`
`US005206018A
`.
`{1t] Patent Number:
`[19
`United States Patent
`
`[45] Date of Patent:
`Sehgal et al.
`
`5,206,018
`Apr. 27, 1993
`
`[54] USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`
`[75]
`Inventors: Surendra N, Sehgal, Princeton, N.J.;
`Claude Vezina, Oka, Canada
`[73] Assi
`A
`McK.
`& Harrison,
`In
`]
`Assignee: Ayerst,McKenna& Harrison,
`,
`[21] Appl. No.: 784,274
`[22] Filed:
`Oct. 29, 1991
`
`Inc»
`
`[60]
`
`
`.-cescecsnen 424/122
`4,885,171 12/1989 Surendra et al.
`- 424/122
`5,066,493 11/1991 Sehgal .....
`
`- 424/122
`5,078,999
`1/1992 Warner...
`
`1/1992 Storm .....ceccscssenseeseseeeeseereee 424/122
`5,080,899
`OTHER PUBLICATIONS
`Us. patent application. Ser. No. 07/717,773 filed Jun.
`18, 1991—(Miller).
`Abst. dist, at Fifth Intl Conf. of Inflamm. Res. Assoc.
`121, Sep. 23, 1990 (Baeder, W. L.).
`Vezina, C. J. Antibiot. 28, 721-726 (1975).
`Related U.S. Application Data
`Sehgal, S. J. Antibiot. 28, 727-732 (1975).
` Continuation-in-part ofSer. No. 682,813, Apr. 9, 1991, Marte ReAne ftasenemas 55, 48 (1977).
`Pat. No. 5,066,493, which is a continuation-in-part of
`mg.
`&.
`J.
`lotics
`37:
`(
`).
`Ser. No. 391,334, Aug. 9, 1989, abandoned, which isa
`FASEB 3:3411 (1989)—{Staruch,M.J}).
`division of Ser. No. $92,193, Mar. 22, 1984, Pat.No.|FASEB 3:5256 (1989)—(Dumont,F. J.).
`4,885,171, which is a continuation of Ser. No. 126,276,
`Med.Sci. Res. 17:877 (1989)—(Morris, R.).
`Mar. 3, 1980, abandoned, which is a continuation of
`.
`.
`Ser. No. 957,626, Nov. 3, 1978, abandoned.
`Primary Examiner—Nathan M. Nutter
`Int. CLS
`AGIK 35/00; AGIK 31/66:
`Attorney, Agent, or Firm—Arnold S. Milowsky
`[51]
`CLS coicccesceceeeeee
`;
`;
`A61K 31/505; AOIN 57/00
`(57]
`ABSTRACT
`[52] US. CU. coccceeccccceccccssecessnseceeseesss 424/122;54/110;
`This invention provides a method oftreating, inhibiting
`.
`:
`>
`the proliferation of, reducing the size of, or eradicating
`[58] Field of Search .............. 424/122; 514/110,am,
`malignant neoplasms in a mammal
`in need thereof
`which comprises
`administering
`an
`antineoplastic
`[56]
`References Cited
`amount of rapamycin to said mammal. In particular,
`rapamycinis useful in treating, inhibiting the prolifera-
`U.S. PATENT DOCUMENTS
`
`tion of, reducing the size of, or eradicating malignant
`
`rere
`Featnaa itor Scheel seseerevennvenoneocens
`mammary and skin carcinomas, and central nervous
`
`"424/122
`4,316,885
`3/1982 Rakhi....
`System neoplasms.
`
`8/1983 Eng «0...
`4,401,653
`424/114
`
`cence 514/291
`4,650,803
`3/1987 Stella et al.
`
`12 Claims, No Drawings
`
`West-Ward Pharm.
`Exhibit 1044
`Page 001
`
`West-Ward Pharm.
`Exhibit 1044
`Page 001
`
`
`
`1
`
`USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`
`5,206,018
`
`5
`
`20
`
`35
`
`40
`
`50
`
`60
`
`This a continuation-in-part application of co-pending
`application Ser. No. 07/682,813, filed Apr. 9, 1991 and
`now U.S. Pat. No. 5,066,493, which in turn is a con-
`tinuation-in-part application of co-pending application
`Ser. No. 07/391,334, filed Aug. 9, 1989 and now aban-
`doned, which in turn is a divisional application of co-
`pending application Ser. No. 06/592,193, filed on Mar.
