Case 1:18-cv-00924-CFC Document 328-1 Filed 07/25/19 Page 1 of 70 PageID #: 25737
`Case 1:18—cv-00924-CFC Document 328-1 Filed 07/25/19 Page 1 of 70 PageID #: 25737
`
`EXHIBIT 230
`    
`
`

`

`lllllllllllHlllUllUlJIHllLllUlltgs
`Wilma/mum
`Case 1:18-cv-00924-CFC Document 328-1 Filed 07/25/19 Page 2 of 70 PageID #: 25738
`Case 1:18-cv-00924-CFC Document 328-1
`6627196B1
`
`(12) United States Patent
`US 6,627,196 B1
`(10) Patent N0.:
`
`Sep. 30, 2003
`(45) Date of Patent:
`Baughman et al.
`
`(54)
`
`(75)
`
`DOSAGES FOR TREATMENT WITH ANTI-
`ERBB2 ANTIBODIES
`
`Inventors: Sharon A. Baughinan, Ventura, CA
`(US); Steven Shak, Burlingame, CA
`(US)
`
`(73)
`
`Assignee: Genentech, Inc., South San Francisco,
`CA (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`
`Appl. N0.: 09/648,067
`
`(22)
`
`Filed:
`
`Aug. 25, 2000
`
`(60)
`
`(51)
`(52)
`
`(58)
`
`(56)
`
`Related US. Application Data
`Provisional application No. 60/213,822, filed on Jun. 23,
`2000, and provisional application No. 60/151,018, filed on
`Aug. 27, 1999.
`
`Int. Cl.7 .............................................. A61K 39/395
`US. Cl.
`................................ 424/138.1; 424/131.1;
`424/1331; 424/1341; 424/1351; 424/1361;
`424/1371; 424/1391; 424/1411; 424/1421;
`424/1431; 424/1441; 424/1451; 424/1461;
`424/1471; 424/1501; 424/1511; 424/1521;
`424/1531; 424/1541; 424/1551; 424/156.1;
`424/158.1; 424/1721; 424/1741
`Field of Search ........................... 424/130.1, 138.1,
`424/141.1, 142.1, 152.1, 155.1, 131.1, 133.1,
`134.1, 135.1, 136.1, 137.1, 139.1, 143.1,
`1441,1451, 146.1, 147.1, 150.1, 151.1,
`153.1, 154.1, 156.1, 158.1, 172.1, 174.1
`
`References Cited
`
`U.S. PATENT DOCUMENTS
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`
`>>>>>>>>>>>>>>>>>>>>>>>>>>>
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`
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`6,333,348 B1 * 12/2001 Vogelet al.
`................ 514/449
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`
`0003089 A1
`0599274 A1
`616812 A1
`0711565 B1
`3—240498
`5—117165
`5—170667
`5—213775
`5—317084
`95006982 B2
`7—59588
`2761543 B2
`2895105 B2
`
`7/1979
`6/1994
`9/1994
`8/1998
`10/1991
`5/1993
`7/1993
`8/1993
`12/1993
`1/1995
`3/1995
`6/1998
`5/1999
`
`(List continued on neXt page.)
`OTHER PUBLICATIONS
`
`Wantanabe et al., ASCO, Vol. 17, abstract 702, May 15—18,
`1998 Annual Meeting.*
`
`(List continued on next page.)
`
`Primary Examiner—Anthony C. Caputa
`Assistant Examiner—Anne L. Hollcran
`
`(74) Attorney, Agent, or Firm—Wendy M. Lee
`ABSTRACT
`
`(57)
`
`The present invention concerns the treatment of disorders
`characterized by the overexpression of ErbB2. More
`specifically, the invention concerns the treatment of human
`patients susceptible to or diagnosed with cancer overex-
`pressing ErbB2 With anti-ErbB2 antibody.
`
`33 Claims, 5 Drawing Sheets
`
`GNE-HER_000657455
`
`

`

`Case 1:18-cv-00924-CFC Document 328-1 Filed 07/25/19 Page 3 of 70 PageID #: 25739
`Case 1:18-cv-00924-CFC Document 328-1 Filed 07/25/19 Page 3 of 70 PageID #: 25739
`
`US. Patent
`
`Sep. 30,2003
`
`Sheet 2 0f5
`
`US 6,627,196 B1
`
`E\
`C)
`
`3c
`
`.9
`'53
`bc:
`a)
`
`oco O E:
`
`1L.
