WO2015013579A1 | 2015-01-29 | |||
WO2019073296A1 | 2019-04-18 | |||
WO2020072948A1 | 2020-04-09 | |||
WO2020208612A1 | 2020-10-15 |
TILLETT DANIEL: "Race Initiates FTO Melanoma Preclinical Study", RACE ONCOLOGY ASX ANNOUNCEMENT, 19 March 2021 (2021-03-19), XP093123813, Retrieved from the Internet
ANONYMOUS: "Melanoma Treatment (PDQ®)-Patient Version", NATIONAL CANCER INSTITUTE, 1 March 2021 (2021-03-01), XP093123815, Retrieved from the Internet
Claims: 1 . A method of treating a patient with melanoma, said method comprising administering to said patient a therapeutically effective amount of an immune checkpoint inhibitor and a therapeutically effective amount of at least a second agent comprising bisantrene or a derivative thereof, or a pharmaceutically acceptable salt of bisantrene or derivative thereof. 2. The method of claim 1 wherein said immune checkpoint inhibitor inhibits: PD-1 ; PD-L1 ; CTLA-4; LAG3 or a combination of at least any two of these targets. 3. The method of claim 1 , wherein the at least one immune checkpoint inhibitor is selected from the group consisting of: (a) ipilimumab (b) nivolumab (c) nivolumab-relatlimab (d) pembrolizumab (e) cemiplimab (f) dostarlimab 4. The method of claim 1 , wherein said at least one immune checkpoint inhibitor is selected from the group consisting of: (a) nivolumab (b) pembrolizumab 5. The method of any one of claims 1 to 4, wherein said second agent is bisantrene or a pharmaceutically acceptable salt thereof. 6. The method of any one of claims 1 to 5 which comprises administering to said patient a therapeutically effective amount of one immune checkpoint inhibitor and a therapeutically effective amount of bisantrene or a pharmaceutically acceptable salt thereof. 7. The method of any one of claims 1 to 6 which comprises treatment of melanoma, optionally immune checkpoint inhibitor resistant melanoma. 8. The method of any one of claims 1 to 7, further comprising administration of at least one additional therapeutic agent for the treatment of melanoma. 9. The method of claim 8, wherein the additional therapeutic agent comprises an immunomodulator, protein kinase inhibitor or a combination of immunomodulatory(s) and protein kinase inhibitor(s). 10. The method of claim 9, wherein the at least one additional therapeutic agent is selected from the group consisting of: (a) binimetinib (b) cobimetinib (c) dabrafenib (d) encorafenib (e) trametinib (f) vemurafenib (g) interleukin-2; and (h) proleukin. 11. The method of any one of claims 1 to 10 comprising administering said at least one immune checkpoint inhibitor to said patient prior to, simultaneously with, or after administration of said second agent to said patient. 12. The method of any one of claims 1 to 10, wherein said at least one immune checkpoint inhibitor and the second agent are administered to said patient at the same time, optionally in a single composition. 13. The method of any one of claims 1 to 12, wherein the dose of said at least one immune checkpoint inhibitor is at least 20% lower than the dose required of said at least one immune checkpoint inhibitor agent when administered without said second agent to achieve the same targeted outcome. 14. A pharmaceutical composition for the treatment of melanoma comprising at least one immune checkpoint inhibitor and a second agent comprising bisantrene or a derivative thereof, or a pharmaceutically acceptable salt of bisantrene or derivative thereof. 15. The composition of claim 14, wherein said immune checkpoint inhibitor inhibits one or more of: PD-1 ; PD-L1 ; CTLA-4; LAG3 or a combination of at least any two of these targets. 16. The composition of claim 14, wherein said at least one immune checkpoint inhibitor is selected from the group consisting of: (a) ipilimumab (b) nivolumab (c) nivolumab-relatlimab (d) pembrolizumab (e) cemiplimab (f) dostarlimab 17. The composition of claim 14, wherein said at least one immune checkpoint inhibitor is selected from the group consisting of: (a) nivolumab (b) pembrolizumab 18. The composition of any one of claims 14 to 17, further comprising at least one additional therapeutic agent for the treatment of melanoma. 19. The composition of claim 18, wherein the additional therapeutic agent comprises an immunomodulator, protein kinase inhibitor or a combination of immunomodulator(s) and protein kinase inhibitor(s). 20. The composition of claim 19, wherein the at least one additional therapeutic agent is selected from the group consisting of: (a) binimetinib (b) cobimetinib (c) dabrafenib (d) encorafenib (e) trametinib (f) vemurafenib (g) interleukin-2; and (h) proleukin. 21. The composition of any one of claims 14 to 20, wherein said second agent is bisantrene or a pharmaceutically acceptable salt thereof. 22. The composition of any one of claims 14 to 20 which comprises a therapeutically effective amount of one immune checkpoint inhibitor and a therapeutically effective amount of bisantrene or a pharmaceutically acceptable salt thereof. 23. The composition of any one of claims 14 to 22 for the treatment of melanoma, optionally immune checkpoint inhibitor resistant melanoma. 24. Use of a composition according to any one of claims 14 to 23 for the manufacture of a medicament for the treatment of melanoma in a patient. 25. The use of claim 24, wherein said medicament is for the treatment of melanoma, optionally immune checkpoint inhibitor resistant melanoma. 26. The use of claim 24 or claim 25, wherein said medicament comprises one immune checkpoint inhibitor and bisantrene or a pharmaceutically acceptable salt thereof. 27. A kit for the treatment of melanoma, said kit comprising at least one immune checkpoint inhibitor and at least a second agent comprising bisantrene or a derivative thereof, or a pharmaceutically acceptable salt of bisantrene or derivative thereof. 28. The kit of claim 27, wherein said immune checkpoint inhibitor inhibits one or more of: PD-1 ; PD-L1 ; CTLA-4; LAG3 or a combination of at least any two of these targets. 29. The kit of claim 27, wherein said at least one immune checkpoint inhibitor is selected from the group consisting of: (a) ipilimumab (b) nivolumab (c) nivolumab-relatlimab (d) pembrolizumab (e) cemiplimab (f) dostarlimab 30. The kit of any one of claims 27 to 29, wherein said second agent is bisantrene or a pharmaceutically acceptable salt thereof. 31 . The kit of any one of claims 27 to 29 which comprises one immune checkpoint inhibitor and bisantrene or a pharmaceutically acceptable salt thereof. 32. The kit of any one of claims 27 to 31 , further comprising at least one additional therapeutic agent for the treatment of melanoma, optionally wherein said additional therapeutic agent comprises an immunomodulator, protein kinase inhibitor or a combination of immunomodulator(s) and protein kinase inhibitor(s). 33. The kit of any one of claims 27 to 32 for the treatment of melanoma, optionally immune checkpoint inhibitor resistant melanoma. |
