(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`6 March 2014 (06.03.2014)
`
`WIPOI PCT
`
`\9
`
`(10) International Publication Number
`
`WO 2014/036412 A2
`
`(51)
`
`International Patent Classification:
`A61K 39/00 (2006.01)
`
`(21)
`
`International Application Number:
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`PCT/US201 3/057542
`
`(22)
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`International Filing Date:
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`30 August 2013 (30.08.2013)
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`(25)
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`(26)
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`(30)
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`(71)
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`(72)
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`(74)
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`(81)
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`Filing Language:
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`Publication Language:
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`English
`
`English
`
`Priority Data:
`61/694,963
`61/846,147
`
`30 August 2012 (30.08.2012)
`15 July 2013 (15.07.2013)
`
`US
`US
`
`Applicant: AMGEN INC. [US/US]; One Amgen Center
`Drive, Thousand Oaks, California 91320-1799 (US).
`
`Inventors: VANDERWALDE, Ari; 419 Essex Place,
`Memphis, Tennessee 38120 (US). SHABOOTI, M0-
`hamed; 29681 Strawberry Hill Drive, Agoura Hills, Cali—
`fornia 91301 (US).
`
`Agent: LINGENFELTER, Susan E.; A111ge11 1110., 1201
`Amgen Court West, Seattle, Washington 98119—3105 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ofnational protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GII, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, No, NZ,
`OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
`SC, SD, SE, SG, SK, SL, SM, ST, sv, SY, TH, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
`ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM, ML, MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to applyfor and be granted a
`patent (Rule 4.1 7(ii))
`Published:
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`without international search report and to be republished
`upon receipt ofthat report (Rule 48.2(g))
`
`(54) Title: A METHOD FOR TREATING MELANOMA USING A HERPES SIMPLEX VIRUS AND AN IMMUNE CHECK-
`POINT INHIBITOR
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`(57) Abstract: The invention relates to methods of treating melanoma using a herpes simplex virus in combination with an immune
`checkpoint inhibitor.
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`
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`WO 2014/036412
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`PCT/USZOl3/057542
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`A METHOD FOR TREATING MELANOMA USING A HERPES SIMPLEX VIRUS AND
`
`AN IMMUNE CHECKPOINT INHIBITOR
`
`CROSS REFERENCE TO RELATED APPLICATION S
`
`This application claims the benefit under 35 U.S.C. 119(e) of United States patent
`
`application number 61/694,963, filed August 30, 2012, and United States patent application
`
`number 61/846,147, filed July 15, 2013, which are incorporated herein by reference.
`
`BACKGROUND
`
`Melanoma is a tumor of melanocytes, cells that are derived from the neural crest.
`
`Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at
`
`other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and
`
`more than half of the cases arise in apparently normal areas of the skin. Early signs in a
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`naevus that would suggest malignant change include darker or variable discoloration, itching,
`
`an increase in size, or the development of satellites. Ulcerations or bleeding are later signs.
`
`Melanoma in women occurs more commonly on the extremities and in men on the trunk or
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`head and neck, but it can arise from any site on the skin surface.
`
`Prognosis is affected by clinical and histological factors and by anatomic location of
`
`the lesion.
`
`Thickness and/or level of invasion of the melanoma, mitotic index,
`
`tumor
`
`infiltrating lymphocytes, and ulceration or bleeding at the primary site affect the prognosis.
`
`Microscopic satellites in stage I melanoma may be a poor prognostic histologic factor, but this
`
`is controversial (Leon et al., Archives of Surgery 126(2): 1461—1468, 1991). Melanomas
`
`arising on the extremities or in women seem to have a better prognosis (Blois et al., Cancer
`
`52(7): 1330—1341, 1983; Clark et al., J. National Cancer Inst. 81(24): 1893—1904, 1989;
`
`Slinguff et al., Cancer 70(7): 1917—1927, 1992; Koh, NEJM 325(3): 171—182, 1991; Shumate
`
`et al., Am J Surgery 162(4): 315—319, 1991). Clinical staging is based on whether the tumor
`
`has spread to regional lymph nodes or distant sites. For disease clinically confined to the
`
`primary site, the greater the thickness and depth of local invasion of the melanoma, the higher
`
`the chance of lymph node metastases and the worse the prognosis. Melanoma can spread by
`
`local extension (through lymphatics) and/or by hematological routes to distant sites. Any
`
`organ may be involved by metastases, but lungs and liver are common sites. The risk of
`
`relapse may decrease substantially over time, although late relapses are not uncommon.