`a)
`(0
`.c
`c»
`
`Concentration
`
`MeanTrough50
`
`40
`
`30
`
`(Mg/ml)
`
`GNE—HER_000657460
`
`3 9
`
`l—
`r:
`(U
`a)
`E
`
`

`

`Case 1:18-cv-00924-CFC Document 328-1 Filed 07/25/19 Page 4 of 70 PageID #: 25740
`Case 1:18-cv-00924-CFC Document 328-1 Filed 07/25/19 Page 4 of 70 PageID #: 25740
`
`US 6,627,196 B1
`
`1
`DOSAGES FOR TREATMENT WITH ANTI-
`ERBB2 ANTIBODIES
`
`RELATED APPLICATIONS
`
`This application is a non-provisional application filed
`under 37 CFR 1.53(b)(1), claiming priority under 35 USC
`119(e) to provisional application No. 60/151,018, filed Aug.
`27, 1999 and No. 60/213,822, filed Jun. 23, 2000,
`the
`
`contents of which are incorporated herein by reference.
`FIELD OF THE INVENTION
`
`10
`
`The present invention concerns the treatment of disorders
`characterized by the overexpression of ErbB2 or disorders
`expressing epidermal growth factor receptor (EGFR), com- 15
`prising administering to a human or animal presenting the
`disorders a therapeutically effective amount of an antibody
`that binds ErbB2. More specifically, the invention concerns
`the treatment of human patients susceptible to or diagnosed
`with cancer overexpressing ErbB2 or expressing EGFR, 20
`where the treatment is with an anti-ErbB2 antibody admin-
`istered by front loading the dose of antibody during treat-
`ment by intravenous and/0r subcutaneous administration.
`The invention optionally includes treatment of cancer in a
`human patient with a combination of an anti-ErbB2 antibody 25
`and a chemotherapeutic agent, such as, but not limited to, a
`taxoid. The taxoid may be, but is not limited to paclitaxel or
`docetaxel. The invention further includes treatment of can-
`
`cer in a human patient with a combination of anti—ErbB2
`antibody and a chemotherapeutic agent, such as, but not 30
`limited to, an anthracycline derivative. Optionally, treatment
`with a combination of anti-ErbB2 and an anthracycline
`derivative includes treatment with an effective amount of a
`
`cardioprotectant.—
`
`DJLII
`
`BACKGROUND OF THE INVENTION
`
`45
`
`40
`
`Proto-oncogenes that encode growth factors and growth
`factor receptors have been identified to play important roles
`in the pathogenesis of various human malignancies, includ-
`ing breast cancer. It has been found that the human ErbB2
`gene (erbB2, also known as her2, or c-erbB-2), which
`encodes a 185-kd transmembrane glycoprotein receptor
`(p185HER2) related to the epidermal growth factor receptor
`(EGFR), is overexpressed in about 25% to 30% of human
`breast cancer (Slamon et al., Science 235:177—182 [1987];
`Slamon et al., Science 244:707—712 [1989]).
`Several lines of evidence support a direct role for ErbB2
`in the pathogenesis and clinical aggressiveness of ErbB2- 50
`overexpressing tumors. The introduction of ErbB2 into
`non-neoplastic cells has been shown to cause their malignant
`transformation (Hudziak et al., Proc. Natl. Acad. Sci. USA
`84:7159—7163 [1987]; DiFiore et al., Science 237278—182
`[1987]). Transgenic mice that express IIER2 were found to 55
`develop mammary tumors (Guy et al., Proc. Natl. Acad. Sci.
`USA 89:10578—10582 [1992]).
`Antibodies directed against human erbB2 protein prod-
`ucts and proteins encoded by the rat equivalent of the erbB2
`gene (neu) have been described. Drebin et al., Cell 60
`41:695—706 (1985) refer to an IgG2a monoclonal antibody
`which is directed against the rat neu gene product. This
`antibody called 7.16.4 causes down-modulation of cell sur-
`face p185 expression on B104-1-1 cells (NIH-3T3 cells
`transfected with the neu proto-oncogene) a inhibits colony 65
`formation of these cells.
