U.S. patent application number 10/044575 was filed with the patent office on 2003-07-17 for method for treating cancer having greater efficacy and reduced adverse effects.
Invention is credited to Hausheer, Frederick H..
Application Number | 20030133994 10/044575 |
Document ID | / |
Family ID | 21933121 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030133994 |
Kind Code |
A1 |
Hausheer, Frederick H. |
July 17, 2003 |
METHOD FOR TREATING CANCER HAVING GREATER EFFICACY AND REDUCED
ADVERSE EFFECTS
Abstract
A method of treating patients with cancer that involves
administration of a combination regimen of a platinum agent, a
taxane agent, and a formula I toxicity-reducing agent. The
preferred order of administration is the formula I compound,
followed by the platinum complex, followed by the taxane agent.
Inventors: |
Hausheer, Frederick H.;
(Boerne, TX) |
Correspondence
Address: |
Thomas J. Dodd
BioNumerik Pharmaceuticals, Inc.
8122 Datapoint Drive, Suite 1250
San Antonio
TX
78229
US
|
Family ID: |
21933121 |
Appl. No.: |
10/044575 |
Filed: |
January 11, 2002 |
Current U.S.
Class: |
424/649 |
Current CPC
Class: |
A61K 33/243 20190101;
A61K 45/06 20130101; A61K 33/24 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/649 |
International
Class: |
A61K 033/24 |
Claims
We claim:
1. A method for treating a patient with cancer comprising
administering the following combination of agents to said patient:
a) 4 g/m.sup.2-80 .mu.m.sup.2 of a compound of formula I:
R.sub.1--S--X.sub.1--R.sub.2; (I) wherein R.sub.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, or --S--X.sub.2--R.sub.3; R.sub.2 and
R.sub.3 are each individually sulfonate or phosphonate; and X.sub.1
and X.sub.2 are each individually C.sub.1-C.sub.6 alkyl, optionally
substituted by one or more hydroxy, sulfhydryl or alkoxy moieties;
then administering b) 10 mg/m.sup.2-300 mg/m.sup.2 of a platinum
complex; then administering c) 20 mg/m.sup.2-300 mg/m.sup.2 of a
taxane antineoplastic agent.
2. The method of claim 1 wherein said taxane is paclitaxel, said
platinum complex is cisplatin and said formula I compound is
dimesna.
3. The method of claim 2 wherein the combination of agents is
administered to the patient once a week.
4. The method of claim 2 wherein the combination of agents is
administered to the patient daily.
5. The method of claim 2 wherein the combination of agents is
administered to the patient biweekly.
6. The method of claim 2 wherein the combination of agents is
administered to the patient once every 21 days.
7. The method of claim 2 wherein the combination of agents is
administered to the patient by IV infusion.
8. The method of claim 1 wherein step a) is repeated after step
b).
9. The method of claim 8 wherein step a) is again repeated after
step c).
Description
FIELD OF THE INVENTION
[0001] This invention relates to a method for treating patients
afflicted with cancer, and will have application to a combination
drug treatment possessed of fewer and less severe unwanted toxic
adverse effects.
BACKGROUND OF THE INVENTION
[0002] Combination chemotherapy is a common, accepted treatment for
many types of cancers. In many cases, the synergistic effects of
combining two or more agents can be the difference between
successful and unsuccessful treatment of the patient.
[0003] Many combination treatment regimens are well known in the
oncology field. As an example, MOPP (an acronym for
mechlorethamine, vincristine, procarbazine, prednisone) is a
curative treatment regimen for Hodgkins' Disease. Several different
combination regimens (which all include cisplatin, vinblastine and
bleomycin) are accepted in the treatment of testicular cancer,
which is curable in up to 98% of diagnosed cases. In all, more than
300 different combination regimens have been used.
[0004] The main drawback to combination chemotherapy is often that
the synergy of action also applies to an increase in the severity,
and even sometimes additional unwanted toxic effects. In addition,
the schedule of administration of each drug in various combination
regimens has, in many circumstance, been observed to result in
greater toxicity. Particularly in cases where the preferred
combination regimen includes the administration of paclitaxel
followed by cisplatin, the combined effects of the two agents tends
to cause dose-limiting neurotoxicity, nephrotoxicity and bone
marrow suppression.
[0005] Another consideration of importance in combination
chemotherapy is the sequence in which the antineoplastic agents are
administered. For instance, where cisplatin and paclitaxel are
administered as a part of a combination treatment regimen, it has
been shown that due to severe toxicity considerations, paclitaxel
must be administered first, followed by administration of
cisplatin. If the order of administration is reversed, the
combination is highly toxic to the patient. The manifestation of
such severe schedule dependent toxicity precludes the
administration of the cisplatin followed by paclitaxel combination
because of the risk of serious toxicities, morbidity and even
death. Currently, there is no method available to allow the safe
and effective administration of cisplatin followed by paclitaxel in
a combination regimen.
