment course, for example, each day for about 12 to
14 days, followed by about 4 to 6 days of no dosing, and then repeated dosing
for
another 12 to 14 days.
In a preferred embodiment, a typical invention combination will be
administered at the following doses shown in Table 1.
Table 1
Paclitaxel Dose Acetyldinaline Dose (oral doses
(mg/m2 infused over 3 hours on Day 1) administered daily on Days 1-14)
175 2.5 mg fixed dose
175 5 mg fixed dose
200 6 mg/m2/day
225 4 mg/m2/day
Another typical dosing embodiment is shown in Table 2.
Table 2
Carboplatin Dose Acetyldinaline Dose (orally dosed each
(mg infused over 30 minutes on Day 1) day for Days 1-14)
150 2.5 mg fixed dose
200 6 mg fixed dose
300 6 mg/m2/day
500 4 mg/m2/day
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An especially preferred embodiment is the combination of all three agents,
and typical dosing is shown in Table 3.
Table 3
Paclitaxel Dose (mg/m2) Carboplatin (infused over Acetyldinaline (orally
(infused over 3 hours on 30 minutes on Day 1 ) dosed daily on
Day 1 Days 1-14)
175 300 2.5 mg fixed dose
175 400 5 mg fixed dose
175 350 4 mg/m2/day
200 450 6 mg/m2/day
250 200 4 mg/m2/day
The combinations provided by this invention have been evaluated in
several assay systems, and the data can be analyzed utilizing a standard
program
for quantifying synergism, additivism, and antagonism among anticancer agents.
The program preferably utilized is that described by Chou and Talalay, in "New
Avenues in Developmental Cancer Chemotherapy," Academic Press, 1987,
Chapter 2.
The method is based on the median-effect principle of the mass-action law
using an enzyme kinetic system as a model. The equation is simple and
describes
the relationships between dose and effect regardless of the shape of the dose-
effect
curve. Two basic equations constitute the pillars of this methodology. To
relate
dose and effect for a single drug in the simplest way possible, the median-
effect
equation derived by Chou is given by:
fa / f" _ (D / D,n )"'
D = D,n [fa /(1- fa )]' ~ ~n
where the right side represents the dose and the left side represents the
effect, in
which fa and fu are the fractions affected and unaffected, respectively, D is
the
dose, Dm is the median-effect dose signifying the potency, and m is a
coefficient
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signifying the shape of the dose-effect curve. From this equation Chou and
Talalay derived the general equation for two or more drugs:
1/m - ) 1/m + ( a/2 1/m - +CC ~ a~l ( a)~ 1/m
~fa ~~,~ ~fa ~ f f f
~fu ~~.Z ~fu ~~ ~fu ~2 ~fu ~~ ~f~ ~2
~D~~ + ~D~~ a ~D~ ~DO
\Dm l1 lDm l1 \Dm ~~ \Dm ~?
where m = 1 is for first-order Michaelis-Menten-type kinetics and m >1 (or m
<1)
is for higher order (or lower order) Hill-type kinetics. When alpha = 0, the
third
term on the right side disappears and when alpha = 1, the third term is
conserved.
Alpha = 0 is used for mutually exclusive drugs and alpha = 1 is used for
mutually
nonexclusive drugs. For drugs that have the same or similar modes of action,
the
effects of both drugs are mutually exclusive. For drugs that have different
modes
of action or act independently, the effects of both drugs are mutually
nonexclusive.
A plot of fraction affected (F~ versus combination index (CI) is called the
Fa CI plot. This plot indicates synergism, additivity, or antagonism of two
drugs
at various effect levels in a mixture that is serially diluted. If several
mixtures are
made, it is possible to estimate the optimal combination ratio for maximal
synergy. Different effect levels usually give different degress of synergism,
additivism, or antagonism. CI values <1 indicate synergism; CI values >1
indicate
antagonism, and CI values that are one or hover around one indicate
additivity.
For anticancer agents, synergism at high effect levels (F~ is clinically more
relevant than synergism at low Fa levels.
While acetyldinaline (CI-994) has not been approved for clinical use, it has
nevertheless been evaluated in several clinical trials. In one such study,
patients
were treated using a dose-escalation scheme that increased both the daily dose
and
the duration of treatment. The majority of patients had received extensive
prior
chemotherapy. The maximum-tolerated dose (MTD) was 15 mg/m2/day when the
duration of treatment was 14 consecutive days. To allow more prolonged
treatment, lower doses were studied. Using a schedule of 8 weeks of continuous
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_g_
daily therapy, followed by a 2-week 'drug holiday', the MTD was 8 mg/m2/day.
The dose-limiting toxicity was thrombocytopenia or neutropenia, usually
occurring within 1 month of the start of therapy. Blood counts tended to
stabilize
even with continued treatment and to recover quickly when treatment was
stopped. There was no evidence of cumulative toxicity following repeated
courses
and prolonged exposures to CI-994. Other toxicities included nausea, vomiting,
diarrhea, anorexia, fatigue, mucositis, headache, dehydration, and increases
in
liver and renal function test values. Responses included one partial response
in a
heavily pretreated patient with NSCLC and a minor response in one patient each
with renal cell cancer and NSCLC.