`
`Melanoma that has not spread beyond the initial site is highly curable. Most of these
`
`cases are those tumors that have not invaded beyond the papillary dermis (State 11; thickness,
`
`1.0 mm or less). Melanoma that has spread to regional
`
`lymph nodes (Stage III) may be
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`curable with wide (2 to 4 cm) excision of the primary tumor and removal of the involved
`
`regional lymph nodes (Karakousis et al, Ann Surg Oncol 13: 533—541, 2006; Batch et al, J
`
`Clin Oncol. 27(36): 6199—6206, 2009). Melanoma that has spread to distant sites (Stage IV)
`
`is infrequently curable with standard therapy, although ipilimumab and vemurafenib both
`
`offer survival benefits, and long-term survival
`
`is occasionally achieved by resection of
`
`metastasis (Overett and Shiu, Cancer 56:1222-1230,1985).
`
`Melanoma is the fifth most common cancer in men and the sixth most common
`
`cancer in women in the United States of America (USA), with an estimated 76,250 new cases
`
`and 9,180 deaths expected in 2012 (Siegel et al., CA Cancer J Clin. 62(1): 10-29, 2102).
`
`In
`
`Europe, the annual incidence of melanoma is somewhat lower than that in the USA, at
`
`approximately 7 per 100,000 as compared to 18 per 100,000 in the USA (Ries et al, 2000). In
`
`Europe, approximately 83,729 new cases were diagnosed in 2008 and approximately 85,086
`
`new cases were expected in 2010 (GLOBOCAN 2008, 2010). The incidence of melanoma is
`
`increasing rapidly worldwide, with a 270% increase in the USA between 1973 and 2002.
`
`This increase is the most rapid of any cancer with the exception of lung cancer in women
`
`(Jemal et al., CA Cancer J Clin. 56: 106—130, 2006; Ries et al., Cancer 88: 2398—2424, 2000).
`
`Traditional nonsurgical therapies for unresectable or advanced melanoma in adults
`
`include, chemotherapy (Dacarbazine,
`
`temozolomide, or other agents either alone or in
`
`combination), or interleukin-2. Although some regimes produced objective responses, they
`
`were usually short—lived. New therapies such as BRAF inhibition (vemurafenib) and immune
`
`stimulatory agents (ipilimumab) have shown significant improvement in overall survival
`
`compared to control treatments for a limited percentage of patients treated, however toxicity
`
`is an issue.
`
`Despite these efforts melanoma is increasing rapidly worldwide. There is a need for
`
`additional melanoma treatments. The present invention addresses this need and others.
`
`SUMMARY OF THE INVENTION
`
`The invention provides a method for the treatment of melanoma comprising
`
`administering to a patient with stages IIIb to IV melanoma an effective amount of an immune
`
`checkpoint inhibitor and a herpes simplex virus, wherein the herpes simplex virus lacks
`
`functional ICP34.5 genes,
`
`lacks a functional ICP47 gene and comprises a gene encoding
`
`human GM-CSF. In one embodiment the administration of the herpes simplex virus precedes
`
`the administration of the immune checkpoint
`
`inhibitor.
`
`In another embodiment
`
`the
`
`checkpoint inhibitor is an anti-CTLA-4 antibody.
`
`In a related embodiment the anti—CTLA—4
`
`antibody is ipilimumab.
`
`In another embodiment the anti-CTLA-4 antibody is tremelimumab.
`
`In another embodiment the checkpoint inhibitor is a PDl blocker. In another embodiment the
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`checkpoint inhibitor is a PD-Ll blocker.
`
`In another embodiment the checkpoint inhibitor is
`
`an anti-PD] antibody.