`22, 1984, now issued as U.S. Pat. No. 4,885,171, on Dec.
`5, 1989, which in turn is a continuation application of
`co-pending application Ser. No. 06/126,276, filed on
`Mar.3, 1980, now abandoned, whichin turn is a contin-
`uation application of co-pending application Ser. No.
`05/957,626, filed Nov. 3, 1978, now abandoned.
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to the use of rapamycin as an
`anti-cancer or anti-tumor agent.
`2. Description of the Prior Art
`Rapamycin is an antifungal antibiotic described by C.
`Vezinaet al., J. Antibiot., 28, 721 (1975), S. N. Sehgal et
`al., J. Antibiot., 28, 727 (1975) and S. N. Sehgal et al.,
`U.S. Pat. No. 3,929,992, issued Dec. 30, 1975, filed Apr.
`12, 1974. Rapamycin is extracted from a streptomycete
`(Streptomyces hygroscopicus)
`isolated from an Easter
`Island soil sample and is particularly effective against
`Candida albicans both in vitro and in vivo.
`In addition, a recént report by R. R. Martelet al.,
`Can. J. Physiol., 55, 48 (1977) describes the use of rapa-
`mycin for the prevention of the development of two
`experimental
`immunopathies
`[(experimental allergic
`encephalomyelitis (EAE) and adjuvantarthritis (AA)].
`Thelatter report also describes the inhibitory effect of
`rapamycin on the formation of humoral (IgE-like) anti-
`body. This report concludes that immunosuppressant
`activity of rapamycin appears to be related to inhibition
`of the lymphatic system.
`SUMMARYOF THE INVENTION
`
`According to this invention a methodis provided for
`treating malignant neoplasms in a mammal which com-
`prises administering to said mammal an antineoplastic
`amount of rapamycin. More specifically, rapamycin
`inhibits the proliferation of malignantcells, controls the
`growth of malignant neoplasms, reduces the size of
`malignant neoplasms, eradicates malignant neoplasms,
`prolongs the survival time of said mammal, kills malig-
`nant cells, and adversely affects malignantcells.
`DETAILS OF THE INVENTION
`
`According to the present method, rapamycin is em-
`ployed as the active agent. Theisolation and description
`of rapamycin is given in U.S. Pat. No. 3,929,992, cited
`above, herein incorporated by reference.
`Rapamycin is administered, either orally or parenter-
`ally, to a carcinogenic tumor bearing mammal for the
`purpose of inhibiting the proliferation of malignant
`cells, controling the growth of malignant neoplasms,
`reducing the size of malignant neoplasms, eradicating
`malignant neoplasms, prolonging the survival time of
`said mammal, killing malignant cells, and adversely
`affecting malignantcells.
`While rapamycin can be administered above, e.g. as a
`sole component of a filled capsule, it is preferred to
`
`2
`formulate the compound in various dosage forms for
`oral or parenteral administration, e.g. tablets or sterile
`solutions. Such formulations are described in U.S. Pat.
`No. 3,929,992, cited above. Rapamycin may also be
`administered in combination with a therapeutically ef-
`fective amount of an antineoplastic agent commonly
`used in cancer therapy.
`When the antifungal antibiotic of this invention is
`employed as an anticancer agent in warm-blooded ani-
`mals, e.g. rats, it may be used alone or in combination
`with a therapeutically effective amount of an antineo-
`plastic agent commonly used in cancer therapy and
`with pharmaceutically acceptable carriers, the propor-
`tion of which is determined bythe solubility and chemi-
`cat nature of the compounds, chosen route of adminis-
`tration and standard biological practice. For example,
`an antineoplastic effective amountofthe antibiotic may
`be administered alone or in combination orally in solid
`form containing such excipients as starch, sugar, certain
`types of clay and so forth. Similarly, such an amount
`may also be administered orally in the form of solutions
`or suspensions, or the antibiotic may be injected paren-
`terally alone or in combination. For parenteral adminis-
`tration the antibiotic may be used alone or in combina-
`tion in the form ofa sterile solution or suspension con-
`taining other solutes or suspending agents, for example,
`enoughsaline or glucose to make the solution isotonic,
`bile salts, acacia, gelatin, sorbitan monooleate, polysor-
`bate 80 (oleate esters of sorbitol and its anhydrides co-
`polymerized with ethylene oxide) and thelike.
