I lllll llllllll II llllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US 20020091137Al
`
`(19) United States
`(12) Patent Application Publication
`Dukart et al.
`
`(10) Pub. No.: US 2002/0091137 Al
`Jul. 11, 2002
`(43) Pub. Date:
`
`(54) USE OF CCI-779 AS AN ANTINEOPLASTIC
`AGENT
`
`(75)
`
`Inventors: Gary Dukart, Ambler, PA (US); James
`J. Gibbons JR., Westwood, NJ (US);
`Lisa A. Speicher, Havertown, PA (US);
`Philip Frost, Morris Township, NJ
`(US); Carolyn M. Discafani-Marro,
`Cortlandt Manor, NY (US)
`
`Correspondence Address:
`Arnold S. Milowsky
`American Home Products Corporation
`Patent Law Department - 2B
`Five Giralda Farms
`Madison, NJ 07940 (US)
`
`(21) Appl. No.:
`
`10/010,584
`
`(22) Filed:
`
`Nov. 13, 2001
`
`Related U.S. Application Data
`
`(63) Non-provisional of provisional application No.
`60/249,077, filed on Nov. 15, 2000.
`
`Publication Classification
`
`(51)
`Int. Cl.7 ..................................................... A61K 31/47
`(52) U.S. Cl. .............................................................. 514/310
`
`(57)
`
`ABSTRACT
`
`(73) Assignee: American Home Products Corpora(cid:173)
`tion, Madison, NJ
`
`This invention provides the use of CCl-779 in the treatment
`of neoplasms.
`
`West-Ward Exhibit 1039
`Dukart USPA '137
`Page 001
`
`

`

`US 2002/0091137 Al
`
`Jul. 11, 2002
`
`1
`
`USE OF CCI-779 AS AN ANTINEOPLASTIC AGENT
`
`BACKGROUND OF THE INVENTION
`[0001] This application claims priority from copending
`provisional application Serial No. 60/249,077, filed Nov. 15,
`2000, the entire disclosure of which is hereby incorporated
`by reference.
`[0002] This invention relates to the use of rapamycin
`42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropi(cid:173)
`onic acid (CCl-779) as an antineoplastic agent.
`[0003] Rapamycin is a macrocyclic triene antibiotic pro(cid:173)
`duced by Streptomyces hygroscopicus, which was found to
`have antifungal activity, particularly against Candida albi(cid:173)
`cans, both in vitro and in vivo [C. Vezina et al., J. Antibiot.
`28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28, 727
`(1975); H. A Baker et al., J. Antibiot. 31, 539 (1978); U.S.
`Pat. No. 3,929,992; and U.S. Pat. No. 3,993,749]. Addition(cid:173)
`ally, rapamycin alone (U.S. Pat. No. 4,885,171) or in com(cid:173)
`bination with picibanil (U.S. Pat. No. 4,401,653) has been
`shown to have antitumor activity.
`[0004] The immunosuppressive effects of rapamycin have
`been disclosed in FASEB 3, 3411 (1989). CyclosporinAand
`FK-506, other macrocyclic molecules, also have been shown
`to be effective as immunosuppressive agents, therefore use(cid:173)
`ful in preventing transplant rejection [FASEB 3, 3411
`(1989); FASEB 3, 5256 (1989); R. Y. Calne et al., Lancet
`1183 (1978); and U.S. Pat. No. 5,100,899]. R. Martel et al.
`[Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that
`rapamycin is effective in the experimental allergic encepha(cid:173)
`lomyelitis model, a model for multiple sclerosis; in the
`adjuvant arthritis model, a model for rheumatoid arthritis;
`and effectively inhibited the formation of IgE-like antibod(cid:173)
`ies.