`
`In another embodiment the checkpoint inhibitor is an anti—PD—L]
`
`antibody. In another embodiment the PD] blocker is nivolumab.
`
`In another embodiment the
`
`PD] blocker is lambrolizumab.
`
`In another embodiment the PD] blocker is nivolumab.
`
`In
`
`another embodiment the PD] blocker is CT-Ol 1.
`
`In another embodiment the PD] blocker is
`
`AMP-224.
`
`In another embodiment
`
`the PD—L] blocker is EMS-936559.
`
`In another
`
`embodiment the checkpoint inhibitor is a LAG-3 inhibitor. In another embodiment the LAG-
`
`3 inhibitor is IMP32].
`
`In another embodiment the checkpoint inhibitor is a B7—H3 inhibitor.
`
`In another embodiment,
`
`the B7-H3 inhibitor is MGA27].
`
`In another embodiment the
`
`checkpoint inhibitor is a B7-H4 inhibitor.
`
`In another embodiment the checkpoint inhibitor is
`
`a TIM3 inhibitor.
`
`In another embodiment
`
`the herpes
`
`simplex virus
`
`is talimogene
`
`laherparepvec.
`
`The invention provides a method for the treatment of melanoma comprising
`
`administering to a patient with stages IIIb to IV melanoma a herpes simplex virus
`
`administered by intratumoral injection into injectable cutaneous, subcutaneous, and nodal
`
`tumors at a dose of up to 4.0 ml of 106 PFU/mL at day l of week 1 followed by a dose of up
`
`to 4.0 ml of 108 PFU/mL at day 1 of week 4, and every 2 weeks thereafter until complete
`
`response, and an anti-CTLA—4 antibody administered intravenously at a dose of 3 mg/kg
`
`every 3 weeks for 4 infilsions beginning after the third dose of the herpes simplex virus, and
`
`wherein the herpes simplex virus lacks functional ICP34.5 genes, lacks a functional ICP47
`
`gene and comprises a gene encoding human GM—CSF. In one embodiment the administration
`
`of the herpes simplex virus precedes the administration of the anti—CTLA—4 antibody.
`
`In one
`
`embodiment the anti-CTLA-4 antibody is ipilimumab.
`
`In another embodiment the herpes
`
`simplex virus is talimogene laherparepvec.
`
`The invention provides a method of promoting a combination treatment comprising a
`
`herpes simplex virus lacking functional ICP34.5 genes, lacking a functional ICP47 gene and
`
`comprises a gene encoding human GM—CSF and an immune checkpoint inhibitor, for the
`
`treatment of a patient with stages IIIb to IV melanoma.
`
`In one embodiment the immune
`
`checkpoint inhibitor is an anti-CTLA-4 antibody.
`
`In a related embodiment the anti—CTLA—4
`
`antibody is ipilimumab.
`
`In another embodiment the anti—CTLA—4 antibody is tremelimumab.
`
`In another embodiment the checkpoint inhibitor is a PD] blocker. In another embodiment the
`
`checkpoint inhibitor is a PD-L] blocker.
`
`In another embodiment the checkpoint inhibitor is
`
`an anti-PD] antibody.
`
`In another embodiment the checkpoint inhibitor is an anti- PD—L]
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`antibody. In another embodiment the PD] blocker is nivolumab.
`
`In another embodiment the
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`
`PD] blocker is lambrolizumab. In another embodiment the PD] blocker is nivolumab.
`
`In
`
`another embodiment the PD] blocker is CT-O] ].
`
`In another embodiment the PD] blocker is
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`WO 2014/036412
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`PCT/USZOl3/057542
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`AMP-224.
`
`In another embodiment
`
`the PD—Ll blocker is EMS-936559.
`
`In another
`
`embodiment the checkpoint inhibitor is a LAG-3 inhibitor. In another embodiment the LAG-
`
`3 inhibitor is IMP321.
`
`In another embodiment the checkpoint inhibitor is a B7-H3 inhibitor.
`
`In another embodiment,
`
`the B7-l-l3 inhibitor is MGA271.
`
`In another embodiment the
`
`checkpoint inhibitor is a B7-H4 inhibitor.