An additional Phase 1 study was conducted in patients with relapsed acute
leukemia or other hematologic malignancy using a once daily high-dose 5-day
dosing schedule. The MTD was 135 mg/m2/day. The dose-limiting toxicity was
acute CNS toxicity manifested as sedation and somnolence. Other adverse events
included nausea, vomiting, hypotension resulting from dehydration,
hypocalcemia, headache, and in one patient each, acute pancreatitis, a
pyramidal
syndrome characterized by hyperreflexia and bilateral Babinski reflexes, and
sepsis. Hematologic toxicities cannot be assessed in this patient population.
Two
patients with AML developed tumor lysis syndrome, resulting in one death.
Transient decreases in peripheral white blood cell counts were noted.
A Phase 2 program is currently being conducted with CI-994, used as a
single agent. The dosing regimen is 8 mg/m2 given orally daily. Over 100
patients
have been treated, including patients with nonsmall cell lung cancer, renal
cell
cancer, pancreatic cancer, head and neck cancer, ovarian cancer, myeloma,
prostate cancer, and breast cancer. Some patients have tolerated dose
increases to
10 mg/m2, while some patients have had to have treatment interrupted due to
thrombocytopenia, and then be restarted on CI-994 at lowered doses. The
adverse
events have been similar to those observed in the chronic dosing Phase 1
protocol.
Thrombocytopenia has been the dose-limiting toxicity. Infrequent neurologic
adverse events including paresthesias, confusion, and hallucinations have been
reported. Objective responses have been seen in patients with nonsmall cell
lung
cancer. Clinical benefit has been reported in patients with renal cell cancer.
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In the solid tumor Phase 1 study, CI-994 doses were administered orally
following a fasting period, and blood samples were collected for
pharmacokinetic
analyses. Preliminary results indicate that the maximum blood level is
achieved
approximately 1 to 2 hours after ingestion, and the terminal elimination half
life
of CI-994 is approximately 15 hours. The maximum plasma CI-994
concentrations achieved with increasing dose levels were less than dose-
proportional. The terminal elimination half life and the apparent clearance
rate
were independent of the dose administered.
One additional objective of this study was to determine whether taking
CI-994 with food affected its rate or degree of absorption. Twelve fasted
patients
were given a single dose of CI-994, 8 mg/m2. One week later, the same patients
were given the same dose of CI-994 with a normal meal. Analysis of
phannacokinetic data revealed that CI-994 can be taken without regard to
meals.
Mass balance/route of elimination studies have not been conducted in
humans. Animal studies indicate that the principal route of elimination is via
renal
excretion, with 80% and 62% of radiolabeled drug appearing in the urine of
monkeys and rats, respectively, within 24 hours.
The following detailed examples further establish the synergy between
CI-994 and paclitaxel and/or carboplatin.
EXAMPLE 1
The synergistic combinations provided by this invention have been
evaluated in standard chemotherapy studies using female BALB/C mice weighing
18 to 20 g. The test mice were obtained from Charles River Laboratories,
Wilmington, MA. On Day 0 of the test, each mouse was surgically implanted
(subcutaneously) with a fragment of LC-12 squamous cell lung carcinoma tumor
weighing approximately 30 to 60 mg. The tumor fragments were implanted using
a 12 gauge trocar. The mice were weighed weekly, and tumor size (width and
length in mm) were measured two times each week with standard calipers. Tumor
mass for each animal was calculated according to the formula:
Tumor weight (mg) _ (a x b2)
2
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where "a'' is width of the tumor in mm, and "b" is the length in mm.
Evaluation of
anticancer activity was established by the formula T-C, where "T" and "C" are
the
median time (in days) required for the treated and control (respectively)
tumors to
reach a predetermined a size of about 750 mg (the ''evaluation size"). Tumors
generally reached size of about 150 to about 200 mg before drug dosing was
initiated. Antitumor activity was assessed according to four parameters: ( 1 )
partial
tumor response (PR); (2) complete tumor response (CR); (3) tumor-free survival
(TF); and (4) tumor growth delay (TL). Tumor growth delay is expressed as a T-
C
value, where T is the median days required for the treatment group tumors to
reach a predetermined size (e.g., 750 mg), and C is the median days for the
control
group tumors to reach this size. From the tumor growth delay value, the net
1og10
tumor cell kill is calculated as follows:
Net log 1 p tumor cell kill = [(T-C) - Rx]/3.32 x Td
where Td is the days for the tumor mass to double, and Rx is the total days of
treatment. Td is estimated from the best fit straight line from a log-linear
plot of
the control-group tumors in exponential growth (200 to 800 mg range). The
conversion of the T-C values to loglp cell kill is possible because the Td for
tumors regrowing after treatment is approximately the same as that for
untreated
control mice. The net log 10 kill value normalizes the efficacy data for tumor
growth during treatment regimens of varied duration and provides an estimate
of
whether an actual regression of the tumor occurred. Positive values indicate
that
an actual reduction of tumor burden occurred. Negative values indicate the
tumor
actually grew (although possibly more slowly) during treatment. Tumor-free
survivors were excluded from these calculations.