`[0005] Rapamycin is also useful in preventing or treating
`systemic lupus erythematosus [U.S. Pat. No. 5,078,999],
`pulmonary inflammation [U.S. Pat. No. 5,080,899], insulin
`dependent diabetes mellitus [U.S. Pat. No. 5,321,009], skin
`disorders, such as psoriasis [U.S. Pat. No. 5,286,730], bowel
`disorders [U.S. Pat. No. 5,286,731], smooth muscle cell
`proliferation and intimal thickening following vascular
`injury [U.S. Pat. Nos. 5,288,711and5,516,781], adult T-cell
`leukemia/lymphoma [European Patent Application 525,960
`Al], ocular inflammation [U.S. Pat. No. 5,387,589], malig(cid:173)
`nant carcinomas [U.S. Pat. No. 5,206,018], cardiac inflam(cid:173)
`matory disease [U.S. Pat. No. 5,496,832], and anemia [U.S.
`Pat. No. 5,561,138].
`[0006] The preparation and use of hydroxyesters of rapa(cid:173)
`mycin, including CCl-779, are disclosed in U.S. Pat. No.
`5,362,718.
`
`DESCRIPTION OF THE INVENTION
`
`[0007] This invention provides the use of CCl-779 as an
`antineoplastic agent, and particularly for neoplasms which
`are refractory to standard therapy, or for whom standard
`therapy is not appropriate. In particular CCl-779 is useful in
`the treatment of renal cancer, soft tissue cancer, breast
`cancer, neuroendocrine tumor of the lung, cervical cancer,
`uterine cancer, head and neck cancer, glioblastoma, non(cid:173)
`small lung cell cancer, prostate cancer, pancreatic cancer,
`lymphoma, melanoma, small cell lung cancer, ovarian can(cid:173)
`cer, endometrial cancer, and colon cancer.
`
`[0008] As used in accordance with this invention, the term
`"treatment" means treating a mammal having a neoplastic
`disease by providing said mammal an effective amount of
`CCl-779 with the purpose of inhibiting growth of the
`neoplasm in such mammal, eradication of the neoplasm, or
`palliation of the neoplasm.
`[0009] As used in accordance with this invention, the term
`"providing," with respect to providing CCl-779, means
`either directly administering CCl-779, or administering a
`prodrug, derivative, or analog which will form an effective
`amount of CCl-779 within the body.
`[0010] As used in accordance with this invention, the term
`"refractory neoplam" refers to neoplasms in patients which
`typically had progressed following treatment with standard
`chemotherapy that was appropriate for that given neoplasm.
`[0011] The preparation of CCl-779 is described in U.S.
`Pat. No. 5,362,718, which is hereby incorporated by refer(cid:173)
`ence.
`[0012] The antineoplastic activity of CCl-779 was con(cid:173)
`firmed in a preclinical in vitro and in vivo standard phar(cid:173)
`macological test procedure which measured the ability of
`CCl-779 to treat human renal cell cancer (a rapidly progres(cid:173)
`sive disease with very limited treatment options), as well as
`in two Phase I human clinical trials. The procedures used
`and results obtained are briefly described below.
`
`PRECLINICAL TEST PROCEDURES
`[0013]
`In vitro test procedure: Renal tumor lines HTB-44
`and CRL-1161 were obtained from the American Tissue
`Culture Collection (ATCC), Bethesda, Md. SN12-C line was
`obtained from Dr. J. Fidler, M.D. Anderson Hospital, Hous(cid:173)
`ton, Tex. Cells were plated in MEM (Gibco) supplemented
`with 2 mM glutamine, 1 mM sodium pyruvate, 5 ml peni(cid:173)
`cillin-streptomycin solution, 1 mM non-essential amino acid
`solution, 10% fetal bovine solution. Cells (5xl03
`) were
`plated in 96 well plates with a final volume of 200 ml and
`incubated for 24 hours at 37° C. Log dilutions of CCl-779
`beginning at 100 µg/ml were then added to the cultures for
`48 hours. Over the last 5 hours, cells were pulsed with 1 µci
`3H-thymidine (New England Nuclear, 6.7 ci/m Mol). Cells
`were then harvested and the degree of thymidine uptake
`determined by liquid scintillation spectrometry. The IC50
`was determined as the concentration that produced 50% of
`the maximum uptake of thymidine in control untreated cells.
