United States Patent
`
`[19]
`
`Sehgal et al.
`
`[54]
`
`[75]
`
`USE OF RAPAMYCIN IN TREATLIENT OF
`TUMORS
`
`Inventors: Surendra N. Sehgal, Princeton, N.J.;
`Claude Vezina, Oka, Canada
`
`Assignee:
`
`Ayerst, McKenna & Harrison, Inc.,
`St. Laurent, Canada
`
`Appl. No.:
`Filed:
`
`784,274
`Oct. 29, 1991
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 682,813, Apr. 9, 1991,
`Pat. No. 5,066,493, which is a continuation-in-part of
`Ser. No. 391,334, Aug. 9, 1989. abandoned, which is a
`division of Ser. No. 592,193, Mar. 22, 1984, Pat. No.
`4,885,171, which is a continuation of Ser. No. 126,276,
`Mar. 3, 1980, abandoned, which is a continuation of
`Ser. No. 957,626, Nov. 3, 1978, abandoned.
`
`Int. Cl.-‘5 ..................... A6lK 35/00; A61K 31/66;
`A61K 31/505; AOIN 57/00
`U.S. Cl. .................................... 424/122; 514/110;
`514/274; 514/291
`Field of Search .............. .. 424/ 122; 514/110, 274,
`514/291
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`2/1976 Sehgal .......................
`3,929,992
`3,993,749 11/1976
`4,316,885
`3/1982
`4,401,653
`8/1983
`4,650,803
`3/1987
`
`424/122
`424/122
`.. 424/122
`.. 424/114
`
`llilll||||1|1|llllllllIllll|||||1l||ll|||||ll|1|||||lllllllllllllllllllllll
`
`USO05206018A
`
`111]
`
`[45]
`
`Patent Number:
`
`5,206,018
`
`Date of Patent:
`
`Apr. 27, 1993
`
`................... 424/122
`4,885,171 12/1989 Surcndra et al.
`. 424/122
`5,066,493 11/1991 Sehgal
`. 424/ 122
`5,078,999
`1/1992 Warner
`5,080,899
`1/1992 Sturm .............................. 424/122
`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).
`Sehgal, S. J. Antibiot. 28, 727-732 (1975).
`Martel. R., Can J. Physiol. Pharmacol., 55, 48 (1977).
`Eng. C. J. Antibiotics 37:l23l (1984).
`FASEB 3:3411 (1989)-——(Staruch, M. J.).
`FASEB 3:5256 (1989)—(Dumont, F. 1.).
`Med. Sci. Res. _l7:877 (1989)—(Morris, 11.).
`Primary Examz‘ner—Nathan M. Nutter
`Attorney, Agent, or Firm—Arnold S. Milowsky
`
`ABSTRACT
`[57]
`This invention provides a method of treating, inhibiting
`the proliferation of, reducing the size of, or eradicating
`malignant neoplasms in a mammal
`in need thereof
`which comprises
`administering
`an
`antineoplastic
`amount of rapamycin to said mammal. In particular,
`rapamycin is useful in treating, inhibiting the prolifera-
`tion of, reducing the size of, or eradicating malignant
`mammary and skin carcinomas, and central nervous
`system neoplasms.
`
`12 Claims, No Drawings
`
`West-Ward Pharm.
`Exhibit 1044
`Page 001
`
`

`

`1
`
`5,206,018
`
`USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`
`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 intum 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, which in 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.
`Vezina et 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 recent 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 adjuvant arthritis (AA)].
`The latter 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.
`SUMMARY OF THE INVENTION
`
`According to this invention a method is 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 malignant cells, 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 malignant cells.
`DETAILS OF THE INVENTION
`
`According to the present method, rapamycin is em-
`ployed as the active agent. The isolation 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 malignant cells.