Acetyldinaline was suspended in 0.5% aqueous methyl cellulose and
administered orally at various dosages in 0.5 mL volumes. Taxol was dissolved
in
0.1 % aqueous saline and administered intravenously at various dosage levels
in
0.5 mL injections.
The animals were divided into groups of eight animals each. One group
served as controls and received no drug treatments. Four groups received oral
doses of acetyldinaline alone at a specified level of active drug (7.5 mg/kg,
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15 mg/kg, 30 mg/kg, and 60 mg/kg). The acetyldinaline was administered daily
on
Days 11-15 (Day 0 being when the tumor was implanted), Days 18-22, and
Days 25-29. One group received Taxol alone at doses of 15 and 20 mg/kg. Four
groups received acetyldinaline at the recited doses, in combination with 15
mg/kg
of Taxol, and another four groups received acetyldinadine at the recited doses
in
combination with Taxol at 20 mg/kg.
RESULTS AND CONCLUSION
The antitumor effects that are produced when CI-994 is used in
combinations with Taxol are shown in Table 4. The MTD of CI-994 was
60 mg/kg/day. This dose produced a 12.5% complete tumor response rate and no
partial tumor responses. The tumor growth delay for the tumors that did not
completely respond to CI-994 was 14.9 days. This delay represents a net tumor
cell kill of -0.18 logl0. None of the mice were tumor free when the study
ended
74 days after the last CI-994 treatment. CI-994 at 30 mg/kg/day (50% its MTD)
did not produce any complete or partial tumor responses. The tumor growth
delay
produced by this dose was 3.2 days, which represents a net tumor cell kill of
-0.7 logl0. The MTD of Taxol was 20 mg/kg/day. This dose produced not
complete or partial tumor responses. The tumor growth delay produced by Taxol
at its MTD was only 2.5 days. This represents a net tumor cell kill of -0.07
log 10.
CI-994 could not be given at its MTD with Taxol at its MTD because of
unacceptable lethality and weight loss. However, CI-994 could be given at 50%
its
MTD with Taxol at its MTD. This combination produced complete and partial
tumor response rates of 37.5% to 25%, respectively. The tumor growth delay for
the tumors that did not completely respond to this combination was 17.7 days,
which represents net tumor cell kills of -0.06 log 10. There were 12.5% of the
mice
tumor free when the study ended 74 days after the last CI-994 treatment.
Better antitumor activity was seen when CI-994 was given at its MTD with
Taxol at 50% its MTD. This combination produced a 100% complete tumor
response rate and 100% of the mice were still tumor free when the study ended
74 days after the last CI-994 treatment.
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These results indicate the antitumor activity is greater than additive when
CI-994 is given at its MTD the same time as Taxol at 50% its MTD.
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EXAMPLE 2
The combination of CI-994 plus paclitaxel was evaluated in mouse colon
carcinoma cells (recombinant 26:10 cells), and the data was analyzed according
to
the Chou and Talalay program which established both combinations to be
synergistic.
Mouse colon carcinoma cells were seeded into 96-well culture plates in
RPMI 1640 culture media supplemented with 20% fetal calf serum and 10 pg/mL
of insulin. Various concentrations of CI-994 and paclitaxel were added
together
24 hours after cells were initially seeded into the culture plates and allowed
to
attach. The effect of CI-994 and Taxol alone and in combination on colon
carcinoma proliferation was determined after 96 hours of incubation at
37°C using
the SRB assay (Skehan P., Stoneng R, Scudiero D, et al. New colorimetric
cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst.,
1990;82:1107-1112). The combination chemotherapy data was analyzed using the
Biosoft program, "Dose Effect Analysis with Microcomputers for IBM PC,"
which is a standard program for quantifying synergism, additivism, and
antagonism among anticancer agents, and is based on the median-effect
principle
of mass-action law using an enzyme kinetic system model described by Chou and
Talalay. Plots of fraction affected (Fa) versus combination index (CI) are
called
Fa-CI plots. These plots indicate synergism, additivity, or antagonism of 2
drugs
at various effect levels in a mixture that is serially diluted. If several
mixture are
made, it is possible to estimate the optimal combination ratio for maximal
synergy. Different effect levels usually give different degrees of synergism,
additivism, or antagonism. CI values <1 indicate synergism; CI values >1
indicate
antagonism and values that hover around 1 as a straight line indicate
additivity.
Figure 1 shows representative Fa-CI plots for CI-994 plus Taxol. In the plots,
CI
values over the entire Fa range are less than one, indicating synergy for the
drug
combinations.
EXAMPLE 3
The general procedure described in Example 1 was followed to evaluate
the antitumor activity of CI-994 in combination with carboplatin.
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CI-994 was given orally for three treatment cycles. Each cycle consisted of
daily treatments for 5 days followed by 2 days rest ( 15 days total
treatment). With
this schedule, the MTD was 60 mg/kg. This dose produced 50% complete
responses and no partial responses. Mice whose tumor completely responded were
tumor free when the study ended on Day 71. For the tumors that didn't
completely
respond, a tumor growth delay of 19.4 days was produced by CI-994 at its MTD.