`[0014]
`In vivo test procedure: Female Balb/c nu/nu mice
`were obtained from Charles River Labs, Wilmington, Del.,
`at 6-8 weeks of age. Mice (n=lO/group) were injected sc
`with 5xl06 cells resuspended in a 50% solution of Matrigel
`(BD Biosciences) and tumors allowed to develop. When
`tumor size reached 100 mg, mice were treated orally with
`CCl-779 at 25 mg/kg. CCl-779 was dosed for 5 consecutive
`days with repeated 14 day cycles throughout the duration of
`the experiment. The formulation used for CCl-779 was a
`50% ethanol, 49% phosal, 1 % tween 80 vehicle for resus(cid:173)
`pending CCl-779, where the stock was resuspended into a
`1:10 dilution of the vehicle prior to dosing. Tumor growth
`was evaluated using a vernier caliper and volume (lxwxh)
`was converted to mass using the formula: lxw2/2.
`[0015] Results:
`[0016] Human renal cell tumors were cultured in vitro in
`the presence or absence of CCl-779 for 3 days and the effect
`
`West-Ward Exhibit 1039
`Dukart USPA '137
`Page 002
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`US 2002/0091137 Al
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`Jul. 11, 2002
`
`2
`
`on growth determined by 3H-thymidine incorporation of
`control versus treated cells. Table 1 shows that IC50 (50%
`growth inhibitory concentration) for all 3 lines tested was in
`the low nM range.
`
`TABE 1
`
`The effect of CCI-779 on the growth of human renal tumor cells in vitro
`
`Renal Tumor Line
`
`CCI-779 IC50 (nM)
`
`HIB-44
`CRL-1161
`SN12-C
`
`5.0
`2.0
`5.5
`
`[0025] 4. At least 4 weeks since any other investiga(cid:173)
`tional agent.
`
`[0026] 5. Age at least 18 years old.
`
`[0027] 6. Adequate bone marrow, renal, and hepatic
`function.
`
`[0028] 7. Serum cholesterol ~350 mg/dL and trig-
`lycerides ~300 mg/dL.
`
`[0029] 8. ECOG performance status 0-2.
`
`[0030] 9. Life expectancy of at least 3 months.
`
`[0031] 10. Signed, dated, witnessed written informed
`consent.
`
`[0017] The effect of CCl-779 in two human renal lines
`(HTB-44 and CRL-1161) were was evaluated in vivo by
`engrafting tumor cells on the flanks of nude mice. Once
`tumors were established at a size of about 100 mg, mice
`were treated with CCl-779 or a vehicle control. Treatment
`with CCl-779 at 25 mg/kg resulted in significant inhibition
`of tumor cell growth in the mice (Table 2).
`
`[0032] A total of 63 patients and 24 patients were enrolled
`in first and second studies, respectively. Dose levels ranged
`from 0.75-24 mg/m2 and 7.5-220 mg/m2
`, with the dailyx5
`every 2 weeks and weekly schedules, respectively.
`
`[0033] The following summarizes the results that were
`obtained:
`
`[0018] Table 2 Effect of CCl-779 on the growth of human
`renal tumor cells in nude mouse xenografts
`
`[0034]
`In patients having renal cancer on the weekly
`schedule, 1 partial response (~50% reduction in tumor size)
`
`TABLE 2
`
`Effect of CCI-779 on the growth of human renal tumor cells in nude mouse xenografts
`
`Drug
`
`Tumor Mass (mg)
`Da s
`
`Cell Line Treatment
`
`0
`
`7
`
`21
`
`35
`
`49
`
`55
`
`HrB-44
`
`Control
`CCI
`%TIC
`CRL-1161 Control
`CCI
`%TIC
`
`288 ± 21
`290 ± 15
`101
`273 ± 18
`272 ± 14
`100
`
`219 ± 18
`156 ± 13*
`71
`355 ± 36
`219 ± 16*
`62
`
`616 ± 55
`252 ± 48*
`41
`413 ± 60
`226 ± 17*
`60
`
`1095 ± 44
`453 ± 85*
`41
`480 ± 127
`200 ± 21 *
`42
`
`2412 ± 342
`2033 ± 247
`980 ± 155* 1050 ± 183*
`48
`44
`546 ± 170
`507 ± 156
`229 ± 28*
`268 ± 30
`42
`53
`
`*p value - <.05
`% TIC - Treated/Control x 100
`
`[0019] Clinical Trial:
`
`[0020] Two single agent (CCl-779) Phase I clinical trials
`have been conducted. In the first study, CCl-779 was admin(cid:173)
`istered as a 30 minute i.v. infusion daily for 5 days, every
`two to three weeks. In the second study, CCl-779 was
`administered as a 30 minute i.v. infusion, once weekly. Both
`trials were open label, ascending dose, single-arm, multi(cid:173)
`center studies. Patients were allowed to continue treatment
`as long as the CCl-779 was tolerated and there was no
`evidence of obvious disease progression. The following
`eligibility criteria were used:
`
`[0021]
`
`Inclusion Criteria
`
`[0022] 1. Patients with a histologic diagnosis of
`advanced cancer (solid tumors and, in the first study,
`lymphomas) who are refractory to standard therapy
`or for whom standard therapy is not appropriate.