[0006] We have made the surprising discovery that the
administration of a platinum compound (cisplatin) prior to the
administration of a taxane (paclitaxel) results in at least
additive antitumor activity in human cancer cells.
[0007] This invention may lead to increased antitumor activity in
patients who are treated with a platinum drug followed by the
administration of a taxane. The invention will allow such
administration to be more safely accomplished in patients with
cancer by the administration of an effective dose of a formula I
compound, followed by the administration of a platinum drug,
optionally followed by administration of formula I compound,
definitively followed by the administration of a taxane and
optionally followed by administration of formula I compound.
[0008] This new invention will result in increased antitumor
activity by the sequential administration of platinum and a taxane
and reduced toxicity due to the administration of a Cytoprotective
agent.
[0009] Disodium 2,2'-dithiobis ethane sulfonate (also referred to
in the literature as Dimesna and BNP7787) has been shown to reduce
the unwanted toxic effects associated with the administration of
single agent cisplatin, and of single agent paclitaxel in human
patients. Dimesna is generally regarded as extremely safe and
efficacious for these uses and others, and has been shown not to
interfere with the cytotoxic effects of the antineoplastic agent(s)
with which it is co-administered.
[0010] U.S. Pat. No. 5,919,816 and others, disclose the use of
dimesna, mesna, and other related compounds to reduce the toxicity
of many antineoplastic agents, as well as the toxicity of various
anti-infective agents, anti-diabetic agents, and others. Other
patents disclosing the use are found in the Information Disclosure
Statement submitted with this application.
SUMMARY OF THE INVENTION
[0011] This invention relates to methods of treating patients with
cancer by administering combination chemotherapy wherein effective
amounts and schedules of administration of two or more
antineoplastic agents are administered to the patient, together
with a toxicity reducing amount of a protective agent of the
following formula I:
R.sub.1--S--X.sub.1--R.sub.2; (I)
[0012] wherein R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl, or
--S--X.sub.2--R.sub.3;
[0013] R.sub.2 and R.sub.3 are each individually sulfonate or
phosphonate; and
[0014] X.sub.1 and X.sub.2 are each individually C.sub.1-C.sub.6
alkyl, optionally substituted by one or more hydroxy, sulfhydryl or
alkoxy moieties.
[0015] Preferred antineoplastic agents include platinum based
chemotherapy drugs (cisplatin, carboplatin, oxaliplatin, and
others) and taxanes (including, but not limited to paclitaxel,
docetaxel), and/or epothilones, and or vinca alkaloids, and/or
oxazaphosphorines or other agents used in the chemotherapy of
cancer, though the method of this invention is contemplated as
useful in any of a vast number of combination chemotherapy
regimens.
[0016] Dosage amounts, order of administration, routes of
administration, dosage schedules, and other factors are taken into
consideration when implementing the method of this invention. Some
preferred schedules are set forth in the description below.
[0017] Accordingly, it is an object of this invention to provide
for an improved method of treating patients with cancer for the
purpose of increasing tumor shrinkage, quality of life, patient
survival and the cure rate of human cancers.
[0018] Another object of this invention is to provide a new method
of treating patients with cancer through combination chemotherapy
along with a toxicity-preventing agent.
[0019] Another object is to provide for novel, safer, more
effective methods of treating patients with cancer.
[0020] Other objects will become apparent upon a reading of the
following description.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0021] The preferred embodiment herein described is not intended to
be exhaustive or to limit the invention to the precise form
disclosed. It is chosen and described to explain the general
principles of the invention, and its application and practical use,
to enable others skilled in the art to utilize and follow its
teachings.
[0022] This invention involves a novel combination chemotherapy
method to treat patients with cancer. By definition, combination
chemotherapy involves administering two or more different
antineoplastic agents using a schedule of administration to the
patient that results in reduced toxicity and increased antitumor
efficacy as a result of the administration of a toxicity reducing
agent. The method of this invention specifically includes in
addition to the antineoplastic agents, the administration of a
toxicity-reducing amount of a protective agent of formula I:
R.sub.1--S--X.sub.1--R.sub.2; (I)
[0023] wherein R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl, or
--S--X.sub.2--R.sub.3;
[0024] R.sub.2 and R.sub.3 are each individually sulfonate or
phosphonate; and
[0025] X.sub.1 and X.sub.2 are each individually C.sub.1-C.sub.6
alkyl, optionally substituted by one or more hydroxy, sulfhydryl or
alkoxy moieties.