`When utilizing rapamycin alone or in combination
`with a therapeutically effective amount of an antineo-
`plastic agent commonly used in cancer therapy for the
`treatment of tumors, the total dose. of active agent can
`range from 0.01 to 250 mg per kg of body weight per
`day with a preferred dosage range from 0.1 to 50 mg per
`kg of body weight per day. However, as the dosage of
`rapamycin to be administered by the method ofthis
`invention will of course vary with the tumor or cancer
`and tolerance of the mammal, and with the nature of the
`other antineoplastic agents used in combination. The
`schedule of dosing can range from one to five times per
`day to a single dose given every two to ten days. In-
`creasing the frequency of administration is expected to
`reduce the amountofactive drug needed per dose. Such
`dosages and scheduling of administration must be deter-
`mined on an individual basis, depending upon the tumor
`or cancer, nutritional state of the mammal, age of the
`mammal, toxicity in each individual, and with the na-
`ture of the other antineoplastic agents used in combina-
`tion, etc.
`Rapamycin was evaluated in several National Cancer
`Institute standard tumor test procedures. The results
`showed that rapamycin reduces tumorsize in and pro-
`longs the survival
`time of tumor-bearing mammals.
`More specifically, rapamycin is useful for controlling
`the following carcinogenic tumorsin standard mamma-
`lian tumor models: lymphatic leukemia, colon, mam-
`mary, melanocarcinoma and ependymoblastoma. The
`effectiveness of rapamycin in this respect was demon-
`strated in the laboratory with rodents having trans-
`planted tumors. Details of methods used to evaluate this
`effect are described in various publications; for exam-
`ple, R. I. Geran et al., Cancer Chemother. Rep., Part 3,
`3, (No. 2) 1-103 (1972) and references therein. In addi-
`tion, the protocols for the antitumortests are available
`from the National Cancer Institute, Bethesda, Md.,
`U.S.A. These models have been adopted by the Na-
`
`-
`
`West-Ward Pharm.
`Exhibit 1044
`Page 002
`
`West-Ward Pharm.
`Exhibit 1044
`Page 002
`
`
`
`5,206,018
`
`4
`TABLE3-continued
`Effect of Rapamycin on Survival Time of CDF) Mice
`Implanted with Colon 26 Tumor
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`days
`mg/kg
`(T+, g)
`12.5
`0.3
`Treatment:
`Single intraperitoneal injection on days 1, 5 and 9 in a vehicle ofsaline with Tween-
`a.
`Evaluation:
`time (MST) in days of treated animals (T)/contro!
`T/C% = Median survival
`animals (C) x 100. A T/C% of 125 or greater is considered as « significant prolon-
`gation of host survival. Evaluation done on day 60.
`
`Survivors
`on Day 5
`10/10
`
`T
`304
`
`c
`19,1
`
`T/C%
`MST
`159
`
`TABLE 4
`Effect of Rapamycin on CD8F
`Mammary Tumors in CD&8F, Rats
`Average
`Dose/ Net Wt. Difference
`MTW
`T/C%
`Survivors
`Inj.
`of Animals
`days
`MTW
`c
`T
`on Day 5
`mg/kg -
`(TC,g)
`~_
`3200
`0
`4/10
`400
`—6.6
`10
`3200
`323
`10/10
`200
`—-6.5
`14
`©3200
`448
`10/10
`100
`4.8
`23
`3200
`755
`10/10
`50
`41
`25
`2.4
`10/10
`825
`3200
`25
`
`12.5
`—0.8
`10/10
`928
`3200
`29
`‘Treatment:
`Single intraperitoneal injection on days 1, 8, 15, 22 and 29 in a vehicle ofsaline with
`Tween-80.
