U.S. patent application number 10/266030 was filed with the patent office on 2005-09-15 for method of administering liposomal encapsulated taxane.
This patent application is currently assigned to NEOPHARM, INC.. Invention is credited to Rahman, Aquilur.
Application Number | 20050202074 10/266030 |
Document ID | / |
Family ID | 24624087 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050202074 |
Kind Code |
A9 |
Rahman, Aquilur |
September 15, 2005 |
Method of administering liposomal encapsulated taxane
Abstract
Liposomal-encapsulated taxane or an antineoplastic derivative
thereof or a mixture thereof is provided which is used to effect a
therapeutically enhanced method of treating cancer. The liposomal
encapsulated paclitaxel allows for administration to a patient,
particularly a human patient, in less than one hour without
substantial toxicity.
Inventors: |
Rahman, Aquilur; (Potomac,
MD) |
Correspondence
Address: |
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO
IL
60601-6780
US
|
Assignee: |
NEOPHARM, INC.
150 Field Drive
Lake Forest
IL
60045
|
Prior
Publication: |
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Document Identifier |
Publication Date |
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US 0035830 A1 |
February 20, 2003 |
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Family ID: |
24624087 |
Appl. No.: |
10/266030 |
Filed: |
October 7, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10266030 |
Oct 7, 2002 |
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10239598 |
Feb 25, 2000 |
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10239598 |
Feb 25, 2000 |
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PCT/US99/14986 |
Jun 29, 1999 |
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10239598 |
Feb 25, 2000 |
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09108509 |
Jul 1, 1998 |
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6146659 |
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10266030 |
Oct 7, 2002 |
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09654250 |
Sep 1, 2000 |
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6461637 |
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09654250 |
Sep 1, 2000 |
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09108509 |
Jul 1, 1998 |
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6146659 |
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Current U.S.
Class: |
424/450 ;
514/449 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 9/127 20130101; A61K 31/337 20130101;
A61K 31/337 20130101 |
Class at
Publication: |
424/450 ;
514/449 |
International
Class: |
A61K 031/337; A61K
009/127 |
Claims
We claim:
1. A method of administering a taxane comprising administering to a
human patient a pharmaceutical composition, over a period of less
than an hour, comprising up to about 300 mg/m.sup.2 of taxane
wherein said pharmaceutical composition further comprises
liposomes.
2. The method of claim 1, wherein said taxane is selected from the
group consisting of paclitaxel, 7-epipaclitaxel, t-acetyl
paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxel,
7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel,
7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, taxotere, and
mixtures thereof.
3. The method of claim 1, wherein the taxane is paclitaxel.
4. The method of claim 1, wherein at least one liposome contains
cardiolipin.
5. The method of claim 4, wherein the cardiolipin is synthetic
cardiolipin.
6. The method of claim 4, wherein the cardiolipin is tetramyristoyl
cardiolipin.
7. The method of claim 1, wherein the liposome further comprises
a-tocopherol.
8. The method of claim 1, wherein the liposome further comprises
cholesterol.
9. The method of claim 1, wherein the amount of taxane is at least
about 75 mg/m.sup.2.
10. The method of claim 1, wherein the amount of taxane is up to
about 75 mg/m.sup.2.
11. The method of claim 1, wherein the amount of taxane is at least
about 135 mg/m.sup.2.
12. The method of claim 1, wherein the amount of taxane is up to
about 135 mg/m.sup.2.
13. The method of claim 1, wherein the amount of taxane is at least
about 175 mg/m.sup.2.
14. The method of claim 1, wherein the amount of taxane is up to
about 175 mg/m.sup.2.
15. The method of claim 1, wherein the amount of taxane is at least
about 250 mg/m.sup.2.
16. The method of claim 1, wherein the amount of taxane is up to
about 250 mg/m.sup.2.
17. The method of claim 1, wherein the amount of taxane is about
300 mg/m.sup.2.
18. The method of claim 1, wherein the taxane is administered by
intravenous infusion.
19. The method of claim 18, wherein the taxane is administered over
a period of about 45 minutes.
20. The method of claim 1, wherein the taxane is administered
continuously over said period.
21. The method of claim 1, wherein the administration of taxane is
repeated at least once every 21 days.
22. The method of claim 1, wherein the taxane is administered to
the peritoneum of a patient suffering from cancer.