[0050] Several clinical trials have investigated the pharmacokinetics of bisantrene in humans, to one trial of patients given a 90 min infusion at 260 mg/m 2 a biphasic elimination with an initial half-life of 65 ± 15 min, a terminal half -life of 1142 ± 226 min, and a steady state volume of distribution (Vdss) of 1845 L/m 2 . Plasma clearance in this trial was 735 mL/min/m2, with 11.3% of the administered dose excreted unchanged in the urine in 24 h. In another trial , doses of 80-250 mg/m2 were assessed, and the initial and terminal half-lives were 0.6 h and 24.7 h, respectively, with a clearance of 1045.5 ± 51.0 mL/kg/h and a calculated volume of distribution of 42.1 ± 5.9 L/kg. In this study only 3.4 ± 1.1% of the administered dose was found in the urine over 96 h. to three other single dose studies triphasic elimination was reported, one with «, p, and y of 3.44 min, 1.33 h and 26.13 h, respectively, another was 3 min, 1 h, and 8 h respectively, and the last revealed clearances of 0.1 h, 1.9 h and 43.9 h, respectively. In one report a large volume of distribution (687 L/m2) was interpreted as tissue sequestration of the drug with a subsequent depot effect, in a 72 h infusion study, a plasma concentration of 12 ± 6 ng/mL was observed at a dose of 56 mg/m 2 , while a dose of 260 mg/m 2 resulted in a plasma concentration of 55 ± 8 ng/mL. in this trial plasma clearance was 1306 ± 179 mL/min/m 2 with urinary excretion of 4.6% of the dose in 24 h. Finally, in another study, a 5-day schedule of 60 min infusions revealed a tl4 a and p of 0.9 and 9.7 h, respectively with 7.1% of the dose excreted in the urine.
[0051] The structure of bisantrene dihydrochloride is shown in Formula (I) [0052] Bisantrene dihydrochloride is a tricyclic aromatic compound with the chemical name, 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2- yl)hydrazine] dihydrochloride. The molecular formula of bisantrene dihydrochloride is C22H22N8 ^ 2HCl and the molecular weight, 471.4 g/mol. The alkylimidazole side chains are very basic and, at physiologic pH, are positively charged. This is believed to facilitate electrostatic attractions to negatively charged ribose phosphate groups in DNA. [0053] Bisantrene is typically administered intravenously, either centrally or peripherally. [0054] Various formulations suitable for use in the administration of bisantrene or derivatives or analogs thereof are known in the art. United States Patent No. 4,784,845 to Desai et al. discloses a composition of matter for delivery of a hydrophobic drug (i.e., bisantrene or a derivative or analog thereof) comprising: (i) the hydrophobic drug; (ii) an oleaginous vehicle or oil phase that is substantially free of butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT); (iii) a co- surfactant or emulsifier; (iv) a co-surfactant or auxiliary emulsifier; and (v) benzyl alcohol as a co-solvent. United States Patent No.4,816,247 by Desai et al. discloses a composition of matter for delivery by intravenous, intramuscular, or intraarticular routes of hydrophobic drugs (such as bisantrene or a derivative or analog thereof) comprising: (i) the hydrophobic drug; (ii) a pharmaceutically acceptable oleaginous vehicle or oil selected from the group consisting of: (a) naturally occurring vegetable oils and (b) semisynthetic mono-, di-, and triglycerides, wherein the oleaginous vehicle or oil is free of BHT or BHA; (iii) a surfactant or emulsifier; (iv) a co-surfactant or emulsifier; (v) an ion-pair former selected from C6-C20 saturated or unsaturated aliphatic acids when the hydrophobic drug is basic and a pharmaceutically acceptable aromatic amine when the hydrophobic drug is acidic; and (vi) water. United States Patent No.5,000,886 to Lawter et al. and United States Patent No. 5,143,661 to Lawter et al. disclose compositions for delivery of pharmaceutical agents such as bisantrene or a derivative or analog thereof comprising a microcapsule, wherein the microcapsule includes a hardening agent that is a volatile silicone fluid. United States Patent No.5,070,082 to Murdock et al., United States Patent No.5,077,282 to Murdock et al., and United States Patent No.5,077,283 to Murdock et al. disclose prodrug forms of poorly soluble hydrophobic drugs, including bisantrene and derivatives and analogs, that are salts of a phosphoramidic acid. United States Patent No.5,116,827 to Murdock et al. and United States Patent No. 5,212,291 to Murdock et al. disclose prodrug forms of poorly soluble hydrophobic drugs, including bisantrene and derivatives and analogs, that are quinolinecarboxylic acid derivatives. United States Patent No.5,378,456 to Tsou includes compositions containing an anthracene antitumor agent, such as bisantrene or a derivative or analog thereof, in which the bisantrene or derivative or analog thereof is conjugated to or admixed with a divinyl ether-maleic acid (MVE) copolymer. United States Patent No.5,609,867 to Tsou discloses polymeric 1,4-bis derivatives of bisantrene and copolymers of bisantrene and another monomer, such as a dianhydride. [0055] Methods and compositions described herein can use a derivative or analog of bisantrene in place of bisantrene itself. Derivatives and analogs of bisantrene are described in in US Patents 10,500,19 and 10,548,876, by Garner et al. Methods for treating melanoma [0056] Surprisingly, the present studies have shown that immune checkpoint inhibitors and bisantrene (or pharmaceutically acceptable salts thereof) show beneficial antitumor effects in a mouse model of melanoma. Furthermore, bisantrene was able to increase the number of antitumorigenic M1 macrophages when combined with a murine PD-1 inhibitor relative to mice treated with the PD-1 inhibitor alone. In addition, bisantrene/Anti-PD-1 combination produced a significant decrease in protumorigenic M2b macrophages in tumours relative to PD-1 inhibition alone, indicating that bisantrene is able to elicit an antitumor immunophenotype through selective effects on myeloid cell populations. Bisantrene/anti-PD-1 combinations also potently downregulated the expression of CTLA4, a