`In Drebin et al. PNAS (USA)
`83:9129—9133 (1986), the 7.16.4 antibody was shown to
`
`2
`inhibit the tumorigenic growth of neu-transformed NIH-3T3
`cells as well as rat neuroblastoma cells (from which the neu
`oncogene was initially isolated) implanted into nude mice.
`Drebin et al. in Oncogene 2:387—394 (1988) discuss the
`production of a panel of antibodies against the rat neu gene
`product. All of the antibodies were found to exert a cyto-
`static effect on the growth of neu-transformed cells sus-
`pended in soft agar. Antibodies of the IgM, IgG2a and lgG2b
`isotypes were able to mediate significant in vitro lysis of
`neu-transformed cells in the presence of complement,
`whereas none of the antibodies were able to mediate high
`levels of antibody-dependent cellular cytotoxicity (ADCC)
`of the neu-transformed cells. Drebin et al. Oncogene
`2:273—277 (1988) report that mixtures of antibodies reactive
`with two distinct regions on the p185 molecule result in
`synergistic anti-tumor effects on neu-transformed NIH-3T3
`cells implanted into nude mice. Biological effects of anti-neu
`antibodies are reviewed in Myers et al., Meth. Enzym.
`198:277—290 (1991). See also WO94/22478 published Oct.
`13, 1994.
`Hudziak et al., Mol. Cell. Biol. 9(3):1165—1172 (1989)
`describe the generation of a panel of anti-ErbB2 antibodies
`which were characterized using the human breast tumor cell
`line SKBR3. Relative cell proliferation of the SKBR3 cells
`following exposure to the antibodies was determined by
`crystal Violet staining of the monolayers after 72 hours.
`Using this assay, maximum inhibition was obtained with the
`antibody called 4D5 which inhibited cellular proliferation by
`56%. Other antibodies in the panel,including 7C2 and 7F3,
`reduced cellular proliferation to a lesser extent in this assay.
`Hudziak et al. conclude that the effect of the 4D5 antibody
`on SKBR3 cells was cytostatic rather than cytotoxic, since
`SKBR3 cells resumed growth at a nearly normal rate fol-
`lowing removal of the antibody from the medium. The
`antibody 4D5 was further found to sensitize p 185
`-overexpressing breast
`tumor cell
`lines to the cytotoxic
`effects of TNF—a. See also W089/06692 published Jul. 27,
`1989. The anti-ErbB2 antibodies discussed in Hudziak et al.
`are further characterized in Fendly et al. Cancer Research
`50:1550—1558 (1990); Kotts et al. In Vitro 26(3):59A
`(1990); Sarup et al. Growth Regulation 1:72—82 (1991);
`Shepard et al. J. Clin. Immunol. 11(3):117—127 (1991);
`Kumar et al. Mol. Cell. Biol. 11(2):9797986 (1991); Lewis
`et al. Cancer Immunol. Immunother. 37:255—263 (1993);
`Pietras et al. Oncogene 921829—1838 (1994); Vitetta et al.
`CancerResearch 54:5301—5309 (1994); Sliwkowski et al.J.
`Biol. Chem. 269(20): 14661—14665 (1994); Scott et al. J.
`Biol. Chem. 266:14300—5 (1991); and D’souza et al. Proc.
`Natl. Acad. Sci.91:7202—7206 (1994).
`Tagliabue et al. Int. J. Cancer 47:933—937 (1991) describe
`two antibodies which were selected for their reactivity on
`the lung adenocarcinoma cell line (Calu-3) which overex-
`presses ErbB2. One of the antibodies, called MGR3, was
`found to internalize, induce phosphorylation of ErbB2, and
`inhibit tumor cell growth in vitro.
`McKenzie et al. Oncogene 4:543—548 (1989) generated a
`panel of anti-ErbB2 antibodies with varying epitope
`specificities, including the antibody designated TA1. This
`TA1 antibody was found to induce accelerated endocytosis
`of ErbB2 (see Maier et al. Cancer Res. 51:5361—5369
`[1991]). Bacus et al. Molecular Carcinogenesis 3:350—362
`(1990) reported that the TA1 antibody induced maturation of
`the breast cancer cell lines AU-565 (which overexpresses the
`erbB2 gene) and MCF-7 (which does not). Inhibition of
`growth and acquisition of a mature phenotype in these cells
`was found to be associated with reduced levels of ErbB2
`receptor at the cell surface and transient increased levels in
`the cytoplasm.