`
`In another embodiment the checkpoint inhibitor is
`
`a TIM3 inhibitor.
`
`In another embodiment the treatment comprises administering to a patient
`
`with stages IIIb to IV melanoma the herpes simplex virus administered by intratumoral
`
`injection into inj ectable cutaneous, subcutaneous, and nodal tumors at a dose of up to 4.0 ml
`
`0f106 PFU/mL at day l ofweek 1 followed by a dose of up to 4.0 ml of 108 PFU/mL at day l
`
`of week 4, and every 2 weeks thereafter until complete response, and the anti—CTLA—4
`
`antibody administered intravenously at a dose of 3 mg/kg every 3 weeks for 4 infiJsions
`
`beginning after the third dose of the herpes simplex virus.
`
`In another embodiment the herpes
`
`simplex virus is talimogene laherparepvec.
`
`In yet another embodiment the promotion is by a
`
`package insert, wherein the package insert provides instructions to receive cancer treatment
`
`with a herpes simplex virus in combination with an immune checkpoint inhibitor.
`
`In another
`
`embodiment the promotion is by a package insert accompanying a formulation comprising the
`
`herpes simplex virus. In yet another embodiment the promotion is by written communication
`
`to a physician or health care provider.
`
`In another embodiment the promotion is by oral
`
`communication to a physician or health care provider.
`
`In another embodiment the promotion
`
`is followed by the treatment of the patient with the herpes simplex virus.
`
`The invention provides a method of instructing a patient with stages IIIb to IV
`
`melanoma by providing instructions to receive a combination treatment with a herpes simplex
`
`virus lacking functional ICP34.5 genes, lacking a functional ICP47 gene and comprising a
`
`gene encoding human GM-CSF and an immune checkpoint inhibitor to extend survival of the
`
`patient. In one embodiment the immune checkpoint inhibitor is an anti—CTLA—4 antibody. In
`
`another embodiment the anti-CTLA-4 antibody is tremelimumab. In another embodiment the
`
`checkpoint inhibitor is a PDl blocker. In another embodiment the checkpoint inhibitor is a
`
`PD—Ll blocker.
`
`In another embodiment the checkpoint inhibitor is an anti—PDl antibody.
`
`In
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`another embodiment
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`the checkpoint
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`inhibitor is an anti—PD—Ll antibody.
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`In another
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`embodiment the FBI blocker is nivolumab.
`
`In another embodiment the PDl blocker is
`
`lambrolizumab.
`
`In another embodiment
`
`the PD] blocker is nivolumab.
`
`In another
`
`embodiment the PDl blocker is CT—Ol 1.
`
`In another embodiment the PDl blocker is AMP—
`
`224. In another embodiment the PD-Ll blocker is EMS-936559. In another embodiment the
`
`checkpoint inhibitor is a LAG—3 inhibitor.
`
`In another embodiment the LAG-3 inhibitor is
`
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`IMP321.
`
`In another embodiment the checkpoint inhibitor is a B7—H3 inhibitor.
`
`In another
`
`embodiment,
`
`the B7—H3 inhibitor is MGA271.
`
`In another embodiment the checkpoint
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`inhibitor is a B7-H4 inhibitor.
`
`In another embodiment the checkpoint inhibitor is a TIM3
`
`inhibitor.
`
`In one embodiment the treatment comprises administering to a patient with stages
`
`IIIb to IV melanoma a herpes simplex virus administered by intratumoral injection into
`
`injectable cutaneous, subcutaneous, and nodal tumors at a dose of up to 4.0 ml of 106
`
`PFU/mL at day 1 of week 1 followed by a dose of up to 4.0 ml of 108 PFU/mL at day 1 of
`
`week 4, and every 2 weeks thereafter Lmtil complete response, and an anti—CTLA—4 antibody
`
`administered intravenously at a dose of 3 mg/kg every 3 weeks for 4 infusions beginning after
`
`the third dose of the herpes simplex virus.
`
`In a related embodiment the anti—CTLA—4
`
`antibody is ipilimumab.
`
`In another embodiment the herpes simplex virus is talimogene
`
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`laherparepvec.