[0026] The preferred protective agents of formula I include various
thiols, disulfides and thioethers. Some preferred compounds of
formula I include, but are not limited to mesna, dimesna, S-methyl
mesna, and various analogues and derivatives of each wherein the
alkylene bridge(s) include one to four --CH.sub.2-- moieties, and
may or may not be substituted by hydroxy or alkoxy moieties. Most
preferred compounds of formula I include mesna and dimesna.
[0027] Preferred combinations of antineoplastic agents include
combinations of taxanes and platinum complex agents; electrophilic
alkylating agents and vinca alkaloids, oxazaphosphorines, platinum
and vinca alkaloids or bleomycin, with or without steroidal
antineoplastic compounds; platinum complexes and vinca alkaloids,
with or without antineoplastic antibiotics; and others, some of
which are shown in the following tables.
[0028] In many cases, it has been observed that the dose, the
duration of drug infusion, the route of administration, and the
order of administration of the antineoplastic agents can determine
the outcome of treatment and to significantly affect the toxicity,
drug related morbidity and death of a patient due to drug
treatment. Also, the timing between doses and the duration of
infusion of each agent has an effect on the safety and the efficacy
outcome of treatment. As an example, the current protocol for
paclitaxel/cisplatin combination therapy+calls for each cycle of
treatment to involve the administration of paclitaxel from 3 hours
to 96 hours of the drug followed by the administration of
cisplatin. Each cycle is repeated at approximately 3-week
intervals.
[0029] It has been observed that the administration of cisplatin
followed by paclitaxel results in an unacceptable incidence of
patient toxicity that precludes its use. The inventors have
discovered that the use of the toxicity reducing agents of formula
I at the proper sequence can reduce or even prevent such toxicity
and thereby allow greater antitumor activity from the otherwise
toxic regimen.
[0030] Administration of toxicity reducing amounts and novel
schedules of administration of a formula I compound in conjunction
with the administration of the combination of antineoplastic agents
is postulated to improve the antitumor efficacy and safety
throughout the course of treatment of the patient. In many cases,
adherence to the method of this invention may allow the physician
to safely administer higher amounts of the antineoplastic agents,
at shorter time intervals, thus improving the probability of
success of a particular course of treatment.
[0031] A preferred course of treatment under the method of this
invention is the administration of effective amounts of a
taxane/platinum combination, in conjunction with a formula I
compound. The preferred course for platinum followed by taxanes
includes the administration, every 1-21 days of:
[0032] a) 10 mg/m.sup.2-300 mg/m.sup.2 of a platinum drug over 15
minutes to 96 hours, followed by the administration of
[0033] b) 10 mg/m.sup.2-400 mg/m.sup.2 of a taxane; administered
over 15 minutes to 96 hours; and
[0034] c) 2 g/m.sup.2-50 g/m.sup.2 of a compound of formula I that
is administered over 15 minutes to 96 hours preceding the platinum
administration and the provisional administration of the formula I
compound over 15 minutes to 96 hours as a single or divided dose
before, during or after the administration of the taxane.
[0035] The preferred course of treatment includes the IV infusion
of first, a formula I compound, followed by IV infusion of the
platinum drug, followed by the administration of the taxane. This
is an entirely novel schedule of platinum and taxane administration
in combination with a toxicity reducing agent.
[0036] Additionally, conventional pre-medication for nausea and
vomiting may be administered as per accepted medical practices.
[0037] Cisplatin is preferably administered by IV infusion over an
extended period, generally from 1-12 hours, most preferably from
1-4 hours
[0038] Dimesna may be administered by IV push or infusion, or may
be administered orally, and is preferably administered immediately
or up to 90 minutes prior to the commencement of the IV cisplatin
infusion. The duration of the dimesna infusion can be from 15
minutes to continuous infusion for as long as needed to prevent
toxicity.
[0039] The following specific examples are presented to disclose
most preferred methods of treatment according to the method of this
invention. These examples are illustrative only and are not
considered as exhaustive or limiting the invention to the precise
details disclosed.
EXAMPLE 1
[0040] A patient suffering from cancer is treated as follows:
[0041] a) 4 g/m.sup.2-80 g/m.sup.2 of dimesna is administered
either by intravenous infusion over 15-90 minutes, or by oral
administration route;
[0042] b) within one hour of completion of a), 15 mg/m.sup.2-250
mg/m.sup.2 of a platinum complex agent is administered either by
intravenous infusion at a rate of 0.5 mg/min-2 mg/min;
[0043] c) within 2 hours of completion of b), 20 mg/m.sup.2-250
mg/m.sup.2 of a taxane agent is administered by either intravenous
infusion over 15 minutes-96 hours, or by oral administration
route.