23. The method of claim 1, wherein the taxane is administered to a
patient patients suffering from colon cancer.
24. The method of claim 1, wherein the taxane is administered to a
patient suffering from prostate cancer.
25. The method of claim 1, wherein the taxane is administered to a
patient suffering from head and neck cancer.
26. The method of claim 1, wherein the taxane is administered to a
patient suffering from ovarian cancer, breast cancer, or lung
cancer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. patent
application Ser. No. 09/654,250, which was filed Sep. 1, 2000 as a
continuation of U.S. patent application Ser. No. 09/108,509, which
was filed on Jul. 1, 1998, and which issued on Nov. 14, 2000 as
U.S. Pat. No. 6,146,659.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to a method of administering a
liposomal encapsulated taxane.
BACKGROUND OF THE INVENTION
[0003] The use of taxanes, such as paclitaxel, as anti-tumor agents
for patients suffering from diseases such as ovarian and breast
cancer, is known. In addition, paclitaxel has been shown to be
clinically potent as a synergistic agent when used in conjunction
with radiation treatment. Paclitaxel has a unique mechanism of
action and a broad spectrum of anticancer activity because
paclitaxel shows stabilization of microtubules rather than
disassembly of microtubules.
[0004] However, paclitaxel has extremely low solubility in water,
which makes it difficult to provide a suitable dosage form.
Currently, paclitaxel is prepared and administered in a vehicle
containing Cremophor EL (a polyethoxylated castor oil) and ethanol
in a 50:50 (vol/vol) ratio. This solution is diluted 1:10 in saline
before being administered to humans. The stability of paclitaxel
once diluted in saline solution is quite low. The drug degrades
within 24 hours and, thus, handling of dosage for the patients
becomes very difficult. Since, the drug precipitates from dilution,
an on-line filter is utilized for the infusion of the drug to the
patients.
[0005] In clinical trials, a consistent problem of anaphylactoid
reaction, dyspnea, hypertension, and flushing have been
encountered. The dose-limiting toxicity is myelosuppression which
necessitates patient hospitalization when the drug is used.
[0006] Attempts to prevent paclitaxel cardiotoxicity and
anaphylactoid reaction have included reliance on pretreatment of
patients with antihistamine and corticosteroids, and by prolonging
the infusion time from six to twenty four hours. U.S. Pat. No.
5,621,001 (Canetta et al.) discloses a prolonged infusion time in a
method for reducing peripheral neurotoxicity symptoms while
maintaining an anti-tumor effect in patients suffering from ovarian
cancer and undergoing paclitaxel therapy. This method involves
administering about 135 mg/m.sup.2 of paclitaxel over a period of
about 24 hours. The administration of paclitaxel is repeated at
least once, about 21 days after the preceding administration.
[0007] U.S. Pat. No. 5,665,761 (Canetta et al.) discloses a
pretreatment stage before administration of paclitaxel. The '761
patent provides for paclitaxel infusions over a duration of less
than six hours, preferably about three hours, utilizing dosages of
between about 135 mg/m.sup.2 and about 275 mg/m.sup.2, preferably
between about 135 mg/m.sup.2 and about 175 mg/M.sup.2, after
patients had been pretreated to alleviate or minimize
hypersensitivity responses. For example, the patients are
pre-medicated with steroids, antihistamines, and
H.sub.2-antagonists sufficient to at least prevent an anaphylactoid
shock capable of causing acute hypersensitivity reactions and
patient death. U.S. Pat. No. 5,670,537 (Canetta et al.) also
discloses this method of administration for a patient suffering
from a paclitaxel-sensitive tumor, such as an ovarian tumor.
[0008] U.S. Pat. No. 5,641,803, discloses the administration of
paclitaxel to a patient, wherein about 135-175 mg/m.sup.2 of
paclitaxel is administered over a period of about three hours. Such
a period purportedly was used to overcome, in part, some of the
aforementioned problems associated with short infusion times, such
as one hour, which had been employed with the conventional
paclitaxel formulations containing polyethoxylated castor oil.
[0009] In yet another attempt to address the toxicity concerns of
the conventional paclitaxel formulation, U.S. Pat. No. 5,696,153
suggests the use of an administration regimen wherein 45 to 120
mg/m.sup.2 of paclitaxel is administered over a period of 60 to 180
minutes, a plurality of times during a 21 day period, with each
infusion being separated by an interval of between 4 to 5 days.