validated immunosuppressive checkpoint target, in CD8 + T-cells, priming these key mediators of antitumor immunity for effective destruction of tumor cells. These effects offer an exciting novel approach for the enhancement of immune checkpoint therapy through the modulation of myeloid cell disposition and immunosuppressive lymphocyte signatures in melanoma patients. It is contemplated that derivatives of bisantrene possessing substantially the same activity will also act enhance with antitumor immune stimulation when combined with checkpoint inhibitors in methods and compositions according to the present invention. [0057] As of 2022 the FDA has approved three PD-1 inhibitors (pembrolizumab [Keytruda], nivolumab [Opdivo], ostarlimab [Jemperli], and cemiplimab [Libtayo]), one PD-L1 inhibitor/LAG3 inhibitor combination (nivolumab-relatlimab), and one CTLA-4 inhibitor (ipilimumab) for use. Other PD-1/ PD-L1 immune checkpoint inhibitors of potential consideration include atezolizumab, bevacizumab, dostarlimab, and durvalumab. [0058] Thus, one aspect of the invention provides a method of treating a patient with melanoma, especially immune checkpoint inhibitor resistant melanoma, said method comprising administering to said patient a therapeutically effective amount of an immune checkpoint inhibitor, such as a PD-1 inhibitor, and a therapeutically effective amount of at least a second agent comprising bisantrene or a derivative thereof, or a pharmaceutically acceptable salt of bisantrene or derivative thereof. [0059] The immune checkpoint inhibitor may inhibit one or more potential immune checkpoint targets associated with melanoma. According to certain embodiments, the immune checkpoint inhibitor or inhibitor combination inhibits PD-1, PD-L1, CTLA- 4, LAG3 or a combination of at least any two of these targets. According to certain embodiments, the immune checkpoint inhibitor inhibits at least one or more of PD-1, PD-L1, LAG3. According to certain embodiments, the immune checkpoint inhibitor inhibits at least one or more of PD-1 or PD-L1. According to certain embodiments, the immune checkpoint inhibitor inhibits PD-1. [0060] According to certain embodiments the at least one immune checkpoint inhibitor or inhibitor combination is selected from the group consisting of: ipilimumab; nivolumab; cemiplimab; nivolumab-relatlimab; and pembrolizumab. [0061] According to specific embodiments, the at least one immune checkpoint inhibitor is selected from the group consisting of: nivolumab; cemiplimab; nivolumab- relatlimab; and pembrolizumab. [0062] According to specific embodiments of the present invention, the at least one immune checkpoint inhibitor is selected from the group consisting of nivolumab, cemiplimab or pembrolizumab. [0063] According to specific embodiments of the present invention, the second agent is bisantrene or a pharmaceutically acceptable salt thereof. [0064] According to certain embodiments, the bisantrene can be administered as a drug compound or as a component of a pharmaceutical composition, as discussed further below. [0065] According to certain specific embodiments, the method comprises administering to said patient a therapeutically effective amount of one immune checkpoint inhibitor and a therapeutically effective amount of bisantrene or a pharmaceutically acceptable salt thereof. [0066] The pharmaceutical compositions and medicaments of the present invention may be administered to a subject by standard enteral or parenteral routes, including, but not limited to, injection (such as intravenous, subcutaneous, intramuscular, bolus, etc.), or by, for example, topical, oral, sublingual, nasal, pulmonary, otic, rectal or vaginal administration routes. In some embodiments, pharmaceutical compositions according to the invention may be administered to a subject by themselves or in combination with other pharmaceutical composition(s). In the latter case, the administration may be simultaneous or sequential, or administration of the pharmaceutical composition(s) may be independent of one another. [0067] In certain embodiments bisantrene (or derivative, or pharmaceutically acceptable salt of either) is administered intravenously, either centrally or peripherally, including by intramuscular, subcutaneous and/or intradermal injection. [0068] In general, the pharmaceutical compositions and medicaments of the present invention can be administered in a manner compatible with the route of administration and physical characteristics of the subject (including health status) and in such a way that the desired effect(s) are induced (i.e. therapeutically effective and/or preventative). For example, the appropriate dosage may depend on a variety of factors including, but not limited to, a subject’s physical characteristics (e.g. age, weight, sex), whether the composition or medicament is being used as single agent, the progression (i.e. pathological state) of the disease or disorder being treated, and other factors readily apparent to those of ordinary skill in the art. [0069] Suitable dosages, dosage frequencies, dosage durations, and routes of administration for chemotherapeutic agents are known in the art. As suggested by Figure 5, bisantrene, derivatives of bisantrene, or pharmaceutically acceptable salts of either can be administered in the same pharmaceutical composition as an immune checkpoint inhibitor, in a separate composition as, but simultaneously with the immune checkpoint inhibitor, or at a different time. If the bisantrene, derivative of bisantrene, or pharmaceutically acceptable salt of bisantrene or derivative of bisantrene, is administered at a different time than the immune checkpoint inhibitor, it can either be administered before or after the immune checkpoint inhibitor and/or at different timings, being administered according to different timing and/or frequency regimes. One of ordinary skill in the art can determine a suitable schedule for administration based on variables such as the age, weight, and sex of the subject, the susceptibility of the subject to side effects of the active agents, genetic markers, the dose of active agent(s), the subjects history with prior active agent(s), and other pharmacokinetic parameters such as heart, liver or kidney function. [0070] Figure 5 shows a prophetic example of a bisantrene/immune checkpoint inhibitor trial to overcome treatment resistance in a model of melanoma. [0071] The methods and compositions provided herein enable a subject to receive a therapy more frequently without having the