This growth delay represents a net tumor cell kill of 0.1 logl p. When CI-994
was
given at 30 mglkg, there were 20% complete responses, 10% partial responses,
and a tumor growth delay of 8.2 days. Little antitumor activity was seen with
lower CI-994 doses. Carboplatin (Paraplatin~, Bristol-Myers Squibb Co.,
Princeton, NJ) was given ip, once a day, for 5 days. At its MTD of 20 mg/kg,
carboplatin produced 20% complete responses, 10% partial responses, and a
tumor growth delay of only 5.9 days. Ten percent complete responses, no
partial
responses, and a tumor growth delay of 8.3 days were produced with carboplatin
at 75% of its MTD (15 mg/kg). Carboplatin was given with CI-994 during the
first
CI-994 treatment course. When given in this manner, CI-994 could be given at
only 25% of its MTD with carboplatin at its MTD without increased lethality.
This dose combination produced 70% complete and 10% partial tumor responses.
Sixty percent of the mice were tumor free at the end of the study on Day 71.
The
tumor growth delay for the tumors that didn't completely respond, or regrew,
was
20.8 days. This represents a greater than additive antitumor effect. When CI-
994
was given at its MTD with carboplatin at 75% of its MTD, there were 100%
complete tumor responses. One hundred percent of the surviving mice were tumor
free when the study ended. This represents a net tumor cell kill of at least
3.8 logl0, which is clearly a greater than additive antitumor effect. There
was one
death in this group, but the cause of this death is unknown.
The results of the foregoing study are presented in Table 5. The results
establish that CI-994 can be given with carboplatin to produce a greater than
additive antitumor effect without a significant increase in toxicity. This
results in a
therapeutic effect that is superior to the effects produced by either drug
alone at
their MTDs.
CA 02386876 2002-04-08
WO 01/34131 1( PCT/US00/30377
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CA 02386876 2002-04-08
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-17
EXAMPLE 4
The general procedure described in Example 1 was followed to evaluate
the antitumor activity of CI-994 in combination with both paclitaxel and with
carboplatin. Each agent was also evaluated alone, and treatment groups were
compared to untreated controls. The MTD of CI-994 was 60 mg/kg/day. This dose
produced a 30 percent complete response rate and no partial tumor responses.
The
mice whose tumors completely responded were still tumor free 40 days after the
last treatment with CI-994. The tumor growth delay for the tumors that did not
completely respond to CI-994 was 16.2 days. Paclitaxel and carboplatin were
both
given alone at their MTD's of 15 and 30 mg/kg, respectively. There were no
complete or partial tumor responses and only a 3.7 day tumor growth delay with
paclitaxel at its MTD. At its MTD, carboplatin did not produce any complete or
partial tumor responses. The tumor growth delay for this dose of carboplatin
was
6.9 days. The results of this study are presented in Table 6.
CI-994 could not be given at its MTD with paclitaxel and carboplatin at its
MTD because of unacceptable deaths. When CI-994 was given at 50% of its MTD
with these drugs at their MTD's, there was one death. However, this dose
combination produced 80 percent tumor responses and the mice were still tumor
free 40 days after the last CI-994 treatment. The tumor growth delay for the
tumors that did not completely respond was greater than 51 days. These results
indicate the antitumor effect is synergistic when tumor bearing mice are
treated
with the combination of CI-994, paclitaxel and carboplatin.
CA 02386876 2002-04-08
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19
EXAMPLE 5
Clinical Evaluation of 2-Component Combination Therapy
This is a multicenter, open-label Phase 1 study of CI-994 given in
combination with paclitaxel to patients with advanced solid tumors.
The obj ectives of this study are to determine the ( 1 ) MTD,
(2) recommended Phase 2 dose, (3) pharmacokinetics, (4) safety profile, and
(5) to
observe for antitumor activity of CI-994 when given in combination with
paclitaxel to patients with advanced solid tumors. The primary efficacy
endpoint
is the attainment of either a PR or a CR. Secondary endpoints include time to
PR
or CR, duration of PR or CR, and survival.
Paclitaxel is administered as an intravenous infusion at 3-week intervals
during the treatment course, using an initial dose of 135 mg/m2. CI-994 is
administered orally as a daily dose for 21 days of a 28-day course, beginning
on
Day 1. Patients may receive subsequent courses of treatment based on
individual
tolerance and response to therapy. Patients whose disease does not respond or
who
develop intolerable adverse events are discontinued from study treatment.
The initial dose level of CI-994 is 4 mg/m2. A minimum of three patients
will be treated at each dose level. Dose levels are increased by 2 mg/m2 until
the
MTD is reached. Ten additional patients are to be treated at the dose level
recommended for Phase 2 studies, which is expected to be the MTD or one dose
level below the MTD.
Once a patient begins study treatment, the addition of other cancer
treatment will confound the assessment of safety and efficacy and therefore is
not
allowed. This restriction precludes the addition of systemic cytotoxic,
hormonal,
immunologic, or other biologic agents while the patient is in the treatment
phase
of this protocol. Patients who require palliative radiotherapy while on study
are
generally considered to have progressive disease and, unless compelling
information exists to the contrary, are to be discontinued from study
medication.
Patients who develop new brain metastases while on study may have treatment
interrupted to receive a course of cranial irradiation, then be restarted on
study
medication after a recovery period of at least 1 week.