[0010] However, even with these manipulations of prolonged infusion
time and pretreatment of patients with antihistamines and
corticosteroids, the patients suffer from serious toxicities which
are often fatal. Different agent delivery systems are being
utilized to enhance tumor cell-fighting effects of the drug and/or
reduce systemic toxicity. Liposomes are one of many carriers that
have been developed to help anti-tumor agents become more efficient
and less toxic. A "liposome" is a closed structure composed of
lipid bi-layers surrounding an internal aqueous space.
[0011] U.S. Pat. No. 5,648,090 (Rahman et al.) and U.S. Pat. No.
5,424,073 (Rahman et al.) provide a liposomal encapsulated
paclitaxel for a method for treating cancer in mammals using such a
liposomal-encapsulated paclitaxel, or antineoplastic derivative
thereof. The '090 and '073 patents disclose a method of modulating
multidrug resistance in cancer cells in a mammalian host by
administering to the host a pharmaceutical composition of a
therapeutically effective number of liposomes which include a
liposome-forming material, cardiolipin, and an agent such as
paclitaxel, or an antineoplastic derivative of paclitaxel, or a
mixture thereof; and a pharmaceutically acceptable excipient.
[0012] Up until the present invention the fastest administration
time tolerated by most patients was optimally a three hour time
period. Consequently, there is a need for methods for rapidly
administering high concentrations of taxane in human cancer
patients without inducing a toxic reaction. Such methods would
improve the efficacy of taxane therapy and alleviate the discomfort
and toxicity associated with previously known taxane administration
methods. The present invention provides such a method.
SUMMARY OF THE INVENTION
[0013] The present invention provides a method of administering
relatively high concentrations of taxane to human patients over a
short period of time. For example, taxane can be administered to
humans in less than an hour in an amount from about 75 to 300
mg/m.sup.2. Unique liposomal formulations of taxane or its
antineoplastic derivatives facilitate such treatments. The method
does not require premedication, as with anti-hypersensitivity
agents, and is not accompanied by substantial toxic reactions in
human patients. As a result, the present invention provides an
improved method for treating cancer with taxane.
[0014] These and other advantages of the present invention, as well
as additional inventive features, will be apparent from the
description of the invention provided herein.
[0015] The invention may best be understood with reference to the
following detailed description of the preferred embodiments.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The present invention provides a method of administering a
taxane to a patient, especially a human patient, in need of
treatment with a taxane. In part, the present invention provides a
delivery system for a taxane to a host which is characterized by
the avoidance of solubility problems of a taxane; the improved
taxane stability; the avoidance of anaphylactoid reactions and
cardiotoxicity; the ability to administer a taxane as a bolus or
short infusion, rather than an extended infusion of free taxane;
the increased therapeutic efficacy of taxane; and the modulation of
multidrug resistance in cancer cells.
[0017] The taxane is delivered in the form of a liposomal
encapsulated taxane or antineoplastic derivative thereof. Any
suitable taxane or derivative can be used in the present method.
Suitable taxanes when used in accordance with the disclosed methods
provide the aforementioned benefits. Preferably, the taxane is
paclitaxel. A suitable derivative of paclitaxel is taxasm. Other
suitable taxanes are 7-epipaclitaxel, t-acetyl paclitaxel,
10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxe- l,
7-xylosylpaclitaxel, 10-desacetyl-7-glutarylpaclitaxel,
7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, taxotere, and
mixtures thereof.
[0018] The pharmaceutical composition may also include a suitable
cardiolipin. Suitable cardiolipin may be from either a natural or
synthetic source. The taxane, such as paclitaxel, is encapsulated
in liposomes using the cardiolipin. In addition to cardiolipin, the
taxane may be encapsulated in liposomes with phosphatidylcholine
and cholesterol. Such lipid compositions provide over 90%
encapsulation of the drug in liposomes.
[0019] The liposomal encapsulated taxane can be prepared by any
suitable process. For example, the taxane or a derivative thereof
can be dissolved in a suitable solvent. Generally, suitable
solvents are non-polar or slightly polar and can be evaporated
without leaving toxic residue behind. Suitable solvents include
such diverse solvents as ethanol, methanol, chloroform, butanol or
acetone. Cardiolipin can also be dissolved in a suitable solvent as
described for taxane and the taxane and the cardiolipin solutions
can be mixed. The remaining lipophilic material can be dissolved in
a suitable solvent, which may be the same as or different from the
taxane containing solvent. The solvent will have low polarity such
as chloroform, butanol or a non-polar solvent, such as n-hexane.