`Evaluation:
`T/C% = Median tumor weight (MTW) estimated from tumordiameter oftreated
`animals (T)/control animals (C) x 100. A T/C% of 42 orless is considered as a
`significant inhibitor of tumor growth. Evaluation done on day 30.
`
`TABLE5
`
`3
`tional Cancer Institute as standard test procedures for
`predicting clinical activity of new chemotherapeutic
`agents.
`Tables 1 to 6 show the effects of therapy with rapa-
`mycin on various tumors or cancers in rodents. More 5
`specifically, Table 1 shows the prolongation of survival
`time of female CDF; mice implanted with lymphatic
`leukemia P388 by administering rapamycin; Table 2
`showsthe reductionin size of colon 38 tumors in female
`BDF; mice by administering rapamycin; Table 3 shows
`the prolongation of survival time of male CDF; mice
`implanted with colon 26 tumors by administering rapa-
`mycin; Table 4 shows the reduction in size of CD8F)
`mammary tumors in male CD8F; rats by administering
`rapamycin; Table 5 showsthe prolongation of survival
`time of female BDF; mice implanted with B16 melono-
`carcinoma by administering rapamycin; and Table 6
`shows the prolongation of survival time of male Swiss
`mice implanted with ependymoblastoma by administer- 39
`ing rapamycin.
`
`TABLE1
`
`25
`
`Effect of Rapamycin on Survival Time of CDF; Mice —
`Implanted with Lymphatic Leukemia P-388 (ascetic)
`Dose/ Ave. Wi. Difference
`MST
`T/C%
`Survivors
`Inj.
`of Animals
`days
`MST
`c
`T
`on Day 5
`mg/kg
`(T-C, g)
`138
`10.2
`144.1)
`6/6
`400
`-19
`128
`10.2
`13.1
`6/6
`200
`—2.4
`134030
`10.2
`13.7
`6/6
`100
`16
`140
`10.2
`143
`6/6
`50
`—-L9
`25
`—16
`6/6
`13.9
`102
`136
`12.5
`—0.6
`6/6
`33.9 10.2
`136
`
`Treatment:
`injections starting on day one in a vehicle of saline with
`Nine intraperitoneal
`Tween-80 [Trade Mark for a derivative of Z-sorbitan mono-9-octadecenoate poly- 35
`{oxy-1,2-ethanediy])].
`Evaluation:
`T/C% = Median Survival Time (MST) in days of treated animals (T)/contro!
`animais (C) x 100. A T/C% of125 orgreater is considered as a significant prolon-
`gation of host survival. Evalustion done on day 30.
`
`TABLE2
`
`40
`
`5
`
`TABLE 3
`Effect of Rapamycin on Survival Time of CDF] Mice
`Implanted with Colon 26 Tumor
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`days
`mg/kg
`(F-C, g)
`
`Survivors
`on Day 5
`
`T
`
`Cc
`
`T/C%
`MST
`
`400
`200
`100
`50
`25
`
`24
`—1h8
`-l4
`—0.8
`—-03
`
`10/10
`10/10
`10/10
`10/10
`10/10
`
`26.3
`25.8
`29.0
`30.6
`30.3.
`
`19.1
`19.1
`19.1
`19.1
`19.1
`
`137
`135
`15)
`160
`158
`
`65
`
`Effect of Rapamycin on B16 Melanocarcinoma in BDF) Mice
`Average
`Dose/ Net Wt. Difference
`MST
`T/C%
`Survivors
`Inj.
`of Animals
`days
`MST
`c
`T
`on Day 5
`mg/kg
`T-c, g)
`109
`20.1
`22.0
`10/10
`400
`—-3.3
`110
`20.1
`22.3.
`10/10
`200
`-15
`139
`20.1
`28.0
`10/10
`100
`-12
`Effect of Rapamycin on Colon 38 Tumor Weight in Mice
`125
`20.1
`25.3
`10/10
`50
`—0.7
`Dose/ Ave. Wt. Difference
`MTW
`25
`Ol
`10/10
`28.0
`20.1
`139
`12.5
`oO!