`
`GNE-HER_000657464
`
`

`

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`US 6,627,196 B1
`
`6
`carcinoma, salivary gland carcinoma, kidney cancer, liver
`cancer, prostate cancer, vulval cancer,
`thyroid cancer,
`hepatic carcinoma and various types of head and neck
`cancer. The method of the invention may further comprise
`administration of a chemotherapeutic agent other than an
`anthracycline, e.g. doxorubicin or epirubicin. The chemo-
`therapeutic agent preferably is a taxoid, such as TAXOL®
`(paclitaxel) or a TAXOL® derivative.
`Preferred anti-ErbB2 antibodies bind the extracellular
`
`domain of the ErbB2 receptor, and preferably bind o the
`epitope 4D5 or 3H4 within the ErbB2 extracellular domain
`sequence. More preferably,
`the antibody is the antibody
`4D5, most preferably in a humanized form. Other preferred
`ErbB2-binding antibodies include, but are not limited to,
`antibodies 7C2, 7F3, and 2C4, preferably in a humanized
`form.
`
`The method of the present invention is particularly suit-
`able for the treatment of breast or ovarian cancer, charac-
`terized by the overexpression of the ErbB2 receptor.
`
`__
`
`In
`particular, the invention provides a method for the treatment
`of cancer (e.g. cancer characterized by overexpression of the
`ErbB2 receptor) in a human patient comprising administer—
`ing to the patient a first dose of an anti-ErbB2 antibody
`followed by at least one subsequent dose of the antibody,
`wherein the first dose and subsequent dose are separated
`from each other in time by at least about two weeks (e.g.
`from about two weeks to about two months), and optionally
`at least about three weeks (e.g. from about three weeks to
`about six weeks). For instance, the antibody may be admin-
`istered about every three weeks, about two to about 20 times,
`e.g. about six times. The first dose and subsequent dose may
`each be from about 2 mg/kg to about 16 mg/kg; e.g. from
`about 4 mg/kg to about 12 mg/kg; and optionally from about
`6 mg/kg to about 12 mg/kg. Generally, two or more subse-
`quent doses (e.g. from about two to about ten subsequent
`doses) of the antibody are administered to the patient, and
`those subsequent doses are preferably separated from each
`other in time by at least about two weeks (e.g. from about
`two weeks to about two months), and optionally at least
`about three weeks (e.g. from about three weeks to about six
`weeks). The two or more subsequent doses may each be
`from about 2 mg/kg to about 16 mg/kg; or from about 4
`nag/kg to about 12 mg/kg; or from about 6 mg/kg to about
`12 mg/kg. The invention additionally provides an article of
`manufacture, comprising a container, a composition within
`the container comprising an anti-ErbB2 antibody, and a
`package insert containing instructions to administer the
`antibody according to such methods.
`The presently described dosing protocols may be applied
`to other anti-ErbB antibodies such as anti-epidermal growth
`factor receptor (EGFR), anti-ErbB3 and anti-ErbB4 anti-
`bodies. Thus,
`the invention provides a method for the
`treatment of cancer in a human patient, comprising admin-
`istering an effective amount of an anti-ErbB antibody to the
`human patient, the method comprising administering to the
`patient an initial dose of at least approximately 5 mg/kg of
`the anti-ErbB antibody; and administering to the patient a
`plurality of subsequent doses of the antibody in an amount
`that is approximately the same or less than the initial dose.
`Alternatively, or additionally,
`the invention pertains to a
`method for the treatment of cancer in a human patient
`comprising administering to the patient a first dose of an
`anti-ErbB antibody followed by at least one subsequent dose
`of the antibody, wherein the first dose and subsequent dose
`are separated from each other in time by at least about two
`
`5
`administered is sufficient to maintain the target trough serum
`concentration such that the interval between administration
`
`cycles is at least one week. Preferably the trough serum
`concentration does not exceed 2500 yg/ml and does not fall
`below 0.01 [Ag/ml during treatment. The front loading drug
`treatment method of the invention has the advantage of
`increased efiicacy by reaching a target serum drug concen-
`tration early in treatment. The subcutaneous delivery of
`maintenance doses according to the invention has the advan-
`tage of being convenient for the patient and health care
`professionals, reducing time and costs for drug treatment.