`While rapamycin can be administered above, e.g. as a
`sole component of a filled capsule, it is preferred to
`
`5
`
`10
`
`15
`
`20
`
`25
`
`35
`
`50
`
`65
`
`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 by the solubility and chemi-
`cal nature of the compounds, chosen route of adminis-
`tration and standard biological practice. For example,
`an antineoplastic effective amount of the 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 of a sterile solution or suspension con-
`taining other solutes or suspending agents, for example,
`enough saline 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 the like.
`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 of this
`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 amount of active 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 tumor size in and pro-
`longs the survival
`time of tumor-bearing mammals.
`More specifically, rapamycin is useful for controlling
`the following carcinogenic tumors in 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 a.l., Cancer Chemother. Rep., Part 3,
`3, (No. 2) 1-103 (1972) and references therein. In addi-
`tion, the protocols for the antitumor tests 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
`
`

`

`5,206,018
`
`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
`specifically, Table 1 shows the prolongation of survival
`time of female CDF1 mice implanted with lymphatic
`leukemia P388 by administering rapamycin; Table 2
`shows the reduction in size of colon 38 tumors in female
`BDF1 mice by administering rapamycin; Table 3 shows
`the prolongation of survival time of male CDF1 mice
`'
`‘
`'
`‘
`‘
`
`4
`TABLE 3mnfinued
`Effect ornxpamycin on Suwim _nm°fCDF1Mi“
`.
`Implanted with Colon 26 Tumor
`Dose, Am wt Dmmnm
`MST
`1nj_
`ofA_njm3]5
`4.5
`mg/kg
`(1-.c, g)
`12.5
`03
`Tmmcm:
`Single intraperitoneal injection on days 1, 5 and 9 in a vehicle oftaline with Tween.
`:_:°;_lm_m_
`1'/cg, = Lugs... n.,..;.,.i .5... (M51) in days or mm .ni..n1. (F)/wntrol
`'
`.
`
`teriseonaideredaaangn1.fiaant''
`lon-
`«-wr
`"'°
`
`survivor;
`on my 5
`10/10
`
`T
`30.4
`
`c
`19_1
`
`1"/car,
`Msr
`159
`
`mammary tumors i.n male CDBF1 rats by administering
`TABLE 4
`rapamycin; Table 5 shows the prolongation of survival
`Effect or Rspamvcin 0" CDSF1
`time of female BDF1 mice implanted with B16 melono-
`
`carcinoma by administering rapamycin; and Table 6 — T““‘°“ i“ CD": R“
`-
`'
`'
`'
`Average
`shows the prolongation of survival time of male Swiss
`/ Net wt‘ Dificmcc
`MTW
`mice implanted with ependymoblastoma by administer- 20
`O1-Animus
`WE
`‘"3 "aPamY°i“-
`Cr-c, g)
`—-6.6
`15:?
`-4.1
`_2.4
`-0.3
`
`Suwivm
`on Day 5
`4/10
`ifififi
`10/10
`10/10
`10/10
`
`T
`c
`0
`3200
`35% 3%
`755
`3200
`325
`31“)
`923
`3200
`
`In}
`mg/kg -
`400
`0
`50
`25
`12.5
`Truman‘:
`Single intraperiional injection on days 1, 8. l5. 22 and 29 in a vehicle ofsaline with
`T"’°°°"‘°-
`Evaluation:
`T/C7-. - Median tumor we‘1ght(M'I'W) estimated from tumor diameter oftreated
`animals (T)/control animals (C) x 100. A T/C% or 42 or less is considered as a
`significant inhibitor of tumor growth. Evaluation done on day 30.