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Antiemetics may be used at the investigator's discretion for prevention
and/or treatment of nausea or vomiting. Every effort should be made to ensure
nausea and vomiting is controlled, as these conditions may preclude a patient
from
taking or absorbing the oral doses of CI-994. This issue is particularly
relevant on
5 Days 1, 8, and 15, when gemcitabine is also administered. Because CI-994
caused
sedation and somnolence at higher doses in the Phase 1 program, antiemetics
that
are least likely to cause these side effects should be used.
Colony-stimulating factors may be used at the investigator's discretion to
treat episodes of severe myelosuppression that are complicated by infection,
but
10 should otherwise not be used to support low blood counts or to maintain
dose
intensity.
If criteria are met for a CR, administer 2 additional courses of treatment
beyond confirmation of the CR and then completely reassess the patient's
disease
state. If the patient is considered to be clinically free of disease at that
time,
15 discontinue the gemcitabine and continue to administer CI-994 for 3
additional
months, using the same dose and schedule (3 weeks on/1 week off). At that
time,
again completely reassess the patient's disease state. If the patient is still
in CR,
the investigator must evaluate the risks and potential benefits of continuing
CI-994 treatment.
20 Treatment Courses
A treatment course consists of Taxol given intravenously on Day 1 of a
28-day course plus CI-994 administered daily orally, beginning on Day 1, for
21 days of a 28-day course. Courses are to be repeated on Day 29 if there has
been
adequate recovery from adverse events and myelosuppression, defined as
nonhematologic parameters of Grade <_1, platelet count >_100,000/~L, and
absolute
neutrophil count >_1500/~L. Subsequent courses may be delayed by weekly
intervals up to 3 weeks. If recovery has not occurred by Day 50, the patient
is to
be discontinued from study medication.
Taxol Dosing
The initial dose of Taxol in each course is 135 mg/m2, given as a 3-hour
intravenous infusion. Dose adjustments may be required during a treatment
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21
course. Follow the manufacturer" s recommendations for information regarding
preparation and administration.
CI-994 Dose Levels
CI-994 doses are calculated based on body surface area (BSA) and must
then be rounded to the closest available capsule strength. CI-994 is available
in
capsule strengths of 2.5, 5, and 25 mg. Doses may be taken without regard to
meals.
The initial CI-994 dose level is 4 mg/m2. Subsequent dose levels will be
increased (or decreased if necessary) by a fixed increment of 2 mg/m2 until
the
MTD is determined. Individual patients may not receive dose escalations of
gemcitabine or CI-994 in subsequent courses. Patients may receive a lower dose
of CI-994 in a subsequent course if dose-limiting toxicities were experienced.
Three new patients will be assessed at each new dose level. The minimum
time that these patients must be followed is 4 weeks before a new dose level
may
be opened (unless treatment was interrupted earlier and the patient is
recovering
from adverse events). If none of these three patients experience a dose-
limiting
toxicity, the next higher dose level will be opened. If one patient develops a
dose-
limiting toxicity, three more patients will be enrolled at that dose level. If
>_2 of
6 patients experience a dose-limiting toxicity at the same level, that dose
level will
be considered the MTD.
An assessable patient is defined as one who received 3 weekly doses of
gemcitabine plus at least 80% of the CI-994 doses (>_17 doses), or a patient
whose
treatment course was discontinued early or was noncompliant (<17 doses) due to
treatment-related adverse events. A patient who took fewer than 17 doses of
CI-994 or did not complete the treatment course because of nontreatment-
related
reasons (e.g., missed appointments, ran out of CI-994 supplies, developed a
coexisting medical condition that rendered the patient unable to swallow
capsules,
developed rapidly progressing disease) is not considered to be an assessable
patient for the tolerability of that dose level.
Patients should be encouraged to take their CI-994 dose at approximately
the same time each day. However, a variance of up to 12 hours either way is
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22
allowed for any given dose, rather than miss a day's dose. If a patient misses
a
day's dose entirely, they must be instructed not to 'make it up' the next day.
If a
patient vomits anytime after taking a dose of CI-994, they must be instructed
not
to 'make it up', but to resume subsequent doses the next day as prescribed.
On Days 1, 8, and 15, the CI-994 dose should be given 2 hours before the
gemcitabine dose, to ensure maximal absorption in the event the patient
develops
vomiting following the gemcitabine dose.
Once the MTD is determined, 10 additional patients will be treated at the
Phase 2 dose level, which is expected to be the MTD or one dose level below
the
MTD.
Dose Adjustments During a Course
Continuation of Taxol and CI-994 during a course is dependent on patient
tolerance and hematologic parameters. Reduced doses of gemcitabine may be
required on Days 8 and 15, as recommended by the manufacturer and shown in
the table below. The dose of CI-994 is not to be increased or decreased during
a
treatment course, although early termination may be required as described
below.
If both study medications must be stopped before a course is completed, do not
complete that course, but instead follow the patient for recovery, then start
another
course using a reduced dose of CI-994.
The decision to discontinue CI-994 dosing during a course is based on
adverse events or hematology results at any time. Example: A patient has a
platelet count on Day 11 of 45,000/qL. Instruct the patient to stop taking CI-
994
capsules (and to return all study medication containers to the site). Obtain
another
CBC on Day 15. If the platelet count on Day 15 is 50,000 to 99,000/pL,
administer 75% of the calculated Taxol dose but do not reinstitute CI-994
dosing.