`
`[0023] 2. Measurable or evaluable disease.
`
`[0024] 3. At least 3 weeks since prior chemotherapy
`and/or radiation therapy (6 weeks since nitrosoureas
`or mitomycin C).
`
`and 2 minor responses (~25% but <50% reduction in tumor
`size) were observed. In renal cancer patients on the dailyx5
`schedule, 1 minor response, 1 unconfirmed minor response,
`and 1 stable disease ( <25% increase to <25% reduction in
`tumor size) lasting approximately 5 months were observed.
`In patients having soft tissue sarcoma on the dailyx5 dosage
`schedule, 1 possible partial response, 2 minor responses, and
`1 stable disease lasting approximately 5¥2 months were
`observed. In patients with breast cancer on the weekly
`dosage schedule, one partial response was observed. In
`patients with neuroendocrine tumor of the lung on the
`weekly dosage schedule, one partial response was observed.
`In patients having cervical cancer on the dailyx5 dosage
`schedule, one minor response was observed. In patients
`having uterine cancer receiving the dailyx5 dosage sched(cid:173)
`ule, one unconfirmed minor response was observed. In
`patients having head and neck cancer receiving the dailyx5
`dosage schedule, 1 stable disease for approximately 8¥2
`months was observed. In patients having non-small cell lung
`cancer receiving the dailyx5 dosage schedule, one partial
`response was observed. These results are particularly sur(cid:173)
`prising, considering that the patients in these studies had
`advanced cancers that were generally refractory to standard
`
`West-Ward Exhibit 1039
`Dukart USPA '137
`Page 003
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`US 2002/0091137 Al
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`Jul. 11, 2002
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`3
`
`treatment, and also considering that these were Phase I
`clinical trials, in which efficacy is often limited, as the
`primary objective of a Phase I trial is to determine the safety
`and tolerability of the drug being evaluated.
`
`[0035] Based on the results of the preclinical and clinical
`test procedures, CCl-779 is useful in treating neoplasms, in
`particular, refractory neoplasms. More particularly, CCl-779
`is useful in treating treatment of renal carcinoma, soft tissue
`carcinoma, breast cancer, neuroendocrine tumor of the lung,
`cervical cancer, uterine cancer, head and neck cancer, glio(cid:173)
`blastoma, non-small cell lung cancer, prostate cancer, pan(cid:173)
`creatic cancer, lymphoma, melanoma, small cell lung can(cid:173)
`cer, ovarian cancer, endometrial cancer, and colon cancer.
`
`[0036] As typical with chemotherapy, dosage regimens are
`closely monitored by the treating physician, based on
`numerous factors including the severity of the disease,
`response to the disease, any treatment related toxicities, age,
`and health of the patient. Based on the results obtained with
`CCl-779, it is projected that initial i.v. infusion dosages will
`be between about 0.1 and 100 mg/m2 when administered on
`a dail;Y dosage regimen, and between about 1 and 1000
`mg/m when administered on a weekly dosage regimen.