`
`-1-/C%
`MTW
`
`19
`23
`25
`29
`
`25
`
`TABLE 1
`’i$°i‘..‘.’.‘...i““.3I‘.‘;“’i°”‘°:.‘I?‘”£:.?J"’;°p°§§°f.1..”§i°*'
`_i__
`‘
`“
`°““
`AVG. W1. Difference
`MST
`of Animals
`Survivors __d.aL_ 170%
`(T-C, g)
`on Day 5
`T
`C
`MST
`_1g
`5/6
`14_]
`101
`133
`-2.4
`6/6
`13.1
`10.2
`128
`‘ 1‘
`5/5
`13-7
`1°-2
`134
`- L9
`6/6
`14-3
`10-1
`140
`— 1.6
`6/6
`13.9
`10.2
`136
`-0.6
`6/6
`13.9
`"102
`136
`
`DOS€/
`mi
`mg/kg
`400
`200
`‘°°
`50
`25
`12.5
`r Treatment:
`injections starting on day one in 11 vehicle of saline with
`Nine iniraperitoneal
`Tween-B0 [Trade Mark for a derivative of Z-sorbitan mono-9-ociadecenoate po|y- 35
`(oxy~l.2-etliancdiyl)].
`Evaluation:
`‘
`T/C% = Median Survival Time (MST) in days of treated animals (T)/control
`animals (C) X 100. A T/C% of 125 or greater is considered as a significant prolon-
`gatiun of host survival. Evaluation done on day 30.
`
`5
`Effect of-R3 am Gin on E16 Mdanocucinoma in BDF Mice
` 1j—
`Avcrfgc
`Dosel
`NC! Wt. Difference
`MST
`of Animals
`Inj.
`dais
`mg/kg
`(T_C. g.)
`‘lo 400
`-3.3
`200
`-1.5
`
`Survivors
`on Diy 5
`10/10
`10/10
`
`T
`22.0
`22.3
`
`C
`20.1
`20.1
`
`T/C%
`MST
`109
`ll0
`
`TABLE2
`
`:
`0.1
`0.1
`
`10/10
`10/10
`
`23.0
`29.0
`
`20.1
`20.1
`
`139
`144
`
`133
`Effect of Rapamycin on Colon 38 Tumor Weight in Mice
`25
`D°5=/ Ave-W1-Difference
`MTW
`12.5
`ofmiimals
`Survivors _2s¥ T/C%
`Ini
`mg/kg
`(T—C, g)
`on Day 5
`T
`C
`MTW 45 Truman
`400
`_3_4
`10/10
`133
`310
`23
`Single intraperitoni.-al injection on each of days I through 9 in a vehicle of aaline
`with Tween-80.
`200
`-2.0
`I0/10
`209
`810
`25
`Evdmdon:
`10°
`’°-3
`“V1°
`272
`31°
`33
`T/C% = Median Survival Time (MST) in days of treated animals ('1) control
`50
`-0.3
`9/10
`320
`310
`39
`animals (c) x 100. A r/car, of 125 or grater is considered as atignificant prolon-
`25
`-0.4
`IO/10
`368
`310
`45
`prion of host survival. Evaluation done on day 60.
`12.5
`0.4
`10/10
`363
`810
`45
`Treatment:
`Single intnperiloneal injection on days 2, 9 and 16 in a vehicle ofsaline with Tween
`Evaluation:
`30'
`_
`T/C% = Median tumor weight (MTVV) mtimated from tumor diameter of treated 55
`animals (T)/control animals (c) x 100. A T/C% of 42 or les is oonidered Is a
`significant inhibitor of tumor growth. Evaluation done on day 20.
`
`TABLE 3
`_
`,
`,
`_
`Effect of Rapamycin on Survival Time of CDF1 Mice
`1!“ ‘Med with C010" 25 T“m°r
`Dosel Ave. Wt. Difference
`MST
`Inj.
`of Animals
`__cl__ay§___ T/C%
`mg/kg
`(T-C, g)
`T
`C
`MST
`400
`-2.4
`26.3
`19.!
`137
`200
`-1.8
`25.8
`19.1
`135
`I00
`-1.4
`29.0
`l9.l
`151
`5o
`._o_g
`3115
`19‘;
`150
`25
`—-0.3
`30.3
`19.1
`158
`
`Survivors
`on Day 5
`10/10
`10/ 10
`IO/10
`10/10
`10/10
`
`Survivors
`on Day 5
`10/10
`10/10
`9/10
`10/10
`10/10
`
`TABLE 6
`Effect of Ragycin on Egdmoblastoma in Swiss Mice
`Averfge
`Dose/ Net Wt. Difference
`of Animals
`In].