If the platelet count on Day 1 ~ remains below 50,000/qL, do not retreat with
gemcitabine. Consider this course to be terminated and follow the patient for
recovery. In either case, the patient may receive a subsequent treatment
course
using the same initial dose of Taxol and a CI-994 dose that has been reduced
by
2 mg/m2.
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Drug Formulation and Stability
Taxol is to be obtained by the site from commercial sources. Follow the
manufacturer's recommendation for preparation, administration, stability, and
storage conditions.
CI-994 is formulated in identically appearing gelatin capsules containing
2.5, 5, or 25 mg of study medication, plus inactive ingredients of lactose,
cornstarch, and talc or polyethylene glycol 6000. Store at controlled room
temperature.
EXAMPLE 6
Clinical Evaluation of 3-Component Combination Therapy
This is a clinical study of oral CI-994 in combination with paclitaxel and
carboplatin in the treatment of patients with advanced solid tumors. Patients
to be
treated will have advanced solid tumors and will not have received more than
two
prior chemotherapy regimens, and for whom paclitaxel and carboplatin are
reasonable treatment options. Primary efficacy parameters will include
response to
treatment classified as complete remission (CR), partial remission (PR),
stable
disease (SD), or progressive disease (PD).
A treatment course consists of paclitaxel and carboplatin given
intravenously on Day 1 of a 21-day course plus CI-994 administered daily
orally,
beginning on Day 1, for 7 or 14 days, depending on the dose level, of a 21-day
course. Courses are to be repeated on Day 22 if there has been adequate
recovery
from adverse events and myelosuppression. Subsequent courses may be delayed
by weekly intervals up to 3 weeks. If recovery has not occurred by Day 43, the
patient is to be discontinued from study medication.
Paclitaxel is to be obtained by the site from commercial sources. Follow
the manufacturer's recommendations for information regarding preparation,
administration, storage, and stability. In particular, note the requirement to
avoid
PVC-containing infusion sets and bags and the recommendation to use an in-line
filter.
Patients must be premedicated prior to receiving each dose of paclitaxel.
The pretreatment regimen currently recommended by the manufacturer consists of
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24
dexamethasone 20 mg PO administered approximately 12 and 6 hours before
paclitaxel, diphenhydramine 50 mg IV 30 to 60 minutes prior to paclitaxel, and
cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes. Vital signs
should
be monitored during paclitaxel infusions in accordance with institutional
policy.
Despite premedication, anaphylactic reactions have occurred with
paclitaxel infusions. Adequate medical supervision must be present and
appropriate intervention must be readily available to diagnose and treat
hypersensitivity reactions.
Carboplatin is to be obtained by the site from commercial sources. Follow
the manufacturer's recommendations for information regarding preparation,
administration, storage, and stability. In particular, note the requirement to
avoid
needles or IV sets that have aluminum components.
Anaphylactic reactions have occurred with carboplatin injections.
Adequate medical supervision must be present and appropriate intervention must
be readily available to diagnose and treat hypersensitivity reactions.
Carboplatin is given as a 30-minute IV infusion immediately following the
completion of the paclitaxel infusion. The carboplatin dose (in mg) to use in
each
course is calculated to produce an area under the concentration time curve
(AUC)
of 6 using the Calvert formula, substituting the creatinine clearance as
determined
by the Cockcroft-Gault formula for the glomerular filtration rate (GFR).
Dose (in mg) = AUC of 6 (GFR + 25)
[(140 - age) x weight in kg)
GFR = x 0.85 for females
(72 x serum creatinine))
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EXAMPLE: Patient characteristics are female, 63 years old, serum
creatinine = 1.1 mg/dL, weight = 66 kg.
(140 - 63) x 66
GFR = x 0.8~ = 54.5
72 x 1.1
Carboplatin dose in mg = 6 (54.5 + 25) = 477 mg (NOT mg/m2)
5 CI-994 doses are calculated based on body surface area (BSA) and must
then be rounded to the closest available capsule strength. CI-994 is available
in
capsule strengths of 2.5, 5, 10, and 25 mg. Doses may be taken without regard
to
meals.
Patients should be encouraged to take their CI-994 dose at approximately
10 the same time each day. However, a variance of up to 12 hours either way is
allowed for any given dose, rather than miss a day's dose. If a patient misses
a
day's dose entirely, they must be instructed not to 'make it up' the next day.
If a
patient vomits anytime after taking a dose of CI-994, they must be instructed
not
to 'make it up', but to resume subsequent doses the next day as prescribed.
15 A Study Medication Diary is to be completed during each treatment course
[date, dose taken or not, vomited or not within 2 hours after taking dose]. On
Day 1 of each course, the CI-994 dose should be given 2 hours before the
paclitaxel dose, to ensure maximal absorption in the event the patient
develops
vomiting following the paclitaxel dose.
20 Dose Levels and Number of Patients
The following table describes the anticipated dose levels. It is designed to
reach the 'standard' dosing of paclitaxel (225 mg/m2) and carboplatin (AUC =
6).