`Other dosage regimens and variations are foreseeable, and
`will be determined through physician guidance. It is pre(cid:173)
`ferred that CCl-779 is administered by i.v. infusion or orally,
`preferably in the form of tablets or capsules. Other routes of
`administration are also feasible, such as via implants,
`parenterally (besides i.v., such as intraperitoneal and subcu(cid:173)
`taneous injections), rectally, intranasally, vaginally, and
`transdermally.
`
`[0037] Dosage regimens are expected to vary according to
`the route of administration. For example, dosages for oral
`administration are often up to tenfold greater than for i.v.
`administration. It is anticipated that CCl-779 may be admin(cid:173)
`istered as the sole active chemotherapeutic agent, or may be
`part of a chemotherapeutic regimen containing more than
`one antineoplastic agent. The use of concomitant chemo(cid:173)
`therapeutic agents often allows for dosage reduction of each
`particular agent, thereby increasing the safety margin of the
`particular agents.
`
`[0038] Oral formulations containing the active compounds
`of this invention may comprise any conventionally used oral
`forms, including tablets, capsules, buccal forms, troches,
`lozenges and oral liquids, suspensions or solutions. Capsules
`may contain mixtures of the active compound(s) with inert
`fillers and/or diluents such as the pharmaceutically accept(cid:173)
`able starches (e.g. corn, potato or tapioca starch), sugars,
`artificial sweetening agents, powdered celluloses, such as
`crystalline and microcrystalline celluloses, flours, gelatins,
`gums, etc. Useful tablet formulations may be made by
`conventional compression, wet granulation or dry granula(cid:173)
`tion methods and utilize pharmaceutically acceptable dilu(cid:173)
`ents, binding agents, lubricants, disintegrants, surface modi(cid:173)
`fying agents
`(including
`surfactants),
`suspending or
`stabilizing agents, including, but not limited to, magnesium
`stearate, stearic acid, talc, sodium lauryl sulfate, microcrys(cid:173)
`talline cellulose, carboxymethylcellulose calcium, polyvi(cid:173)
`nylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan
`gum, sodium citrate, complex silicates, calcium carbonate,
`glycine, dextrin, sucrose, sorbitol, dicalcium phosphate,
`calcium sulfate, lactose, kaolin, mannitol, sodium chloride,
`talc, dry starches and powdered sugar. Preferred surface
`
`modifying agents include nonionic and anionic surface
`modifying agents. Representative examples of surface modi(cid:173)
`fying agents include, but are not limited to, poloxamer 188,
`benzalkonium chloride, calcium stearate, cetostearl alcohol,
`cetomacrogol emulsifying wax, sorbitan esters, colloidal
`silicon dioxide, phosphates, sodium dodecylsulfate, magne(cid:173)
`sium aluminum silicate, and triethanolamine. Oral formula(cid:173)
`tions herein may utilize standard delay or time release
`formulations to alter the absorption of the active com(cid:173)
`pound(s). The oral formulation may also consist of admin(cid:173)
`istering the active ingredient in water or a fruit juice,
`containing appropriate solubilizers or emulsifiers as needed.
`[0039]
`In some cases it may be desirable to administer the
`compounds directly to the airways in the form of an aerosol.
`[0040] The compounds of this invention may also be
`administered parenterally or intraperitoneally. Solutions or
`suspensions of these active compounds as a free base or
`pharmacologically acceptable salt can be prepared in water
`suitably mixed with a surfactant such as hydroxy-propyl(cid:173)
`cellulose. Dispersions can also be prepared in glycerol,
`liquid polyethylene glycols and mixtures thereof in oils.
`Under ordinary conditions of storage and use, these prepa(cid:173)
`ration contain a preservative to prevent the growth of
`microorganisms.
`[0041] The pharmaceutical forms suitable for injectable
`use include sterile aqueous solutions or dispersions and
`sterile powders for the extemporaneous preparation of sterile
`injectable solutions or dispersions. In all cases, the form
`must be sterile and must be fluid to the extent that easy
`syringability exists. It must be stable under the conditions of
`manufacture and storage and must be preserved against the
`contaminating action of microorganisms such as bacteria
`and fungi. The carrier can be a solvent or dispersion medium
`containing, for example, water, ethanol, polyol (e.g., glyc(cid:173)
`erol, propylene glycol and liquid polyethylene glycol), suit(cid:173)
`able mixtures thereof, and vegetable oils.