`10/10
`29.0
`20.1
`144
`
`T/C%
`Survivors
`Inj.
`of Animals
`mg
`Treatment:
`MTW
`Cc
`T
`on Day 5
`mg/kg
`(T-C, g)
`Single intraperitoneal injection on each of days 1 through 9 in a vehicle ofsaline
`
`
`
`
`400 188=810—3.4 10/10 23
`with Tween-80.
`200
`—2.0
`10/10
`209
`810
`25
`Evaluation:
`100
`—0.8
`10/10
`272-810
`33
`T/C% = Median Survival Time (MST) in days of treated animals (T) control
`50
`—0.8
`9/10
`320-810
`39
`animals (C) x 100. A T/C% of 125 or greater is considered as a significant prolon-
`gation of host survival. Evaluation done on day 60.
`
`
`
`
`
`25 368=810—04 10/10 45 50
`
`
`
`
`
` 12.5 368=8100.4 10/10 45
`Treatment:
`Single intraperitoneal injection on days 2, 9 and 16 in s vehicle ofsaline with Tween
`80.
`Evaluation:
`T/C% = Median tumor weight (MTW) estimated from tumor diameter oftreated
`animals (T)/control animals (C) x 100. A T/C% of 42 or less is considered as a
`significant inhibitor of tumor growth. Evaluation done on day 20.
`
`TABLE6
`Effect of Rapamycin on Ependymoblastoma in Swiss Mice
`Average
`Dose/ Net Wt. Difference
`Inj.
`of Animals
`mg/kg
`(T-C,g)
`200
`-33
`100
`22
`50
`-13
`25
`-2.0
`12.5
`-10
`Treatment:
`Single intraperitoneal injection on each of days | through 9 in a vehicle ofsaline
`with Tween-80,
`Evaluation:
`T/C% = Median Survival Time (MST) in days of treated animals (T} control
`animals (C) x 100. A T/C% of125 or greater is considered as 2 significant prolon-
`gation of host survival. Evaluation done on day 60.
`
`Survivors
`onDay5
`10/10
`10/10
`9/10
`10/10
`10/10
`
`MST
`days
`
`T
`44.0
`26.0
`34.0
`34.0
`32.3
`
`C
`181
`18.1
`18.1
`18.1
`18.1
`
`T/C%
`MST
`243
`143
`187
`187
`178
`
`West-Ward Pharm.
`Exhibit 1044
`Page 003
`
`West-Ward Pharm.
`Exhibit 1044
`Page 003
`
`
`
`5,206,018
`
`5
`The standard animal models used can be divided into
`two types based on how the results are expressed. Re-
`sults can be expressed as a comparison of the median
`survival time for mammals in the treated (T) group
`(those treated with rapamycin) versus the median sur-
`vival time for mammals in the untreated control (C)
`group. The result is given as a percentage of T/C; a
`high percent T/C indicates that the compound that was
`tested was effective in treating the malignant neoplasm
`that was evaluated. Statistically significant results are
`observed at either 125 or 130% T/C, depending on the
`neoplasm that was evaluated. Alternatively, the results
`of certain tests for solid tumors can be expressed based
`on the tumor weightof the solid tumorafter the evalua-
`tion period. The tumor weight in the test (T) animalsis
`compared with the tumorin the control (C) animals and
`the results are expressed as a percent T/C. Whenresults
`are expressed as a function of tumor weight, a low %
`T/C indicates effective treatment of the neoplasm, as
`the tumorsin the test animals are smaller than tumors in
`the untreated control animals. A percent T/C ofless
`than 42 is considered to be statistically significant.
`The results of the above described National Cancer
`Institute standard tumor test procedures demonstrate
`Tapamycin’s antineoplastic activity in mammals. As
`such rapamycin is useful
`in treating malignant neo-
`plasms. Treating broadly includes, butis not limited to,
`inhibiting the proliferation of malignant cells, control-
`ling the growth of malignant neoplasms, reducing the
`size of malignant neoplasms, eradicating malignant neo-
`plasms, prolonging the survival time of said mammal,
`killing malignant cells, and adversely affecting malig-
`nant cells. Preferred embodiments of this invention, that
`are described below, are based on the specific types of
`malignant neoplasms that rapamycin has been shown to
`be effective in treating. The scope of this invention,
`however, is not limited to these specific embodiments,
`as other neoplasms that rapamycinis effective in treat-
`ing will be apparent to one skilled in the art.