`
`The invention provides a kit comprising a herpes simplex virus lacking functional
`
`ICP34.5 genes, lacking a functional ICP47 gene and comprises a gene encoding human GM-
`
`CSF and a package insert or label with directions to treat stages IIIb to IV melanoma by using
`
`a combination of the herpes simplex virus and an immune checkpoint inhibitor.
`
`In one
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`embodiment
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`the immune checkpoint inhibitor is an anti-CTLA—4 antibody.
`
`In another
`
`embodiment
`
`the anti—CTLA—4 antibody is tremelimumab.
`
`In another embodiment
`
`the
`
`checkpoint inhibitor is a PDl blocker.
`
`In another embodiment the checkpoint inhibitor is a
`
`PD—Ll blocker.
`
`In another embodiment the checkpoint inhibitor is an anti-PD-Ll antibody.
`
`In another embodiment
`
`the checkpoint
`
`inhibitor is an anti—PDl antibody.
`
`In another
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`embodiment the PD] blocker is nivolumab.
`
`In another embodiment the PD] blocker is
`
`lambrolizumab.
`
`In another embodiment
`
`the PD] blocker is nivolumab.
`
`In another
`
`embodiment the PD] blocker is CT—Ol 1. In another embodiment the PD—Ll blocker is AMP—
`
`224. In another embodiment the PD-Ll blocker is EMS-936559. In another embodiment the
`
`checkpoint inhibitor is a LAG—3 inhibitor.
`
`In another embodiment the LAG-3 inhibitor is
`
`IMP321.
`
`In another embodiment the checkpoint inhibitor is a B7-H3 inhibitor.
`
`In another
`
`embodiment,
`
`the B7—H3 inhibitor is MGA271.
`
`In another embodiment the checkpoint
`
`inhibitor is a B7-H4 inhibitor.
`
`In another embodiment the checkpoint inhibitor is a TIM3
`
`inhibitor.
`
`In another embodiment the directions to treat stages IIIb to IV melanoma comprise
`
`instructions to administer to a patient with stages IIIb to IV melanoma a herpes simplex virus
`
`administered by intratumoral injection into injectable cutaneous, subcutaneous, and nodal
`
`tumors at a dose of up to 4.0 ml of 106 PFU/mL at day l of week 1 followed by a dose of up
`
`to 4.0 ml of 108 PFU/mL at day l of week 4, and every 2 weeks thereafter until complete
`
`response, and an anti-CTLA—4 antibody administered intravenously at a dose of 3 mg/kg
`
`every 3 weeks for 4 infusions beginning after the third dose of the herpes simplex virus.
`
`In a
`
`related embodiment the anti—CTLA—4 antibody is ipilimumab.
`
`In another embodiment the
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`herpes simplex virus is talimogene laherparepvec.
`
`In a related embodiment is a method of
`
`manufacturing the kit as described above.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The invention provides a method for the treatment of melanoma comprising
`
`administering to a patient with, stages IIIb to IV melanoma, an effective amount of an
`
`immune checkpoint inhibitor and a herpes simplex virus, wherein the herpes simplex virus
`
`lacks functional ICP34.5 genes, lacks a functional ICP47 gene and comprises a gene encoding
`
`human granulocyte macrophage colony stimulating factor (GM—CSF). Tumor cells are
`
`transfected by direct injection of the virus into accessible tumor lesions where the virus
`
`replicates in the tumor cells, bringing about tumor cell necrosis and the liberation of tumor
`
`antigens. Local expression of human GM—CSF induces local and distant immunological
`
`responses to the tumor antigens at both the injected and distant tumor deposits.
`
`CTLA—4 is an immune checkpoint molecule that down-regulates pathways of T-cell
`
`activation. CTLA-4 is a negative regulator of T—cell activation. Blockade of CTLA-4 has
`
`been shown to augment T-cell activation and proliferation. The combination of the herpes
`
`simplex virus and the anti—CTLA—4 antibody is intended to enhance T—cell activation through
`
`two different mechanisms in order to augment the anti—tumor immune response to tumor
`
`antigen released following the lytic replication of the virus in the tumor. Therefore, the
`
`combination of the herpes simplex virus and the anti—CTLA—4 antibody may enhance the
`
`destruction of the injected and un—injected/distal tumors, improve overall tumor response, and
`
`extend overall survival, in particular where the extension of overall survival is compared to
`
`that obtained using an anti—CTLA—4 antibody alone.