The solvent mixture containing the taxane and cardiolipin can be
mixed with the solution containing the remaining lipophilic
components.
[0020] The solvent is removed, from the mixture by a suitable
method such as by lyophilization to afford a dry lipid film that
contains the drug. The mixture is stored in this form, optionally
under an inert gas atmosphere, such as an N.sub.2 atmosphere. The
dry lipid film can be stored at low temperatures, such as
-20.degree. C. for extended periods of time until liposomes are
hydrated and prior to use.
[0021] Liposomes can be formed by adding any suitable solution to
the lipid film. Typically, suitable solutions are polar solutions,
preferably, aqueous saline solutions. Once the solution is added,
liposomes can be formed by mixing, for example, as by vortexing.
Where smaller vesicles, such as unilamellar vesicles, are desirable
the solution can be sonicated. In certain methods, suitable
preparations can be mixtures of multilamellar vesicles and
unilamellar vesicles.
[0022] The liposome is a closed structure composed of lipid
bilayers surrounding an internal aqueous space. Generally, the
liposomes may be neutral, negative or positively charged liposomes.
For example, positively charged liposomes can be formed from a
solution containing phosphatidyl choline, cholesterol, and stearyl
amine. Negative liposomes can be formed, for example, from
solutions containing phosphatidyl choline, cholesterol, and
phosphatidyl serine or more preferably, cardiolipin. Other
additives can also be included in the liposomes to modify the
properties of the resulting preparations. For example, preferred
preparations also include .sup..alpha.-tocopherol.
[0023] Storage conditions can vary. Preferably, mixtures of
lipophilic components are stored as dry lipid films at about
-20.degree. C. Once hydrated, liposome suspensions of the
pharmaceutical composition can be stored and are stable in
buffered, neutral pH saline solutions for periods of hours to
months, depending upon the temperature, paclitaxel content, and
phospholipid constituents.
[0024] The liposomal drug delivery system which features a high
drug to carrier ratio can alter drug pharmacokinetics, maintaining
the plasma concentration of the drug at an increased level over a
longer period of time. The biodegradability and the low inherent
toxicity and immunogenicity of liposomal preparations reduces
toxicity with respect to free-floating taxanes in the plasma.
[0025] The present liposomal formulations provide a drug-delivery
system which allows infusion of high concentrations of taxane in a
relatively stable form and which provides sustained therapeutic
benefits at target sites, while maintaining low concentrations of
insoluble free taxane and minimal adverse toxic effects than were
previously known. For example, infusion of encapsulated paclitaxel
provides higher peak plasma concentrations, longer presence of the
drug in the body, and higher AUC ("area under the curve"
measurement of plasma concentration over time) than the
conventional paclitaxel.
[0026] The present pharmaceutical composition can be administered
in amounts of at least 50 to 300 mg of active compound/m.sup.2 of
mammalian host surface area, within a period of less than about
three hours, preferably in less than about one hour, and most
preferably 45 minutes without causing a substantial toxic reaction.
For example, in a 70 kg human, about 0.5 to 5.0 mg active compound
per kg of body weight can be safely administered in about 45
minutes. Preferably, about 1.0-3.0 mg of active compound per kg of
body weight is administered. Alternatively, preferable amounts
include 75, 135, 175, 250, and 300 mg/m.sup.2.
[0027] Liposomal encapsulated taxane has a substantial beneficial
effect in overcoming multidrug resistance in cancer cells which are
subjected to chemotherapy. By using the liposomal composition of
the present invention, it is possible to reduce the tendency of
cancer cells subjected to chemotherapy to develop resistance to the
chemotherapeutic agents used for chemotherapy such as anthracycline
glycosides. This method includes administering to a host a
pharmaceutical composition of a liposomal encapsulated taxane of
the present invention in accordance with the administration
protocol.
[0028] Taxanes and the anti-neoplastic derivatives thereof may be
used to treat any form of mammalian cancer. Such compounds are
thought to function by promoting the assembly of microtubules or
prohibiting the tubulin disassembly process. Taxane and the
anti-neoplastic derivatives thereof are of particular advantageous
use in the treatment of mammalian lymphoma, ovarian, breast, lung
and colon cancer, and particularly those conditions in humans.