`Based on the ability of rapamycin to significantly
`inhibit tumor growth in the Colon 38 standard test pro-
`cedure, as seen by a reduction in tumorsize, and in-
`crease survival time of the host mammalin the Colon 26
`standard test procedure, rapamycinis useful in treating
`mammalian carcinomas of the colon and rectum. The
`use of rapamycin in treating colon canceris covered in
`U.S. Pat. No. 4,885,171.
`In the CD8F) mammary tumortest procedure, rapa-
`mycin caused a reduction in tumor size at doses of up to
`200 mg/kg. Mammary tumors were reduced in weight
`by 71% at 12.5 mg/kg and by 90% at a dose of 200
`mg/kg, indicating an almost complete eradication ofthe
`Mammary carcinoma. As such, rapamycin is useful in
`treating mammalian breast neoplasms.
`A significant increase in survival time of the host
`mamma! was observed in the B16 melanocarcinoma
`standard test procedure for mice that were treated with
`doses of up to 100 mg/kg. As such, rapamycin is useful
`in treating skin carcinomas suchas basal cell carcinoma,
`squamous cell carcinoma, malignant melanoma, and the
`like.
`The ependymoblastoma standard test procedure is
`predictive of a compound’s ability to treat malignant
`central nervous system neoplasms. At a dase of 50
`mg/kg, a % T/C of 187 was obtained, and at a dose of
`200 mg/kg, a % T/C of 243 was obtained (median
`survival time of 44.0 days for mammals treated with
`rapamycin versus median survival time of 18.1 days for
`
`20
`
`40
`
`45
`
`6
`
`-
`
`6
`untreated control group). Atall doses tested, rapamycin
`caused a significant increase in survival time of the host
`mammalin the ependymoblastoma standard test proce-
`dure, and is therefore useful in treating malignant cen-
`tral nervous system neoplasms. The extremely favor-
`able results obtained in this test procedure also indicate
`that rapamycin is capable of reaching the intracranial
`neoplasm by crossing the blood brain barrier. Malignant
`central nervous system neoplasms describes a broad
`class of intracranial neoplasms which include, but are
`not
`limited to:
`intracranial meningiomas, sarcomas,
`gliomas,
`astrocytomas, medulloblastomas,
`schwan-
`nomas, ependymomas, meningiomas, germinomas, and
`the like.
`Rapamycin was weakly active in the P-388 leukemia
`standard test procedure; a maximal % T/C of 140 was
`achieved at a dose of 50 mg/kg. When comparing these
`data to other data obtained for other anti-leukemic com-
`pounds described in the literature, rapamycin is notfelt
`to be useful in treating higher mammalian leukemias.
`Rapamycin also can be used to produce beneficial
`effects in the treatment of malignant neoplasms when
`combined with a therapeutically effective amount of an
`antineoplastic agent commonly used in cancer therapy.
`Such antineoplastic agents
`include the alkylating
`agents, for example, busulfan, chlorambucil, cyclophos-
`phamide, mechlorethamine hydrochloride, melphalan,
`pipobroman, thiotepa and uracil mustard; antimetabo-
`lites, for example, cytarabine, fluorouracil, floxuridine,
`mercaptopurine, methotrexate and thioguanine; miscel-
`laneous anticancer agents, for example, dacarbazine,
`hydroxyurea, mitotane, procarbazine hydrochloride,
`quinacrine hydrochloride, vinblastine sulfate and vin-
`cristine sulfate; estogens, for example, chlorotrianisene,
`conjugate estogens (e.g. PREMARIN ®), diethylstil-
`bestrol and the like; androgens, for example, methyltes-
`tosterone, testosterone and the like; adrenal corticoster-
`oids, for example, prednisone and the like; progesta-
`gens,
`for example, megestrol, hydroxyprogesterone
`caproate and thelike; radioactive isotopes; and antibiot-
`ics, for example, bleomycin sulfate, doxorubicin hydro-
`chloride and the like. Suitable methods of administra-
`tion, compositions and dosages of the antineoplastic
`agents are described in medical textbooks; for instance,
`“PHYSICIANS’ DESK REFERENCE”, 32nd ed.,
`Medica! Economics Co., Oradell, N.J. U.S.A., 1978 and
`“AMA DRUG EVALUATIONS”, 3rd ed. PSG Pub-
`lishing. Company,
`Inc., Littleton, Mass., U.S.A. pp
`1106-1151, 1977. When used in combination, rapamycin
`is administered as described previously; however, a
`lower dose can be used for efficacious results.