`
`As used herein, the term “immune checkpoint inhibitor” refers to molecules that
`
`totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
`
`Checkpoint proteins regulate T-cell activation or function. Numerous checkpoint proteins are
`
`known, such as CTLA-4 and its ligands CD80 and CD86; and PD] with its ligands PDLl and
`
`PDL2 (Pardoll, Nature Reviews Cancer 12: 252—264, 2012). These proteins are responsible
`
`for co-stimulatory or inhibitory interactions of T—cell responses. Immune checkpoint proteins
`
`regulate and maintain self-tolerance and the duration and amplitude of physiological immune
`
`responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.
`
`As used herein, the term “antibody” includes reference to both glyeosylated and non-
`
`glycosylated immunoglobulins of any isotype or subclass or to an antigen—binding region
`
`thereof that competes with the intact antibody for specific binding, unless otherwise specified,
`
`including monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies,
`
`synthetic antibodies, antibody mimetics, chimeric antibodies, humanized antibodies, human
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`antibodies,
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`antibody fusions, antibody conjugates,
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`single chain antibodies,
`
`antibody
`
`derivatives, antibody analogues and fragments thereof, respectively. Also included are
`
`immunological fragments of an antibody (e.g., a Fab, a Fab’, a F(ab’)2, or a scFv), irrespective
`
`of whether such antibodies are produced, in whole or in part, via immunization, through
`
`recombinant technology, by way of in vitro synthetic means, or otherwise. Thus, the term
`
`“antibody” is inclusive of those that are prepared, expressed, created or
`
`isolated by
`
`recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is
`
`transgenic for human immunoglobulin genes or a hybridoma prepared therefrom,
`
`(b)
`
`antibodies isolated from a host cell
`
`transfected to express the antibody, e.g.,
`
`from a
`
`transfectoma, (c) antibodies isolated from a recombinant, combinatorial antibody library, and
`
`((1) antibodies prepared, expressed, created or isolated by any other means that involve
`
`splicing of immunoglobulin gene sequences to other DNA sequences. Such antibodies have
`
`variable and constant regions derived from germline immunoglobulin sequences of two
`
`distinct species of animals.
`
`ln certain embodiments, however, such antibodies can be
`
`subjected to in vitro mutagenesis (or, when an animal transgenic for human immunoglobulin
`
`sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH
`
`and VL regions of the antibodies are sequences that, while derived from and related to the
`
`germline VH and VL sequences of a particular species (e. g., human), may not naturally exist
`
`within that species’ antibody germline repertoire in vivo. Unless otherwise indicated, the term
`
`“antibody” includes, in addition to antibodies comprising two full-length heavy chains and
`
`two filll—length light chains, derivatives, variants, fragments, and muteins thereof.
`
`In some
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`instances “antibody” may include fewer chains such as antibodies naturally occurring in
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`camelids which may comprise only heavy chains.
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`As used herein, the terms "patien ," or “subject” are used interchangeably and mean a
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`mammal, including, but not limited to, a human or non-human mammal, such as a bovine,
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`equine, canine, ovine, or feline. Preferably, the patient is a human.
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`As used herein, “objective response rate” is the incidence rate of either a confirmed
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`complete response or partial response per the modified Immune-Related Response Criteria
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`(irRC) (Wolchok et al, Clin Cancer Res, 15(23):7412-7420, 2009) incorporated herein in its
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`entirety.
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`As used herein, “time to response” refers to the time from treatment to the date of the
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`first confirmed objective response, per the modified irRC.
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`As used herein, “duration of response” is the time from first confirmed objective
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`response to confirmed disease progression per the modified irRC or death, whichever occurs
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`As used herein, “progression free survival” is the time from treatment to the date of
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`first of confirmed disease progression per modified irRC criteria.
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`As used herein, ”survival” refers to the patient remaining alive, and includes overall
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`survival as well as progression free survival.