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26
Dose paclitaxel Dose Carboplatin AUC,CI-994 Dose orally
(mg/m2)
Level infused over 3 infused over
hours on
Day 1 30 minutes on
Day 1
14-DAY
SCHEDULE
CI-994
-2 175 6 2.5 mg fixed dose
on
Days 1-14
-1 175 6 5 mg fixed dose on
Days 1-14
1 175 6 4 mg/m2/day on Days
1-14
2 175 6 6 mg/m2/day on Days
1-14
3 * 200 6 4 mg/m2/day on Days
1-14
4* 225 6 4 mg/m2/day on Days
1-14
5* 225 6 6 mg/m2/day on Days
1-14
7-DAY
SCHEDULE
CI-994
6* 200 6 4 mg/m2/day on Days
1-7
7* 225 6 4 mg/m2/day on Days
1-7
8+ 225 6 6 mg/m2/day on Days 1-7
* After Dose Level 3, Dose Level 7 or higher will be opened sequentially in
the event that the results of
the ongoing patient experience indicated adequate tolerability of the
preceding dose level. Dose Level 3
has met MTD criteria, and thus Dose Levels 4 and 5 will NOT be evaluated
immediately following Dose
Level 3. Dose Level 6 will NOT be evaluated immediately following Dose Level
3, as experience at this
dose level has been obtained via early patient discontinuation of CI-994 in
Dose Level 3 (approximating
Dose Level 6's abbreviated CI-994 dosing schedule). Dose Level 6 will be
opened if Dose Level 7 meets
the criteria for MTD.
+ Should Dose Level 8 not meet the MTD, additional dose levels will be opened
at increments of
2 mg/m2/day CI-994. Each of these Dose Levels would include paclitaxel and
carboplatin as described
for Dose Level 8.
The initial CI-994 dose level is 4 mg/m2 which represents approximately
25% of the MTD when CI-994 was given as a single agent for 14 days in a
Phase 1 study, and 50% of the daily dose when given as a single agent on a
chronic daily basis in the ongoing Phase 2 program. See the section for a
summary
of the CI-994 clinical experience.
Three new patients will be assessed at each new dose level. The minimum
time that these patients must be followed is 3 weeks before a new dose level
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27
may be opened (unless treatment was interrupted earlier and the patient is
recovering from adverse events). If none of these 3 patients experience a dose-
limiting toxicity of any kind, OR if 1 patient develops dose-limiting
neutropenia
(see criteria in dose-limiting toxicity section), the next higher dose level
will be
opened. If 1 patient develops a dose-limiting toxicity except neutropenia, OR
if
2 patients develop dose-limiting neutropenia, 3 more patients will be enrolled
at
that dose level. If >_2 of 6 patients experience a dose-limiting toxicity
except
neutropenia at the same level, OR if >_3 of 6 patients develop dose-limiting
neutropenia, that dose level will be considered the MTD.
Number of Patients Number of Patients Action
Meeting DLT Criteria, Meeting Neutropenia
Excluding Neutropenia DLT Criterion
Initial Assessment of Dose Level (3 patients enrolled to dose level):
0/3 OR <1/3 Dose escalate
1 /3 OR 2/3 Enroll 3 additional
patients at the same dose
level
>_2/3 OR 3/3 MTD met
Final Assessment of Dose Level (6 patients enrolled to dose level):
<_1/6 OR <_2/6 Dose escalate
1/6 AND 2/6 Dose escalate
>_2/6 OR >_3/6 MTD met
Once the MTD is determined, 6 additional patients will be treated at the
Phase 2 dose level, which is expected to be the MTD or one dose level below
the
MTD.
To be considered an assessable patient for the safety of a given dose level,
a patient must have received a full dose of paclitaxel and carboplatin plus at
least
75% of the CI-994 regimen, or was discontinued early or was noncompliant due
to
treatment-related adverse events. A 75% compliance level is >_11 doses on the
14-day schedule and >_6 doses on the 7-day schedule. A patient who took fewer
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28
than 75% of the doses of CI-994 or did not complete the treatment course
because
of nontreatment-related reasons (e.g., missed appointments, misplaced their
CI-994 supplies, developed a coexisting medical condition that rendered the
patient unable to swallow capsules, developed rapidly progressing disease) is
not
considered to be an assessable patient for the tolerability of that dose
level.
Dose Adjustments During a Course
Paclitaxel and carboplatin are both given only on Day 1 of each treatment
course and as such are not subject to dose adjustments during a course.
Continuation of CI-994 during a course is dependent on patient tolerance and
hematologic parameters. The dose of CI-994 is not to be increased or decreased
during a treatment course, although early termination may be required.
Discontinue CI-994 dosing during a treatment course if any of the following
conditions are met:
~ Platelet count is <40,000/~L;
~ Absolute neutrophil count is <500/~L; and
~ Nonhematologic treatment-related adverse event is >_Grade 3 (except alopecia
or controllable nausea or vomiting).
Instruct the patient to stop taking CI-994 capsules and to return all study
medication containers to the site. Follow the patient for recovery, then start
another course using reduced doses of study medications as described below in
the
Dose Adjustments and Timing of the Next Treatment Course section.