dosage regimen significantly altered by the risk of side-effects, such as cardiotoxicity. The dose(s) of a immune checkpoint inhibitor and bisantrene, derivative of bisantrene, or pharmaceutically acceptable salt of bisantrene or derivative of bisantrene, may be administered to a subject in one or more doses per day. In some cases, the daily dose of the chemotherapeutic agent may be administered together with bisantrene, derivative of bisantrene, or pharmaceutically acceptable salt of either, in a single dose. [0072] The pharmaceutical compositions described herein may be administered to a patient one or more times per day. In some cases, the pharmaceutical composition may be administered to a patient once per day. In some cases, the pharmaceutical composition may be administered to a patient at least 2 times, 3 times, 4 times 5 times, or 6 times per day. For example, a pharmaceutical composition may be administered to a patient 3 times per day. [0073] In methods described herein, suitable dosages of bisantrene (or a derivative of bisantrene, or a pharmaceutically acceptable salt of either) can be determined by one of ordinary skill in the art. The selected dosage level depends upon a variety of pharmacokinetic factors including the amount of active agent(s) being administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the severity of the condition, other health considerations affecting the subject, and the status of liver and kidney function of the subject. It also depends on the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular therapeutic agent employed, as well as the age, weight, condition, general health and prior medical history of the subject being treated, and like factors. Methods for determining optimal dosages are described in the art, e.g., Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20 th ed., 2000, and Gilman et al., (Eds), (1990), “Goodman And Gilman's: The Pharmacological Bases of Therapeutics”, Pergamon Press. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. [0074] According to certain embodiments, administration of bisantrene is performed at a dosage of from about 0.1 mg/m 2 /day to about 400 mg/m 2 /day, such as from about 0.2 mg/m 2 /day to about 300 mg/m 2 /day, from about 0.5 mg/m 2 /day to about 200 mg/m 2 /day, from about 0.5 mg/m 2 /day to about 100 mg/m 2 /day, from about 0.5 mg/m 2 /day to about 50 mg/m 2 /day, from about 0.5 mg/m 2 /day to about 30 mg/m 2 /day, from about 0.5 mg/m 2 /day to about 20 mg/m 2 /day, from about 1.0 mg/m 2 /day to about 10 mg/m 2 /day, from about 1.0 mg/m 2 /day to about 8 mg/m 2 /day, about 1 mg/m 2 /day, about 2 mg/m 2 /day, about 3 mg/m 2 /day, about 4 mg/m 2 /day, about 5 mg/m 2 /day, about 6 mg/m 2 /day, about 7 mg/m 2 /day, or about 10 mg/m 2 /day. In some embodiments, bisantrene is administered daily or weekly, once every two weeks, once every three weeks, once every four weeks, over a period of, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days or 63 days. In certain embodiments, bisantrene is administered once or multiple times over a period of 28 days, optionally once or multiple times daily or weekly, once every two weeks, once every three weeks, once every four weeks, at a dosage of about 20-50 mg/m 2 /28 days. Administration of pharmaceutically acceptable salts of bisantrene or derivatives or pharmaceutically acceptable salts thereof may be performed at similar dosage rates, adjusted for molar equivalence. [0075] Dosing regimens for immune checkpoint inhibitors will depend on the particular immune checkpoint inhibitor, and have been published for known immune checkpoint inhibitors, including for treatment of melanoma. In addition, suitable dosages of a given immune checkpoint inhibitor can be readily determined by one of ordinary skill in the art using known approaches and techniques as discussed above in relation to bisantrene. [0076] According to certain embodiments, and as a result of the beneficial biologic activity observed when bisantrene (or derivative of bisantrene, or a pharmaceutically acceptable salt of either) is administered with a immune checkpoint inhibitor, a therapeutic outcome may be achieved more effectively for a given dose rate for that immune checkpoint inhibitor. This biologic activity of the bisantrene (or derivative of bisantrene, or a pharmaceutically acceptable salt of either) may also allow for use, or expanded use of immune checkpoint inhibitor which at normal dosages may have deleterious side-effects, such as immune-related adverse events. [0077] Alternatively, when administered in combination with bisantrene (or derivative of bisantrene, or a pharmaceutically acceptable salt of either), the immune checkpoint inhibitor may be administered to a patient at a lower dosage than it would normally be administered, over a longer period while maintaining a comparable ongoing therapeutic outcome. This is particularly important for active agents with deleterious side-effects, such as immune-related adverse events. Thus, in certain embodiments of methods according to the present invention, when administered in combination with bisantrene (or derivative of bisantrene, or a pharmaceutically acceptable salt of either), the immune checkpoint inhibitor may be administered at a rate which is significantly lower than the recommended dosage rate for that immune checkpoint inhibitor when administered alone, such as at a rate which is at least 10%, 20%, 30%, 40%, 50%, 60% or 70% lower than the dosage rate for that immune checkpoint inhibitor when administered alone. Additional active agents [0078] Programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death 1 (PD-1) regulate the activation of immune cells. Checkpoint inhibitors can assist in suppressing this regulation, allowing immune cells to destroy tumors. Known checkpoint inhibitors include antibodies that target PD-1, PD-L1, CTLA4 and LAG3. [0079] In addition to immune checkpoint inhibitors, some studies have shown that immunomodulators such as cytokines that regulate immune cell maturation, growth and activation, including interleukin-2 (Aldesleukin/ Proleukin), interferon alpha-2a, interferon alpha-2b (and Peginterferon alpha-2b), and Granulocyte-macrophage colony-stimulating factor (GM-CSF) have also been approved for treatment of various cancers via immunostimulation. Interleukin-2 (or the recombinant human version Aldesleukin/ Proleukin) has been approved for the treatment of melanoma. [0080] Also in addition to immune checkpoint inhibitors, targeted therapeutic