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`1-year survival rate and 2—year survival rate
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`refers to the K—M estimate of the proportion of subjects alive at 12 month or 24 months.
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`By "extending survival" is meant increasing overall survival and/or progression free
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`survival in a treated patient relative to a control treatment protocol, such as treatment with
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`only ipilimumab. Survival is monitored for at least about one month, two months, four
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`months, six months, nine months, or at least about 1 year, or at least about 2 years, or at least
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`about 3 years, or at least about 4 years, or at least about 5 years, or at least about 10 years,
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`etc., following the initiation of treatment or following the initial diagnosis.
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`By ”reduce or inhibit” is meant the ability to cause an overall decrease of 20%, 30%,
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`40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. Reduce or inhibit can refer to
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`the symptoms of the disorder being treated, the presence or size of metastases, or the size of
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`the primary tumor.
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`For the methods of the invention, the term "instructing" a patient means providing
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`directions for applicable therapy, medication, treatment, treatment regimens, and the like, by
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`any means, but preferably in writing. Instructing can be in the form of prescribing a course of
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`treatment, or can be in the form of package inserts or other written promotional material.
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`For the methods of the invention, the term "promoting" means offering, advertising,
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`selling, or describing a particular drug, combination of drugs, or treatment modality, by any
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`means, including writing, such as in the form of package inserts. Promoting herein refers to
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`promotion of therapeutic agent(s), such as a herpes simplex virus, wherein the herpes simplex
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`virus lacks functional lCP34.5 genes, lacks a functional lCP47 gene and comprises a gene
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`encoding human GM-CSF, for an indication, such as melanoma treatment, where such
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`promoting is authorized by the Food and Drug Administration (FDA) as having been
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`demonstrated to be associated with statistically significant therapeutic efficacy and acceptable
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`safety in a population of subjects. Promotion also includes the combination of a herpes
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`simplex virus, wherein the herpes simplex virus lacks functional ICP34.5 genes,
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`lacks a
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`functional ICP47 gene and comprises a gene encoding human GM—CSF in combination with
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`an immune checkpoint inhibitor for an indication, such as melanoma treatment.
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`The term “marketing” is used herein to describe the promotion, selling or distribution
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`of a product (e.g., drug). Marketing specifically includes packaging, advertising and any
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`business activity with the purpose of commercializing a product.
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`The invention provides a herpes simplex virus (HSV) which lacks functional ICP34.5
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`genes, lacks a functional ICP47 gene and comprises a gene encoding human GM—CSF. In one
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`embodiment the herpes simplex virus is HSV-1. The ICP34.5 gene is located in the terminal
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`repeats of the long region of HSV and therefore there are two copies per genome. Previous
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`studies have shown that functional deletion of the neurovirulence gene, ICP34.5, renders the
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`virus avirulent. The ICP47 gene is located in the unique short region of HSV. The ICP47
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`gene product interacts with the transporter associated with antigen processing (TAPl and
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`TAP2) and blocks antigen processing via MHC class I molecules. Deletion of the ICP47
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`gene allows greater antigen processing within infected cells and is intended to result in a
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`concomitant increase in the immune response to infected cells. GM-CSF is a cytokine known
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`to be involved in the stimulation of immune responses. Using homologous recombination
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`with plasmid DNA, heterologous genes, such as that encoding human GM-CSF, can be
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`inserted into the I-ISV viral genome, and viral genes, such as ICP34.5 and ICP47, can be
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`functionally deleted.
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`In one embodiment,
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`the herpes
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`simplex Virus
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`is
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`talimogene
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`laherparepvec.
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`Talimogene laherparepvec, HSV—l [strain JS1] ICP34.5—/ICP47—/hGM—CSF, (previously
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`known as OncoVEXGM'CSF),
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`is an intratumorally delivered oncolytic immunotherapy
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`comprising an immune-enhanced HSV-1 that selectively replicates in solid tumors.
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`(Lui et
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`a1., Gene Therapy,
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`10:292—303, 2003; US Patent No. 7,223,593 and US Patent No.