[0029] The present liposome compositions can be administered
intravenously, intraperitoneally, to an isolated portion of a
mammalian body particularly a human body, such as an arm or leg, or
in the case of a human, a hand, or can be injected directly into a
tumor.
[0030] The following examples further illustrate the present
invention but, of course, should not be construed as in any way
limiting its scope.
EXAMPLE 1
[0031] Paclitaxel can be encapsulated in liposomes of cardiolipin,
phosphatidylcholine, cholesterol and .sup..alpha.-tocopherol. The
composition described in this example, provides for over 90%
encapsulation of the drug in liposomes. The paclitaxel in liposomal
formulation is stable for days at room temperature and at
-20.degree. C. for at least 5 months. No degradation or
precipitation of paclitaxel is observed at any storage temperature
and the preparation appears to be ideally suited for systemic
administration in accordance with the present invention.
[0032] The proportion of lipids per mg of paclitaxel is:
[0033] 1.8 mg cardiolipin
[0034] 9.0 mg phophatidylcholine
[0035] 3.0 mg cholesterol
[0036] 0.1 mg .sup..alpha.-tocopheryl
[0037] The liposome encapsulated paclitaxel can be manufactured
using the following procedure.
[0038] 8.89 kilograms of t-butyl alcohol are added to a 12.0 liter
flask and heated to 40-45.degree. C. The following additions are
made sequentially with mixing until dissolution and heating at
40-45.degree. C.: 3.412 grams of D-.sup..alpha.-tocopheryl acid
succinate, 205 grams of egg phosphatidylcholine, 22.78 grams of
paclitaxel, 41.00 grams of tetramyristoyl cardiolipin, 68.33 grams
of cholesterol.
[0039] The resulting solution is filtered through a 0.22 micron
filter. The resulting filtrate is filled into sterile vials, each
containing about 10.1 grams of filtrate. The vials are stoppered
and subjected to lyophilization. They can be stored at -20.degree.
C. until use.
[0040] Liposomes are prepared from the dry lipid film, as needed,
with 25 ml of normal saline solution. The mixture is allowed to
hydrate at room temperature for about one hour, after which time
the vials are vortexed for about one minute and sonicated for about
10 minutes in a bath type sonicator at maximum frequency. An
appropriate amount of the contents of the vial can be transferred
to an infusion bag and infused into a patient in accordance with
the present invention.
EXAMPLE 2
[0041] The following study demonstrates that a large quantity of
taxane can be rapidly administered to humans without inducing a
substantial toxic reaction. Both hematological toxicity and
nonhematological toxicity were evaluated. In addition, the study
was used to determine in human patients the dose-limiting toxicity,
the maximum tolerated dose and the untolerated dose for the
liposomal formulation described in Example 1.
[0042] Vials containing liposomal paclitaxel were prepared as in
Example 1. The preparations were 1 mg/ml paclitaxel in liposomes.
The contents of the vials were transferred to infusion bags at the
appropriate dosages and administered to patients over about a 45
minute period.
[0043] Patients selected for the study had a measurable or
evaluable metastatic or locally recurrent malignancy and had no
significant hope of cure or palliation by other conventional
therapies. In addition, they had no evidence of spinal cord
compression or carcinomatous meningitis. Patients had not undergone
chemotherapy or radiotherapy within the four weeks prior to
treatment. Those patients that had undergone prior chemotherapy or
radiotherapy exhibited complete hematologic recovery prior to
treatment in this study. All patients had an ECOG (Eastern
Cooperative Oncology Group) performance status of 0 or 1 and had a
life expectancy of at least 3 months. Patients in the study were
all over the age of 18, were free of infection and had recovered
from the effects of any major surgery which must have occurred more
than three weeks prior to entering the study. Within the immediate
two weeks prior to the instant tests all patients had a white blood
cell count of over 3000/mm.sup.3, a platelet count of over
100,000/mm.sup.3, serum creatinine of less than 1.8 mg/dl or
creatinine clearance of more than 60/cc/min and serum bilirubin of
less than 1.5 mg/dl.