agents that have been FDA approved for treating melanoma include: binimetinib, cobimetinib, dabrafenib, encorafenib, trametinib, and vemurafenib. [0081] Thus, methods according to the present invention may further comprise administration of at least one additional therapeutic agent, such as immunomodulators, protein kinase inhibitors, or combinations of immunomodulators, protein kinase inhibitors for the treatment of melanoma. [0082] The protein kinase inhibitor may inhibit one or more potential protein kinase targets associated with melanoma. According to certain embodiments, the protein kinase inhibitor inhibits at least one or more of RAS, MEK and BRAF. According to certain embodiments, the protein kinase inhibitor inhibits BRAF. [0083] According to certain embodiments at least one protein kinase inhibitor is selected from the group consisting of: binimetinib, cobimetinib, dabrafenib, encorafenib, trametinib, and vemurafenib. [0084] According to specific embodiments at least one protein kinase inhibitor is selected from the group consisting of: binimetinib, cobimetinib and trametinib. [0085] According to more specific embodiments at least one protein kinase inhibitor is selected from the group consisting of: dabrafenib, encorafenib and vemurafenib. [0086] According to still more specific embodiments at least one protein kinase inhibitor is selected from the group consisting of: binimetinib, cobimetinib and vemurafenib. [0087] According to even more specific embodiments the protein kinase inhibitor is vemurafenib. [0088] According to certain embodiments the additional therapeutic agent is an immunomodulator selected from interleukin-2 (Aldesleukin/ Proleukin), interferon alpha-2a, interferon alpha-2b (and Peginterferon alpha-2b), and GM-CSF. According to certain embodiments the at least one additional therapeutic agent comprises interleukin-2 (Aldesleukin/ Proleukin). [0089] Suitable dosages, dosage frequencies, dosage durations, and routes of administration for these additional agents are known in the art. As suggested by Figure 5, these additional agents can either be administered simultaneously with the bisantrene or the derivative or analog of bisantrene, or at a different time than the bisantrene or the derivative or analog of bisantrene. If the additional agent is administered at a different time than the bisantrene or the derivative or analog of bisantrene, it can either be administered before or after the bisantrene or the derivative or analog of bisantrene and/or at different timings, being administered according to different timing and/or frequency regimes. Similarly, and independently of bisantrene considerations, these additional agents can either be administered simultaneously with the immune checkpoint inhibitor, or at a different time than the immune checkpoint inhibitor. If the additional agent is administered at a different time than the immune checkpoint inhibitor, it can either be administered before or after the immune checkpoint inhibitor and/or at different timings, being administered according to different timing and/or frequency regimes. One of ordinary skill in the art can determine a suitable schedule for administration based on variables such as the age, weight, and sex of the patient, the severity of the cancer, genetic markers such as further described below, and pharmacokinetic parameters such as liver and kidney function. Pharmaceutical compositions for the treatment of melanoma [0090] The present invention also provides pharmaceutical compositions for the treatment of melanoma comprising at least one immune checkpoint inhibitor, as described above, and a second agent comprising bisantrene or a derivative thereof, or a pharmaceutically acceptable salt of bisantrene or derivative thereof. As described above, the compositions of the invention may comprise an additional agent selected from immunomodulators, protein kinase inhibitors or combinations thereof. [0091] According to certain embodiments, the immune checkpoint inhibitor or inhibitor combination inhibits PD-1, PD-L1, CTLA-4, LAG3 or a combination of at least any two of these targets. According to certain embodiments, the immune checkpoint inhibitor inhibits at least one or more of PD-1, PD-L1 or CTLA-4. According to certain embodiments, the immune checkpoint inhibitor inhibits at least one or more of PD-1 or PD-L1. According to certain embodiments, the immune checkpoint inhibitor inhibits PD-1. [0092] According to certain embodiments the at least one immune checkpoint inhibitor or inhibitor combination is selected from the group consisting of: ipilimumab; nivolumab; nivolumab-relatlimab; cemiplimab; dostarlimab; and pembrolizumab. [0093] According to certain embodiments, the at least one immune checkpoint inhibitor is selected from the group consisting of: nivolumab; nivolumab-relatlimab; and pembrolizumab. [0094] According to specific embodiments of the present invention, the at least one immune checkpoint inhibitor is selected from the group consisting of nivolumab or pembrolizumab. [0095] According to specific embodiments of the present invention, the second agent is bisantrene or a pharmaceutically acceptable salt thereof. [0096] According to specific embodiments of the present invention, the composition may comprise a therapeutically effective amount of one immune checkpoint inhibitor and a therapeutically effective amount of bisantrene or a pharmaceutically acceptable salt thereof. [0097] Compositions according to the present invention may further comprise administration of at least one additional therapeutic agent for the treatment melanoma. [0098] According to certain embodiments the additional therapeutic agent is a checkpoint inhibitor or an immunomodulator such as those discussed above. According to certain embodiments the at least one additional therapeutic agent comprises a an immunomodulator selected from interleukin-2 (Aldesleukin/ Proleukin), interferon alpha-2a, interferon alpha-2b (and Peginterferon alpha-2b), and GM-CSF. According to certain embodiments the at least one additional therapeutic agent comprises interleukin-2 (Aldesleukin/ Proleukin). [0099] According to certain embodiments the additional therapeutic agent is at least one protein kinase inhibitor selected from the group consisting of: binimetinib, cobimetinib, dabrafenib, encorafenib, trametinib, and vemurafenib. According to specific embodiments the at least one protein kinase inhibitor is selected from the group consisting of: binimetinib, cobimetinib and trametinib. According