`Preferably, the initial dose (or the last dose within an initial
`dose series) is separated in time from the first subsequent
`dose by 4 weeks or less, preferably 3 weeks or less, more
`preferably 3 weeks or less, most preferably 1 week or less.
`In an embodiment of the invention, the initial dose of
`anti-ErbB2 is 6 mg/kg, 8 mg/kg, or 12 mg/kg delivered by
`intravenous or subcutaneous administration, such as intra-
`venous infusion or subcutaneous bolus injection. The sub-
`sequent maintenance doses are 2 mg/kg delivered once per
`week by intravenous infusion, intravenous bolus injection,
`subcutaneous infusion, or subcutaneous bolus injection. The
`choice of delivery method for the initial and maintenance
`doses is made according to the ability of the animal or
`human patient to tolerate introduction of the antibody into
`the body. Where the antibody is well-tolerated, the time of
`infusion may be reduced. The choice of delivery method as
`disclosed for this embodiment applies to all drug delivery
`regimens contemplated according to the invention.
`
`10
`
`15
`
`20
`
`25
`
`
`
`40
`
`the invention includes initial
`In another embodiment,
`doses of at least 1 mg/kg, preferably 4 mg/kg, anti-ErbB2
`antibody on each of days 1, 2 and 3, followed by subsequent
`maintenance doses of 6 mg/kg once per 3 weeks.
`In another embodiment, the invention includes an initial
`dose of 4 mg/kg anti-ErbB2 antibody, followed by subse-
`quent maintenance doses of 2 mg/kg twice per week,
`wherein the maintenance doses are separated by 3 days.
`In still another embodiment,
`the invention includes a
`cycle of dosing in which delivery of anti-ErbB2 antibody is
`2—3 times per week for 3 weeks. In one embodiment of the
`invention, each dose is approximately 25 mg/kg or less for
`a human patient, preferably approximately 10 mg/kg or less.
`This 3 week cycle is preferably repeated as necessary to
`achieve suppression of disease symptoms.
`In another embodiment, the invention includes a cycle of
`dosing in which delivery of anti-ErbB2 antibody is daily for
`5 days. According to the invention, the cycle is preferably
`repeated as necessary to achieve suppression of disease
`symptoms.
`The disorder preferably is a benign or malignant tumor
`characterized by the overexpression of the ErbB2 receptor,
`e.g. a cancer, such as, breast cancer, squamous cell cancer,
`small-cell
`lung cancer, non-small cell
`lung cancer, gas-
`trointestinal cancer, pancreatic cancer, glioblastoma, cervi-
`cal cancer, ovarian cancer,
`liver cancer, bladder cancer,
`hepatoma, colon cancer, colorectal cancer, endometrial
`
`45
`
`50
`
`55
`
`60
`
`65
`
`GNE-HER_000657466
`
`

`

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`US 6,627,196 B1
`
`5
`
`10
`
`33
`intravenous administration as a bolus or by continuous
`infusion over a period of time, by intramuscular,
`intraperitoneal,
`intracerobrospinal, subcutaneous,
`intra-
`articular, intrasynovial, intrathecal, oral, topical, or inhala-
`tion routes. Intravenous or subcutaneous administration of
`the antibody is preferred.
`invention involves the
`The treatment of the present
`administration of an anti-ErbB2 antibody to an animal or
`human patient, followed at intervals by subsequent doses of
`equal or smaller doses such that a target serum concentration
`is achieved and maintained during treatment. Preferably,
`maintenance doses are delivered by bolus delivery, prefer-
`ably by subcutaneous bolus administration, making treat-
`ment convenient and cost-effective for the patient and health
`care professionals.
`Where combined administration of a chemotherapeutic
`agent (other than an antracycline) is desired, the combined
`administration includes coadministration, using separate for-
`mulations or a single pharmaceutical formulation, and con-
`secutive administration in either order, wherein preferably .