[0044] Treatments were administered intravenously over about a 45
minute period. At least three patients were treated at each dosage
level. Dosages were about 90 mg/m.sup.2, 135 mg/m.sup.2, 175
mg/m.sup.2, 250 mg/m.sup.2, and 300 mg/m.sup.2 allowing for normal
laboratory and therapeutic dose variation. The formulation was
given as a single agent without pretreatment with steroids,
antihistamines or other therapeutic agents such as anaphylaxis
inhibitors. Where the treating physician considered it appropriate,
treatments were repeated every 21 days. Each patient was subjected
to a single treatment regimen.
[0045] Hematologic toxicity was evaluated in test patients by
taking blood specimens of 5 mls from each patient. Samples were
taken just prior to drug infusion, at the end of the infusion
(time=0), then at 2, 4, 6, 10, 20, 30, 60, 240 minutes and 24 hours
after infusion. The samples were collected in heparinized tubes
which were gently inverted after filling to ensure mixing of the
heparinized blood. The vials were kept cool until the plasma was
isolated from each sample. As soon as practical, the samples were
centrifuged at 2000 rpm, for 15 minutes to collect the plasma
layer. Approximately 1 or 2 ml of the plasma was transferred to a
cryotube which was capped and immediately frozen at -20.degree. C.
in an upright position until hematological toxicity analysis.
Nonhematological toxicity and drug efficacy were also evaluated.
The results of this study are shown in Table I below.
[0046] Common toxicity grades established by the National Cancer
Institute were employed to determine drug toxicity. Dose-limiting
toxicity is defined as any grade 3 or higher non-hematologic
toxicity for 7 or more days occurring during cycle 1 of
chemotherapy. An untolerable dose is defined as the dose level at
which at least 1/3 to 2/3 of the patients have dose-limiting
toxicity. The maximum tolerated dose level is defined as the dose
level at which {fraction (0/6)} or 1/6 patients experience
dose-limiting toxicity and at least 2/3 or {fraction (4/6)}
patients treated at the next higher dose level experience
dose-limiting toxicity.
[0047] This study demonstrated that a large quantity of taxane
could be administered to a human without inducing a substantial
hematological or nonhematological toxic reaction. Nonhematological
toxicity was generally minor but became more pronounced at the
highest dosage level. Similarly, hematological toxicity was mild
but became more pronounced at the highest dosage. At least 300
mg/m.sup.2 of taxane could be administered to a human patient in a
45 minute period without inducing substantial hematological
toxicity or anaphylaxis. The dose limiting toxicity was about 300
mg/m.sup.2 when drug was administered in a 45 minute period. The
untolerable and maximum tolerable doses were not determinable from
this study but were at least 300 mg/m.sup.2. With one exception,
the cancer had not progressed or was improved in each of the
patients studied.
1TABLE I Patient Treatment Dose Heme Number Cycles (mg/m.sup.2)
Toxicity.sup.1 Nonhematological Toxicity Best Response Off study
due to 001 2 90 None HSR.sup.2 P.D..sup.3 002 11+ 90 Mild Stable
003 6 90 Mild (Seizure) Stable P.D. 004 2 135 HSR P.D. 005 6 135
Mild Muscular & hepatic Stable elective 006 8+ 135 Mild (HA,
fever, pharyngitis, Progressed wheezing) 007 3 175 Mild (diarrhea)
P.D. 008 2 175 Mild Mild hepatic P.D. 009 1 175 Mild Recurrent HSR;
HSR Nausea/fatigue; Mild hepatic 010 2 250 Mod (hemoptysis) P.D.
011 4+ 250 Mild Mild hepatic (HA, Stable diarrhea, chills &
sweats) Esophagitis grade 3 after cycle 3 012 3 250 Mild Mild
hepatic P.D. 013 2+ 250 Mild Mild GI, HSR 014 2+ 300 Mod Hepatic,
Esophagitis grade Improved 3 015 1+ 300 Severe Mild HSR, Hepatic
016 1+ 300 Severe Esophagitis grade 3 .sup.1neutropenia, anemia,
thrombopenia .sup.2hypersensitivity reaction: flushing, back pain,
pruritis .sup.3physician or patient discretion
[0048] All of the references cited herein, including patents,
patent applications, and publications, are hereby incorporated in
their entireties by reference.
[0049] While this invention has been described with an emphasis
upon preferred embodiments, it will be obvious to those of ordinary
skill in the art that variations of the preferred embodiments may
be used and that it is intended that the invention may be practiced
otherwise than as specifically described herein. Accordingly, this
invention includes all modifications encompassed within the spirit
and scope of the invention as defined by the following claims.
* * * * *