to other specific embodiments at least one protein kinase inhibitor is selected from the group consisting of: dabrafenib, encorafenib and vemurafenib. According to still more specific embodiments at least one protein kinase inhibitor is selected from the group consisting of: binimetinib, cobimetinib and vemurafenib. According to even more specific embodiments the protein kinase inhibitor is vemurafenib. [0100] Compositions according to the present invention may be administered by any route, and in a form suitable for that route, as known in the art. Thus, compositions according to the present invention may be adapted for administration by enteral or parenteral routes, including by injection (such as intravenous, subcutaneous, intramuscular, bolus, etc.), or by, for example, topical, oral, sublingual, nasal, pulmonary, otic, rectal or vaginal administration routes. [0101] Typically, the pharmaceutical compositions described herein include at least one pharmaceutically acceptable carrier or excipient and/or diluents. For preparing the pharmaceutical compositions and medicaments, inert, pharmaceutically acceptable carriers can be either solid or liquid. Liquid form preparations include solutions, suspensions and emulsions, for example water or water-propylene glycol solutions for parenteral injection. Also included are solid form preparations, such as tablets, or amorphous or crystalline powders, including lyophilized preparations, that are intended to be converted, shortly before use, to liquid form preparations for either oral or injection administration. Such liquid forms include solutions, suspensions and emulsions. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in, for example, “Remington: The Science and Practice of Pharmacy”, Mack Publishing Co., 20 th ed., 2000, and Gilman et al., (Eds), (1990), “Goodman And Gilman's: The Pharmacological Bases of Therapeutics”, Pergamon Press. [0102] Pharmaceutically acceptable carriers and excipients include: (i) a liquid carrier; (ii) an isotonic agent; (iii) a wetting or emulsifying agent; (iv) a preservative; (v) a buffer; (vi) an acidifying agent; (vii) an antioxidant; (viii) an alkalinizing agent; (ix) a carrying agent; (x) a chelating agent; (xi) a coloring agent; (xii) a complexing agent; (xiii) a solvent; (xiv) a suspending and/or viscosity-increasing agent; (xv) an oil; (xvi) a penetration enhancer; (xvii) a polymer; (xviii) a stiffening agent; (xix) a protein; (xx) a carbohydrate; (xxi) a bulking agent; and (xxii) a lubricating agent. [0103] Other pharmaceutically acceptable carriers and excipients known in the art may be used. [0104] The carriers, diluents, excipients and adjuvants must be “acceptable” in terms of being compatible with the other ingredients of the composition or medicament, and are generally not deleterious to the subject thereof. Non-limiting examples of pharmaceutically acceptable carriers or diluents are demineralised or distilled water; saline solution; vegetable-based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil; sesame oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxylpropyl- methylcellulose; lower alkanols, for example ethanol or isopropanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1,3- butylene glycol or glycerin; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate; polyvinylpyrolidone; agar; gum tragacanth or gum acacia, and petroleum jelly. Typically, the carrier or carriers will form from about 10% to about 99.9% by weight of the composition, vaccine or medicament. [0105] For administration as an injectable solution or suspension, non-toxic parenterally acceptable diluents or carriers can include, Ringer’s solution, isotonic saline, phosphate buffered saline, ethanol and 1,2 propylene glycol. Methods for preparing parenterally administrable pharmaceutical compositions and medicaments are apparent to those of ordinary skill in the art, and are described in more detail in, for example, “Remington: The Science and Practice of Pharmacy”, Mack Publishing Co., 20 th ed., 2000, and Gilman et al., (Eds), (1990), “Goodman And Gilman's: The Pharmacological Bases of Therapeutics”, Pergamon Press. [0106] For oral administration, some examples of suitable carriers, diluents, excipients and adjuvants include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin. In addition these oral formulations may contain suitable flavouring and colourings agents. When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl stearate which delay disintegration. [0107] Solid forms for oral administration may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatine, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate. [0108] Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof. [0109] Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl- pyrrolidone, sodium alginate or acetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or- laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like. [0110] In certain embodiments, the pharmaceutical composition may comprise a liposome. A liposomal formulation suitable for bisantrene or a cardioprotective derivative thereof comprises small unilamellar or multilamellar liposomes of size range between 0.01 and 100 ^M, and between about 50-95% liposome-entrapped bisantrene, composed of hydrogenated soy phosphatidylcholine, distearoyl phosphatidylglycerol, and cholesterol of natural or synthetic origin lipids, in aqueous solution which can be reconstituted from a lyophilized form to an injectable liposome suspension. The composition is prepared by reconstituting a lyophilized bisantrene/liposome composition to a liposome concentrate, then diluting the concentrate for parenteral administration for the treatment of melanoma. [0111] In yet another embodiment, the pharmaceutical composition may comprise a complex with a beta-cyclodextrin. A liposomal formulation suitable for bisantrene, a therapeutically active derivative of bisantrene, or a pharmaceutically acceptable salt of bisantrene or derivative thereof, comprises a complex formed in aqueous solution which may be reconstituted from a lyophilized form to an injectable suspension. One such composition is prepared by reconstituting a lyophilized bisantrene/beta- cyclodextrin composition to a concentrate, then diluting the concentrate for parenteral administration. Beta-cyclodextrin complexes and methods for preparing such complexes are known in the art and are described in., for example, WO 2019/073296 by Rothman. [0112] Various formulations suitable for use in