`mg/kg
`(PC. 8)
`200
`-3.3
`100
`-2.2
`50
`_l‘3
`25
`-2.0
`12.5
`-1.0
`Tmmml:
`Single intraperitoneal injection on inch of days I through 9 in a vehicle of aaline
`with Tweenvflio.
`Evdumrum
`T/C% = Median Survival Time (MST) in days or treated animals (n control
`animals (C) x ICO. A ‘!'/C% of 125 or grater is considered as a significant prolon-
`gaiion of host survival. Evaluation done on day 60.
`
`MST
`dlxg
`
`T
`44.0
`26.0
`343
`34.0
`32.3
`
`C
`18.1
`18.1
`13.1
`13.1
`13.1
`
`T/C%
`MST
`243
`I43
`‘S7
`137
`173
`
`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 weight of the solid tumor after the evalua-
`tion period. The tumor weight in the test (T) animals is
`compared with the tumor in the control (C) animals and
`the results are expressed as a percent T/C. When results
`are expressed as a function of tumor weight, a low %
`T/C indicates effective treatment of the neoplasm, as
`the tumors in the test animals are smaller than tumors in
`the untreated control animals. A percent T/C of less
`than 42 is considered to be statistically significant.
`The results of the above described National Cancer
`Institute standard tumor test procedures demonstrate
`rapamycin's antineoplastic activity in mammals. As
`such rapamycin is useful
`in treating malignant neo-
`plasms. Treating broadly includes, but is 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 35
`be effective in treating. The scope of this invention,
`however, is not limited to these specific embodiments,
`as other neoplasms that rapamycin is 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 tumor size, and in-
`crease survival time of the host mammal in the Colon 26
`standard test procedure, rapamycin is useful in treating
`mammalian carcinomas of the colon and rectum. The
`use of rapamycin in treating colon cancer is covered in
`U.S. Pat. No. 4,885,171.
`In the CDSF1 mammary tumor test procedure, rapa-
`mycin caused a reduction in tumor size at doses of up to
`200 mg/kg. Mammary minors 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 of the
`mammary carcinoma. As such, rapamycin is useful in
`treating mammalian breast neoplasms.
`A significant increase in survival time of the host
`mammal 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 such as 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 dose of 50
`mg/kg, a % T/C of 187 was obtained, and at a dose of 65
`200 mg/kg, a % T/C of 243 was obtained (median
`survival time of 4-4.0 days for mammals treated with
`rapamycin versus median survival time of 18.1 days for
`
`-
`
`6
`untreated control group). At all doses tested, rapamycin
`caused a significant increase in survival time of the host
`mammal in 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 meuingiomas, sarcomas,
`gliomas,
`astrocytomas, medulloblastomas,
`schwan-
`nomas, ependymomas, meningiomas, genninomas, 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 not felt
`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; a.ntimetabo-
`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 vi.n-
`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; progester-
`gens,
`for example, megestrol, hydroxyprogesterone
`caproate and the like; 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,
`“PI-IYSICIANS’ DESK REFERENC ”, 32nd ed.,
`Medical 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 of treating 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 mammal 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
`
`

`

`5,206,018
`
`7
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`4. A method of inhibiting the proliferation of malig-
`nant cells selected from the group consisting of a mam-
`mary carcinoma, a skin carcinoma, and a central ner- 5
`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 neoplmm in a mammal in need thereof which
`comprises administering an antineoplastic amount of
`rapamycin to said mammal orally or parenterally with 25
`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, mening-ioma, and germinoma.
`10. A method of eradicating a malignant neoplmm
`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.
`t
`t
`I
`t
`#
`
`West-Ward Pharm.
`Exhibit 1044
`Page 005
`
`