`[0042] For the purposes of this disclosure, transdermal
`administrations are understood to include all administrations
`across the surface of the body and the inner linings of bodily
`passages including epithelial and mucosal tissues. Such
`administrations may be carried out using the present com(cid:173)
`pounds, or pharmaceutically acceptable salts thereof, in
`lotions, creams, foams, patches, suspensions, solutions, and
`suppositories (rectal and vaginal).
`[0043] Transdermal administration may be accomplished
`through the use of a transdermal patch containing the active
`compound and a carrier that is inert to the active compound,
`is non toxic to the skin, and allows delivery of the agent for
`systemic absorption into the blood stream via the skin. The
`carrier may take any number of forms such as creams and
`ointments, pastes, gels, and occlusive devices. The creams
`and ointments may be viscous liquid or semisolid emulsions
`of either the oil-in-water or water-in-oil type. Pastes com(cid:173)
`prised of absorptive powders dispersed in petroleum or
`hydrophilic petroleum containing the active ingredient may
`also be suitable. A variety of occlusive devices may be used
`to release the active ingredient into the blood stream such as
`a semi-permeable membrane covering a reservoir containing
`the active ingredient with or without a carrier, or a matrix
`containing the active ingredient. Other occlusive devices are
`known in the literature.
`[0044] Suppository formulations may be made from tra(cid:173)
`ditional materials, including cocoa butter, with or without
`
`West-Ward Exhibit 1039
`Dukart USPA '137
`Page 004
`
`

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`US 2002/0091137 Al
`
`Jul. 11, 2002
`
`4
`
`the addition of waxes to alter the suppository's melting
`point, and glycerin. Water soluble suppository bases, such as
`polyethylene glycols of various molecular weights, may also
`be used.
`
`What is claimed is:
`1. A method of treating a neoplasm in a mammal in need
`thereof, which comprises providing to said mammal an
`effective amount of CCl-779.
`2. A method of treating a refractory neoplasm in a
`mammal in need thereof, which comprises providing to said
`mammal an effective amount of CCl-779.
`3. The method according to claim 1, wherein the neo(cid:173)
`plasm is renal cancer.
`4. The method according to claim 1, wherein the neo(cid:173)
`plasm is soft tissue sarcoma.
`5. The method according to claim 1, wherein the neo(cid:173)
`plasm is breast cancer.
`6. The method according to claim 1, wherein the neo(cid:173)
`plasm is a neuroendocrine tumor of the lung.
`7. The method according to claim 1, wherein the neo(cid:173)
`plasm is cervical cancer.
`8. The method according to claim 1, wherein the neo(cid:173)
`plasm is uterine cancer.
`
`9. The method according to claim 1, wherein the neo(cid:173)
`plasm is a head and neck cancer.
`10. The method according to claim 1, wherein the neo(cid:173)
`plasm is glioblastoma.
`11. The method according to claim 1, wherein the neo(cid:173)
`plasm is non-small cell lung cancer.
`12. The method according to claim 1, wherein the neo(cid:173)
`plasm is prostate cancer.
`13. The method according to claim 1, wherein the neo(cid:173)
`plasm is pancreatic cancer.
`14. The method according to claim 1, wherein the neo(cid:173)
`plasm is lymphoma.
`15. The method according to claim 1, wherein the neo(cid:173)
`plasm is melanoma.
`16. The method according to claim 1, wherein the neo(cid:173)
`plasm is small cell lung cancer.
`17. The method according to claim 1, wherein the neo(cid:173)
`plasm is ovarian cancer.
`18. The method according to claim 1, wherein the neo(cid:173)
`plasm is colon cancer.
`19. The method according to claim 1, wherein the neo(cid:173)
`plasm is endometrial cancer.
`* * * * *
`
`West-Ward Exhibit 1039
`Dukart USPA '137
`Page 005
`
`