the administration of bisantrene, a therapeutically active derivative of bisantrene, or a pharmaceutically acceptable salt of bisantrene or derivative thereof, are known in the art. United States Patent No. 4,784,845 to Desai et al. discloses a composition for delivery of a hydrophobic drug (i.e., bisantrene or a cardioprotective derivative thereof) comprising: (i) the hydrophobic drug; (ii) an oleaginous vehicle or oil phase that is substantially free of butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT); (iii) a co- surfactant or emulsifier; (iv) a co-surfactant or auxiliary emulsifier; and (v) benzyl alcohol as a co-solvent. United States Patent No.4,816,247 by Desai et al. discloses a composition for delivery by intravenous, intramuscular, or intraarticular routes of hydrophobic drugs (such as bisantrene or a cardioprotective derivative or analog thereof) comprising: (i) the hydrophobic drug; (ii) a pharmaceutically acceptable oleaginous vehicle or oil selected from the group consisting of: (a) naturally occurring vegetable oils and (b) semisynthetic mono-, di-, and triglycerides, wherein the oleaginous vehicle or oil is free of BHT or BHA; (iii) a surfactant or emulsifier; (iv) a co-surfactant or emulsifier; (v) an ion-pair former selected from C6-C20 saturated or unsaturated aliphatic acids when the hydrophobic drug is basic and a pharmaceutically acceptable aromatic amine when the hydrophobic drug is acidic; and (vi) water. [0113] According to certain embodiments, compositions according to the present invention may be adapted for administration of bisantrene at a dosage of from about 0.1 mg/m 2 /day to about 100 mg/m 2 /day, such as from about 0.2 mg/m 2 /day to about 50 mg/m 2 /day, from about 0.5 mg/m 2 /day to about 20 mg/m 2 /day, from about 1.0 mg/m 2 /day to about 10 mg/m 2 /day, from about 1.0 mg/m 2 /day to about 8 mg/m 2 /day, about 1 mg/m 2 /day, about 2 mg/m 2 /day, about 3 mg/m 2 /day, about 4 mg/m 2 /day, about 5 mg/m 2 /day, about 6 mg/m 2 /day, about 7 mg/m 2 /day, or about 10 mg/m 2 /day. In some embodiments, compositions according to the present invention may be adapted for administration of bisantrene once or multiple times daily or weekly, once every two weeks, once every three weeks, once every four weeks, over a period of, for example, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days or 63 days. In certain embodiments, compositions according to the present invention may be adapted for administration of bisantrene over a period of 28 days, optionally once or multiple times daily or weekly, once every two weeks, once every three weeks, once every four weeks, at a dosage of about 20-50 mg/m 2 /28 days. Compositions according to the present invention comprising pharmaceutically acceptable salts of bisantrene or therapeutically active derivatives or pharmaceutically acceptable salts thereof may be adapted to deliver similar dosage rates, adjusted for molar equivalence. [0114] Dosing regimens for immune checkpoint inhibitors will depend on the particular immune checkpoint inhibitor, and have been published for known immune checkpoint inhibitors, including for treatment of melanoma. In addition, suitable dosages of a given immune checkpoint inhibitor can be readily determined by one of ordinary skill in the art using known approaches and techniques as discussed above in relation to bisantrene. Compositions according to the invention may be formulated to include the immune checkpoint inhibitor(s) at their recommended dosage rates, or different dosage rates as discussed below. [0115] According to certain embodiments, and as a result of the beneficial biologic activity observed when bisantrene (or derivative of bisantrene, or a pharmaceutically acceptable salt of either) is administered with a immune checkpoint inhibitor, the dosage of immune checkpoint inhibitor in a composition according to the present invention may be lower than it would be when administered to a patient by itself. This is particularly important for active agents with deleterious side-effects, such as immune related adverse events. Thus, in certain embodiments of compositions according to the present invention, the immune checkpoint inhibitor may be included in the composition at a dosage which is significantly lower than the recommended dosage rate for that immune checkpoint inhibitor when administered alone, such as at a rate which is at least 10%, 20%, 30%, 40%, 50%, 60% or 70% lower than the dosage rate for that immune checkpoint inhibitor when administered alone. [0116] Similarly, where compositions according to the present invention include an additional therapeutic agent, being an immunomodulatory or a protein kinase inhibitor, that additional therapeutic agent may be included in the composition at its known recommended rate(s) for the treatment of melanoma, or even lower rates if synergy amongst the components is determined. Uses of compositions for the manufacture of medicaments for the treatment of melanoma [0117] The present invention also provides uses of compositions according to the invention for the manufacture of a medicament for the treatment of melanoma, especially immune checkpoint inhibitor resistant melanoma in a patient. [0118] The parameters for such manufacture, including immune checkpoint inhibitors, bisantrene, bisantrene derivatives and salts thereof, as well as immunomodulators, protein kinase inhibitors, or both as optional additional therapeutic agent(s), and dosages/dosing for all actives, dosage forms and other components are described above. Kits for the treatment of melanoma [0119] The present invention also provides kits for the treatment of melanoma, especially immune checkpoint resistant melanoma, the kit comprising at least one immune checkpoint inhibitor and at least a second agent comprising bisantrene or a derivative thereof, or a pharmaceutically acceptable salt of bisantrene or derivative thereof. [0120] The parameters for such kits, including immune checkpoint inhibitors, bisantrene, bisantrene derivatives and salts thereof, as well as immunomodulators, protein kinase inhibitors, or both as optional additional therapeutic agent(s), and dosages/dosing for all actives, dosage forms and other components are described above. [0121] In some cases, the kit may also comprise vials, tubes, needles, packaging, or other materials. [0122] Kits with unit doses of one or more of the active agents described herein, usually in injectable doses, are provided. Such kits may include containers containing unit