EXAMPLE 2
[0044] A patient suffering from cancer is treated as follows:
[0045] a) 4 g/m.sup.2-80 .mu.m.sup.2 of dimesna is administered
either by intravenous infusion over 15-90 minutes, or by oral
administration route;
[0046] b) within one hour of completion of a), 15 mg/m.sup.2-250
mg/m.sup.2 of a platinum complex agent is administered either by
intravenous infusion at a rate of 0.5 mg/min-2 mg/min;
[0047] c) within one hour of completion of b), 4 g/m.sup.2-80
g/m.sup.2 of dimesna is again administered either by intravenous
infusion over 15-90 minutes, or by oral administration route;
[0048] d) within 2 hours of completion of c), 20 mg/m.sup.2-250
mg/m.sup.2 of a taxane agent is administered by either intravenous
infusion over 15 minutes-96 hours, or by oral administration
route.
EXAMPLE 3
[0049] A patient suffering from cancer is treated as follows:
[0050] a) 4 g/m.sup.2-80 .mu.m.sup.2 of dimesna is administered
either by intravenous infusion over 15-90 minutes, or by oral
administration route;
[0051] b) within one hour of completion of a), 15 mg/m.sup.2-250
mg/m.sup.2 of a platinum complex agent is administered either by
intravenous infusion at a rate of 0.5 mg/min-2 mg/min;
[0052] c) within 24 hours of completion of b), 4 g/m.sup.2-80
.mu.m.sup.2 of dimesna is again administered either by intravenous
infusion over 15-90 minutes, or by oral administration route;
[0053] d) within 2 hours of completion of c), 20 mg/m.sup.2-250
mg/m.sup.2 of a taxane agent is administered by either intravenous
infusion over 15 minutes-96 hours, or by oral administration
route;
[0054] e) within 2 hours of completion of d), 4 g/m.sup.2-80
.mu.m.sup.2 of dimesna is again administered either by intravenous
infusion over 15-90 minutes, or by oral administration route.
[0055] In vitro experiments were conducted to determine the
efficacy of platinum/taxane combination therapy and to determine if
the order of administration of the agents affected the
cytotoxicity. The agents used were cisplatin (CDDP) and paclitaxel
(Taxol.RTM.), and the cell line used was MCF7/WT (breast cancer).
The results of the experiments are shown below in Tables 1 and
2.
1TABLE 1 Sequential Treatment of MCF7/WT With Taxol .RTM. followed
by CDDP MCF7/WT 2 hour-% cell survival Average STD Taxol .RTM. (27
nM) 88 3 CDDP (8.5 .mu.M) 52 2 Taxol .RTM. (27 nM) + CDDP (8.5 uM)
49 4 Taxol .RTM. (27 nM) 88 3 CDDP (4.25 uM) 73 1 Taxol .RTM. (27
nM) + CDDP (4.25 uM) 63 1 Taxol .RTM. (45 nM) 82 7 CDDP (4.25 uM)
73 1 Taxol .RTM. (45 nM) + CDDP (4.25 uM) 58 6 Taxol .RTM. (45 nM)
82 7 CDDP (8.5 uM) 52 2 Taxol .RTM. (45 nM) + CDDP (8.5 uM) 46
6
[0056]
2TABLE 2 Sequential Treatment of MCF7/WT with CDDP followed by
Taxol .RTM. MCF7/WT 2 hour-% cell survival Average STD CDDP (4.25
uM) 71 4 Taxol .RTM. (45 nM) 45 1 CDDP (4.25 uM) + Taxol .RTM. (45
nM) 26 5 CDDP (4.25 uM) 71 4 Taxol .RTM. (27 nM) 71 5 CDDP (4.25
uM) + Taxol .RTM. (27 nM) 43 5 CDDP (8.5 uM) 50 3 Taxol .RTM. (27
nM) 71 5 CDDP (8.5 uM) + Taxol .RTM. (27 nM) 27 3 CDDP (8.5 uM) 50
3 Taxol .RTM. (45 nM) 45 1 CDDP (8.5 uM) + Taxol .RTM. (45 nM) 18
3
[0057] The results of the experiments clearly elucidate at least
additive cytotoxicity of the combination of platinum, then taxane,
administration. Administration of a toxicity-reducing amount (4
g/m.sup.2-80 g/m.sup.2) of the formula I compound in the manner
described above will reduce the unwanted toxicity of this
combination and route to render the combination relatively safe and
effective for administration to mammalian subjects, particularly to
human subjects.
* * * * *