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`7,537,924). The HSV-1 was derived from Strain JS1 as deposited at the European collection
`
`of cell cultures (ECAAC) under accession number 01010209.
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`In talimogene laherparepvec,
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`the HSV—1 viral genes encoding ICP34.5 have been functionally deleted. Functional deletion
`
`of ICP34.5, which acts as a Virulence factor during HSV infection, limits replication in non-
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`dividing cells and renders the virus non-pathogenic. The safety of ICP34.5-functionally
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`deleted HSV has been shown in multiple clinical studies (MacKie ct al, Lancet 357: 525-526,
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`2001; Markert et a1, Gene Ther 7: 867—874, 2000; Rampling et al, Gene Ther 7:859-866,
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`2000; Sundaresan et al, J. Virol 74: 3822-3841, 2000; Hunter et al, J Virol Aug; 73(8): 6319-
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`6326, 1999).
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`In addition,
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`ICP47 (which blocks Viral antigen presentation to major
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`histocompatibility complex class I and II molecules) has been functionally deleted from
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`talimogene laherparepvec. Functional deletion of ICP47 also leads to earlier expression of
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`US11, a gene that promotes virus growth in tumor cells without decreasing tumor selectivity.
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`The coding sequence for human GM—CSF, a cytokine involved in the stimulation of immune
`
`responses, has been inserted into the viral genome of talimogene laherparepvec. The insertion
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`of the gene encoding human GM—CSF is such that it replaces nearly all of the ICP34.5 gene,
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`ensuring that any potential recombination event between talimogene laherparepvec and wild—
`
`type virus could only result in a disabled, non-pathogenic virus and could not result in the
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`generation of wild-type Virus carrying the gene for human GM—CSF. The HSV thymidine
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`kinase (TK) gene remains intact
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`in talimogene laherparepvec, which renders the Virus
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`sensitive to anti—viral agents such as acyclovir. Therefore, acyclovir can be used to block
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`talimogene laherparepvec replication, if necessary.
`
`Talimogene laherparepvec produces a direct oncolytic effect by replication of the Virus in
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`the tumor, and induction of an anti—tumor immune response enhanced by the local expression
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`of GM—CSF. Since melanoma is a disseminated disease, this dual activity is beneficial as a
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`therapeutic treatment. The intended clinical effects include the destruction of injected tumors,
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`the destruction of local,
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`locoregional, and distant uninjected tumors, a reduction in the
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`deVelopment of new metastases, a reduction in the rate of overall progression and of the
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`relapse rate following the treatment of initially present disease, and prolonged overall
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`survival.
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`Talimogene laherparepvec has been tested for efficacy in a variety of in vitro (cell
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`line) and in viva murine tumor models and has been shown to eradicate tumors or
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`substantially inhibit their growth at doses comparable to those used in clinical studies.
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`Nonclinical evaluation has also confirmed that GM-CSF enhances the immune response
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`generated, enhancing both injected and uninj ected tumor responses, and that increased surface
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`levels of MHC class I molecules result
`
`from the deletion of ICP47.
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`Talimogene
`
`laherparepvec has been injected into normal and tumor—bearing mice to assess its safety.
`
`In
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`general, the virus has been well tolerated, and doses up to 1 x 108 PFU/dose have given no
`
`indication of any safety concerns.
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`(See, for example, Liu et al., Gene Ther 10: 292—303,
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`2003)
`
`Clinical studies have been or are being conducted in several advanced tumor types
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`(advanced solid tumors, melanoma, squamous cell cancer of the head and neck, and
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`pancreatic cancer), with over 400 subjects treated with talimogene laherparepvec (see, for
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`example, Hu et al., Clin Can Res 12: 6737-6747, 2006; Harrington et al., J Clin Oncol.
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`27(15a):abstract 6018, 2009; Kaufman et al., Ann Surgic Oncol. 17: 718-730, 2010; Kaufman
`
`and Bines, Future Oncol. 6(6): 941-949, 2010). Clinical data indicate that talimogene
`
`laherparepvec has the potential to provide overall clinical benefit to patients with advanced
`
`melanoma.
`
`In particular, a high rate of complete response was achieved in stage IIIC to IV