`there is a time period while both (or all) active agents
`simultaneously exert their biological activities. Preparation
`and dosing schedules for such chemotherapeutic agents may
`be used according to manufacturers’
`instructions or as
`determined empirically by the skilled practitioner. Prepara-
`tion and dosing schedules for such chemotherapy are also
`described in Chemotherapy Service Ed., M. C. Perry, Wil-
`liams & Wilkins, Baltimore, Md. (1992). The chemothera-
`peutic agent may precede, or follow administration of the
`antibody or may be given simultaneously therewith. The
`antibody may be combined with an anti-estrogen compound
`such as tamoxifen or an anti-progesterone such as onapris-
`tone (see, EP 616 812) in dosages known for such mol-
`ecules.
`
`25
`
`30
`
`It may be desirable to also administer antibodies against
`other tumor associated antigens, such as antibodies which
`bind to the EGFR, ErbB3, ErbB4, or vascular endothelial
`growth factor (VEGF). Alternatively, or additionally, two or
`more anti-ErbB2 antibodies may be co-administered to the
`patient. Sometimes, it may be beneficial to also administer
`one or more cytokines to the patient. The ErbB2 antibody
`may be co-administered with a growth inhibitory agent. For
`example, the growth inhibitory agent may be administered
`first, followed by the ErbB2 antibody. However, simulta-
`neous administration, or administration of the ErbB2 anti-
`body first is also contemplated. Suitable dosages for the
`growth inhibitory agent are those presently used and may be
`lowered due to the combined action (synergy) of the growth
`inhibitory agent and anti—ErbB2 antibody.
`In addition to the above therapeutic regimens, the patient
`may be subjected to surgical removal of cancer cells and/
`or-radiation therapy.
`For the prevention or treatment of disease, the appropriate
`dosage of anti-ErbB2 antibody will depend on the type of
`disease to be treated, as defined above, the severity and
`course of the disease, whether the antibody is administered
`for preventive or therapeutic purposes, previous therapy, the
`patient’s clinical history and response to the antibody, and
`the discretion of the attending physician. The antibody is
`suitably administered to the patient at one time or over a
`series of treatments. Where the treatment involves a series of
`treatments, the initial dose or initial doses are followed at
`daily or weekly intervals by maintenance doses. Each main-
`tenance dose provides the same or a smaller amount of
`antibody compared to the amount of antibody administered
`in the initial dose or doses.
`
`Depending on the type and severity of the disease, about
`1 gig/kg to 15 mg/kg (e.g. 0.1—20 mg/kg) of antibody is an
`initial candidate dosage for administration to the patient,
`
`40
`
`45
`
`50
`
`60
`
`65
`
`34
`for example, by one or more separate
`whether,
`administrations, or by continuous infusion. A typical daily
`dosage might range from about 1 yg/kg to 100 mg/kg or
`more, depending on the factors mentioned above. For
`repeated administrations over several days or
`longer,
`depending on the condition, the treatment is sustained until
`a desired suppression of disease symptoms occurs. The
`progress of this therapy is easily monitored by conventional
`techniques and assays.
`
`
`
`initial doses of 4 mg/kg
`As an alternative regimen,
`anti-ErbB2 antibody may be administered on each of days 1,
`2 and 3, followed by subsequent maintenance doses of 6
`mg/kg once per 3 weeks.
`An additional regimen involves an initial dose of 4 mg/kg
`anti-ErbB2 antibody, followed by subsequent maintenance
`doses of 2 mg/kg twice per week, wherein the maintenance
`doses are separated by 3 days.
`Alternatively, the invention may include a cycle of closing
`in which delivery of anti-ErbB2 antibody is 2—3 times per
`week for 3 weeks. The 3 week cycle is preferably repeated
`as necessary to achieve suppression of disease symptoms.
`The invention further includes a cyclic dosage regimen in
`which delivery of anti-ErbB2 antibody is daily for 5 days.
`According to the invention, the cycle is preferably repeated
`as necessary to achieve suppression of disease symptoms.
`Further information about suitable dosages is provided in the
`Examples below.