`We claim:
`1. A method oftreating a malignant neoplasm se-_
`lected from the group consisting of a mammary carci-
`noma, a skin carcinoma, and a central nervous system
`neoplasm in a mammal in need thereof which comprises .
`administering an antineoplastic amount of rapamycin to
`said mamma! orally or parenterally with the proviso
`that said malignant neoplasm has not been transplanted
`into said mammal.
`2. The method of claim 1 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`carcinoma, squamous cell carcinomas, and malignant
`melanoma.
`3. The method of claim 1 wherein the central nervous
`system neoplasm is an intracranial neoplasm selected
`from the group consisting of a meningioma, sarcoma,
`
`West-Ward Pharm.
`Exhibit 1044
`Page 004
`
`West-Ward Pharm.
`Exhibit 1044
`Page 004
`
`
`
`5,206,018
`
`7
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`4. A method ofinhibiting the proliferation of malig-
`nant cells selected from the group consisting of a mam-
`mary carcinoma, a skin carcinoma, and a central ner-
`vous system neoplasm in a mammal in need thereof
`which comprises
`administering an
`antineoplastic
`amount of rapamycin to said mammal orally or paren-
`terally with the proviso that said malignant cells have
`not been transplanted into said mammal.
`5. The method of claim 4 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`carcinoma, squameous cell carcinomas, and malignant
`melanoma.
`6. The method of claim 4 wherein the central nervous
`system neoplasm is an intracranial neoplasm selected
`from the group consisting of a meningioma, sarcoma,
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`7. A method of reducing the size of a malignant neo-
`plasm selected from the group consisting of a mammary
`carcinoma, a skin carcinoma, and a central nervous
`system neoplasm in a mammal in need thereof which
`comprises administering an antineoplastic amount of
`Tapamycin to said mammalorally or parenterally with
`the proviso that said malignant neoplasm has not been
`transplanted into said mammal.
`
`8
`8. The method of claim 7 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`carcinoma, squameous cell carcinomas, and malignant
`melanoma.
`9, The method of claim 7 wherein the central nervous
`system neoplasm is an intracranial neoplasm selected
`from the group consisting of a meningioma, sarcoma,
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`10. A method of eradicating a malignant neoplasm
`selected from the group consisting of a mammary carci-
`noma, a skin carcinoma, and a central nervous system
`neoplasm in a mammal in need thereof which comprises
`administering an antineoplastic amount of rapamycin to
`said mammal orally or parenterally with the proviso
`that said malignant neoplasm has not been transplanted
`into said mammal.
`11. The method of claim 10 wherein the skin carci-
`noma is selected from the group consisting of a basal
`cell carcinoma, squameous cell carcinomas, and malig-
`nant melanoma.
`12. The method of claim 10 wherein the central ner-
`vous system neoplasm is an intracranial neoplasm se-
`lected from the group consisting of a meningioma, sar-
`coma, glioma, astrocytoma, medulloblastoma, schwan-
`noma, ependymoma, meningioma, and germinoma.
`**
`*¢*
`*
`*
`*€
`
`10
`
`20
`
`30
`
`35
`
`45
`
`50
`
`35
`
`65
`
`West-Ward Pharm.
`Exhibit 1044
`Page 005
`
`West-Ward Pharm.
`Exhibit 1044
`Page 005
`
`