Dose Adjustments and Timing of the Next Treatment Course
The dose adjustments for paclitaxel, carboplatin, and CI-994 for the next
treatment course are based on the absolute neutrophil count nadir, the
platelet
count nadir, and nonhematologic toxicities experienced during the prior
course.
Dose increases of paclitaxel, carboplatin, or CI-994 are not permitted in
subsequent courses, other than carboplatin dose increases that result from
recalculation based on the patient's current serum creatinine value and
weight.
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Maximum Condition Dose Adjustments
for Next
Treatment
Course
Within
a Patient
From Prior Course % of Prior % of Prior Dose Level Adjustment
for
Paclitaxel Carboplatin CI-994
Dose Dosea
Absolute Neutrophil
Count Nadir
>_ 500/~L 100 100 No change
<500/qL 75 75 Decrease by 2
mg/m2/ dayb
-OR-
Platelet Count Nadir
>_40,000/qL 100 100 No change
<40,000/qL 75 75 Decrease by 2
mg/m2/ dayb
-OR-
Treatment-Related
Nonhematologic Toxicity
Grade 0 to 2 (other 100 100 No change
than CNS)
Grade 2 CNS; 75 75 Decrease by 2
mg/m2/dayb
Grade 3 or 4 (exclude
alopecia
or
Controllable nausea or
vom
a If a dose reduction is required, recalculate the carboplatin dose to an AUC
= 6, using the patient's most
recent parameters, and then give 75% of this dose.
b If the patient is receiving a total dose of ~ mg/day, the patient's dose may
be decreased to 2.5 mg/day,
if in the investigator's clinical judgment, the patient would benefit from
further protocol treatment.
This decision should be reached in conjunction with the sponsor based upon the
patient's tolerance and
response to therapy.
Delay the start of the next treatment course until all of the following
conditions are met:
~ Absolute neutrophil count is >_2000/~tL;
~ Platelet count is >_100,000/E.tL; and
~ Nonhematologic treatment-related toxicities have recovered to Grade 0 or l,
with the exception of alopecia.
If a patient undergoes multiple dose decreases in subsequent courses such
that he/she no longer is receiving any amount of CI-994, or experiences a
significant hypersensitivity reaction to paclitaxel or carboplatin that
precludes
rechallenge, that patient is to be discontinued from the study.
Dose-Limiting Toxicity
Any of the following conditions is considered to be a dose-limiting
toxicity (DLT):
~ Platelet count nadir <25,000/~,L;
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~ Absolute neutrophil count <500/~L for 5 days or more, or was associated with
an infection or fever;
~ Grade 2 treatment-related CNS toxicities such as sedation, somnolence,
disorientation, confusion, or hallucinations lasting for >_24 hours;
5 ~ Grade 3 or 4 treatment-related nonhematologic toxicities (except alopecia
of
any grade, or controllable nausea or vomiting);
~ Failure to recover from adverse events (except alopecia) or hematologic
toxicities by Day 43; and
~ A terminated or noncompliant treatment course (fewer than 11 doses of
10 CI-994 taken on the 14-day schedule; fewer than 6 doses of CI-994 taken on
the 7-day schedule) due to a treatment-related toxicity of any grade.
Maximum-Tolerated Dose
The MTD is that dose level which produces any DLT except dose-limiting
neutropenia in >_2 of 6 assessable patients, OR dose-limiting neutropenia in
>_3 of
15 6 assessable patients in their first treatment course.
Safe Handling
Paclitaxel, carboplatin, and CI-994 are cytotoxic agents that must be
handled and administered with care. Inhalation of powder or contact with skin
and
mucous membranes, especially those of the eyes, must be avoided. Should
20 accidental eye contact occur, copious irrigation with water should be
instituted
immediately, followed by prompt ophthalmologic consultation. Should accidental
skin contact occur, the exposed area should be irrigated immediately with
copious
amounts of water for at least 15 minutes. As with other cytotoxic
antineoplastic
agents, appropriate precautions should be followed in accordance with OSHA
25 Guidelines.
Drug Formulation and Stability
CI-994 is formulated in identically appearing gelatin capsules containing
2.5, 5, 10, or 25 mg of study medication, plus inactive ingredients of
lactose,
cornstarch, and talc or polyethylene glycol 6000. Store at controlled room
30 temperature.
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31
The foregoing data establish an unexpectedly favorable interaction
between acetyldinaline in combination with either paclitaxel or carboplatin,
and in
combination with both paclitaxel and carboplatin. Accordingly, this invention
provides a method of treating susceptible neoplasms comprising administering
acetyldinaline in a regimen together with paclitaxel or carboplatin, or
together
with both paclitaxel and carboplatin. The combination generally will include
each
active ingredient packaged separately, thereby avoiding any interaction
between
the agents prior to administration. If desired, the individually packaged
drugs can
be placed in a single carton as a kit, thereby providing convenience to the
attending physician or medical attendant. The susceptible neoplasms to be
treated
according to this invention include solid tumors, especially advanced solid
tumors
and nonsmall cell lung cancer, as well as renal cell cancer, pancreatic
cancer, head
and neck cancer, ovarian cancer, myeloma, prostate cancer, and breast cancer.