`VI. Articles of Manufacture
`
`In another embodiment of the invention, an article of
`manufacture containing materials useful for the treatment of
`the disorders described above is provided. The article of
`manufacture comprises a container, a label and a package
`insert. Suitable containers include, for example, bottles,
`Vials, syringes, etc. The containers may be formed from a
`variety of materials such as glass or plastic. The container
`holds a composition which is effective for treating the
`condition and may have a sterile access port (for example,
`the container may be an intravenous solution bag or a vial
`having a stopper pierceable by a hypodermic injection
`needle). At least one active agent in the composition is an
`anti-ErbB2 antibody. The label on, or associated with, the
`container indicates that the composition is used for treating
`the condition of choice. The article of manufacture may
`further comprise a second container comprising a
`pharmaceutically-acceptable buffer, such as phosphate-
`buffered saline, Ringer’s solution and dextrose solution. It
`may further include other materials desirable from a com—
`mercial and user standpoint,
`including other buifers,
`diluents, filters, needles, and syringes. In addition, the article
`of manufacture may comprise a package inserts with instruc-
`
`GNE-HER_000657480
`
`

`

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`US 6,627,196 B1
`
`37
`intravenously, over a 90-minute period. Beginning on day 7,
`patients received weekly administration of 2 mg/kg antibody
`(i.V.) over a 90-minute period.
`Chemotherapy
`The patients received one of two chemotherapy regimens
`for a minimum of six cycles, provided their disease was not
`progressing: a) cyclophosphamide and doxorubicin or epi-
`rubicin (AC), if patients have not received anthracycline
`therapy in the adjuvant setting, or b) paclitaxel
`(T,
`TAXOLO),
`if patients have received any anthracycline
`therapy in the adjuvant setting. The initial dose of the
`HERCEPTIN® anti-ErbB2 antibody preceded the first cycle
`of either chemotherapy regimen by 24 hours. Subsequent
`doses of the antibody were given immediately before che-
`motherapy administration, if the initial dose of the antibody
`was well tolerated. If the first dose of the antibody was not
`well tolerated, subsequent infusions continued to precede
`chemotherapy administration by 24 hours. Patients were
`permitted to continue receiving chemotherapy beyond six
`cycles if, in the opinion of the treating physician, they were
`continuing to receive treatment benefit.
`Cyclophosphamide (600 mg/mz) was given either by iv
`push over a minimum period of 3 minutes or by infusion
`over a maximum period of 2 hours.
`Doxorubicin (60 mg/m2) or epirubicin (75 mg/m2) were
`given either by slow iv push over a minimum period of 375
`minutes or by infusion over a maximum period of 2 hours,
`according to institutional protocol.
`Paciltaxel (TAXOL®) was given at a dose of 175 mg/m2
`over 3 hours by intravenous administration. All patients
`receiving paclitaxel were premedicated with dexamethasone
`(or its equivalent) 20 mg><2, administered orally 12 and 6
`hours prior
`to paclitaxel; diphenhydramine (or its
`equivalent) 50 mg,
`iv, administered 30 minutes prior to
`paclitaxel, and dimetidine (or another H2 blocker) 300 mg,
`iv, administered 30 minutes prior to paclitaxel.
`Response Criteria
`Progressive Disease
`Objective evidence of an increase of 25% or more in any
`measurable lesion. Progressive disease also includes those
`instances when new lesions have appeared. For bone lesions,
`progression is defined as a 25% increase in objective mea-
`surement by plain film, CT, MRI; symptomatic new lesions
`not due to fracture; or requirement for palliative radio-
`therapy.
`Complete Response
`Disappearance of all radiographically and/or visually
`apparent tumor for a minimum of 4 weeks. Skin and chest
`wall complete responses had to be confirmed by biopsy.
`Partial Response
`A reduction of at least 50% in the sum of the products of
`the perpendicular diameters of all measurable lesions for a
`minimum period of 4 weeks. No new lesions may have
`appeared, nor may any lesions have progressed in size.
`Minor Response
`A reduction of 25% to 49% in the sum of the products of
`the perpendicular diameters of all measurable lesions. No
`new lesions may have appeared, nor may any lesions have
`progressed in size.
`Stable Disease
`
`No change of greater than 25% in the size of measurable
`lesions. No lesions may have appeared.
`Time to disease progression (TTP) was calculated from
`the beginning of therapy to progression. Confidence limits
`for response rates were calculated using the exact method
`for a single proportion. (Fleiss, J L, Statistical Methods for
`Rates and Proportions (ed.2), New York, N.Y., Wiley, 1981,
`pp 13—17).