doses, informational package inserts describing the use and attendant benefits of the drugs in treating the disease, and optionally appliance(s) or device(s) for delivery of the composition. [0123] The kit may further comprise any device suitable for administration of the composition. For example, a kit may comprise a needle suitable for intravenous administration. [0124] In some cases, kits may be provided with instructions. The instructions may be provided in the kit or they may be accessed electronically. The instructions may provide information on how to use the compositions of the present disclosure. The instructions may further provide information on how to use the devices of the present disclosure. The instructions may provide information on how to perform the methods of the disclosure. In some cases, the instructions may provide dosing information. The instructions may provide drug information such as the mechanism of action, the formulation of the drug, adverse risks, contraindications, and the like. In some cases, the kit is purchased by a physician or health care provider for administration at a clinic or hospital. In some cases, the kit is purchased by a laboratory and used for screening candidate compounds. [0125] Preferred forms of the present invention will now be described, by way of example only, with reference to the following examples, including comparative data, and which are not to be taken to be limiting to the scope or spirit of the invention in any way. EXAMPLES Example 1: Evaluation of Efficacy of Zantrene and RMP1-14 in the Subcutaneous B16-F10 Mouse Cancer Tumor Model in Female C57BL/6 Mice [0126] Two hundred and seventy female C57BL/6 mice were subcutaneously inoculated with B16-F10 mouse skin cancer cells. Six days post-inoculation, animals were randomised into six groups for efficacy assessment (20 per group) and six groups for flow cytometry analysis (10 per group). [0127] Antibody control rat IgG2a and RMP1-14 (each 10 mg/kg) were administered via intraperitoneal injection (i.p.) every three days. Vehicle (8% w/v Sulfobutyl-ether-β-Cyclodextrin (SBECD) and Zantrene (5 or 15 mg/kg) were administered via intravenous injection (i.v.) every second day. The high dose of Zantrene was reduced from 15 mg/kg to 10 mg/kg from Study Day 8 onwards due to adverse events at the higher dose. Combinations of rat IgG2a / Vehicle, RMP1- 14/Vehicle, rat IgG2a / 5 mg/kg Zantrene, rat IgG2a / 15 mg/kg Zantrene, RMP1-14 / 5 mg/kg Zantrene and RMP1-14 / 15 mg/kg Zantrene were administered. Ten doses of Vehicle (8% w/v SBECD) and Zantrene, and seven doses of rat IgG2a and RMP1- 14 were administered to efficacy groups. Seven doses of Vehicle (8% w/v SBECD) and Zantrene, and five doses of rat IgG2a and RMP1-14 were administered to flow groups. [0128] Animals were observed daily. Body weights, tumor volumes and clinical observations were recorded three times per week. Floor food was given to animals throughout the study. Flow study animals were euthanised on Study Day 7 or 13 (five per group at each time-point), unless earlier due to ethical limits or were found dead. Tumors and spleens were excised and weighed for flow cytometry analysis. Efficacy study animals were euthanised as ethical limits were reached or were found dead. Remaining animals were euthanised and the study was terminated on Study Day 20. [0129] The majority of animals treated with 10 mg/kg rat IgG2a / Vehicle (8% w/v SBECD) and 10 mg/kg RMP1-14 / Vehicle (8% w/v SBECD) were euthanised from Study Day 9 onwards as tumor burden reached the ethical limit. [0130] Assessment of tumor growth in efficacy study animals on Study Day 12 reveled smaller tumors in animals receiving treatments that included Zantrene as a component of the combination compared with 10 mg/kg rat IgG2a / Vehicle (8% w/v SBECD) control treatment and 10 mg/kg RMP1-14 / Vehicle (8% w/v SBECD). [0131] Enhanced inhibition of tumor growth was observed for the combination of Zantrene 5 mg/kg/ RMP1-1410 mg/kg compared to Zantrene 5 mg/kg/IgG2a isotype control 10 mg/kg at Day 14 in well-established tumor with a volume >170 mm 3 by Day 5 following implantation. [0132] Spleen levels of CD4+ PD-1+ cells (PD-1+ as % of CD4+) on Study Day 7 were substantially higher in animals treated with RMP1-14 monotherapy compared with all other treatments, significantly (p≤0.05) [0133] Combination of Bisantrene 5 mg/kg with/RMP1-1410 mg/kg produced a 56% increase in the number of antitumor M1 macrophages relative to animals treated with RMP1-1410 mg/kg alone (p = 0.0189). [0134] Additionally, a 56% decrease in the number of protumorigenic M2b macrophages was found in tumors from mice treated Bisantrene 5 mg/kg with/RMP1-1410 mg/kg combination relative to RMP1-1410 mg/kg alone at Day 13 (p = 0.0264) [0135] Combination of Bisantrene 5 mg/kg with/RMP1-1410 mg/kg produced a 83% decrease in the number of CD8 + T-cells co-expressing immunosuppressive checkpoint protein CTLA4 relative to animals treated with RMP1-1410 mg/kg alone (p = 0.0279). ADVANTAGES OF THE INVENTION [0136] The present invention provides a new paradigm for treating of melanoma by the administration of bisantrene, an antineoplastic agent that has multiple mechanisms of action, including DNA intercalation, inhibition of topoisomerase, inhibition of the fat and obesity associated protein (FTO), and activation of the immune system. Bisantrene is well tolerated and, in particular, lacks the cardiotoxicity that is characteristic of some other anthracene derivatives. Bisantrene can be used together with other therapeutic agents that are used for the treatment of melanoma. [0137] The inventions illustratively described herein can suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. As used herein the use of the term “comprising” as a transitional phrase in claims is intended to include therein the use of the transitional phrases “consisting essentially of” or “consisting of” if the narrower transitional phrases are not expressly excluded. Although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions herein disclosed can be resorted by those skilled in the art, and that such modifications and variations are considered to be within the scope of the inventions disclosed herein. The inventions have been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the scope of the generic disclosure also form part of these inventions. This includes the generic description of each invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised materials specifically resided therein.