`Results
`At a median follow-up of 10.5 months, assessments of
`time to disease progression (TTP in months) and response
`
`10
`
`15
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`38
`rates (RR) showed a significant augmentation of the che-
`motherapeutic effect by HERCEPTIN® anti-ErbBZ
`antibody, without increase in overall severe adverse events
`(AE):
`
`TABLE 1
`
`HERCEPTIN ® Anti-ErbBZ Antibody Efficacy
`
`CRX
`CRx + 14
`AC
`AC + H
`T
`T + H
`
`Enrolled
`234
`235
`145
`146
`89
`89
`
`TTP (months)
`5.5
`8.6"
`6.5
`9.0
`4.2
`7.1
`
`RR (%)
`36.2
`62.00M
`42.1
`64.9
`25.0
`57.3
`
`AE (%)
`66
`69
`71
`68
`59
`70
`
`*p < 0.001 by log-rank test; ** p < 0.01 by X2 test; CRx: chemotherapy;
`AC: anthracycline/cyclophosphamide treatment; H: HERCEPTLN ® anti-
`ErbBZ antibody; T: TAXOL ®
`
`A syndrome of myocardial dysfunction similar to that
`observed with anthracyclines was reported more commonly
`with a combined treatment of AC+H (18% Grade 3A) than
`with AC alone (3%), T (0%), or T+H (2%).
`These data indicate that the combination of anti-ErbB2
`antibody treatment with chemotherapy markedly increases
`the clinical benefit, as assessed by response rates and the
`evaluation of disease progression. However, due to the
`increased cardiac side-effects of doxorubicin or epirubicin,
`the combined use of anthracyclines with anti-ErbB2 anti-
`body therapy is contraindicated. The results,
`taking into
`account risk and benefit, favor treatment with HERCEP-
`TIN® anti-ErbB2 antibody and paclitaxel (TAXOL®)
`where a combined treatment regimen is desired.
`
`
`
`GNE-HER_000657482
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`US 6,627,196 B1
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`39
`were available for 195 of the 212 patients. For the seventh
`infusion, trough serum concentration data were available for
`137/212 patients and peak serum concentration data were
`available for 114/212 patients. Table 2 presents a summary
`of statistics from trough and peak serum concentrations for
`the first 8 weeks of treatment. Peak samples were drawn
`shortly after the end of HERCEPTIN® anti-ErbB2 antibody
`administration;
`trough samples were drawn prior to the
`subsequent dose (i.e., 1 week later). Serum concentrations of
`HERCEPTIN® anti-ErbB2 antibody were determined as
`disclosed herein.
`
`TABLE 2
`
`HERCEPTIN ® Anti-ErbB2 Antibody Trough and Peak Serum
`Concentrations for the First 8 Weeks of Treatment gig/ml
`Dose
`Number
`
`Mean
`
`SD
`
`Minimum Maximum
`
`11
`
`Peak
`Trough
`Peak
`Trough
`Peak
`Trough
`Peak
`Trough
`Peak
`Trough
`Peak
`Trough
`Peak
`Trough
`Peak
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`195
`195
`190
`167
`167
`179
`175
`132
`128
`141
`137
`115
`114
`137
`133
`
`100.3
`25.0
`74.3
`30.4
`75.3
`33.7
`80.2
`38.6
`85.9
`42.1
`87.2
`43.2
`89.7
`48.8
`95.6
`
`35.2
`12.7
`31.3
`16.0
`26.8
`17.9
`26.9
`20.1
`29.2
`24.8
`32.2
`24.0
`32.5
`24.9
`35.9
`
`30.7
`0.16
`20.8
`0.2
`16.1
`0.2
`22.2
`0.2
`27.8
`0.2
`28.9
`0.2
`16.3
`0.2
`11.4
`
`274.6
`60.7
`307.9
`74.4
`194.8
`98.2
`167
`89.4
`185.8
`148.7
`218.1
`109.9
`187.8
`105.2
`295.6
`
`The data in Table 2 suggest that there was an increase in
`trough serum concentration over time. Of the many patients
`studied, there were 18 patients fo