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Claims for Patent: 6,670,384

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Claims for Patent: 6,670,384

Title: Methods of administering epothilone analogs for the treatment of cancer
Abstract:A process for formulating certain epothilone analogs for parenteral administration is disclosed wherein the analog is dissolved in a mixture of at least 50% by volume tertiary-butanol in water, the mixture is lyophilized, the resulting lyophilized product is packaged in one vial with a sufficient amount of solvent comprising anhydrous ethanol and a suitable nonionic surfactant in a second vial. All steps are carried out with protection from light. In use, the contents of the second or diluent vial are added to the lyophilized product and mixed to constitute the epothilone analog and the resulting solution is diluted with a suitable diluent to produce a solution for intravenous injection containing the epothilone analog in a concentration of from about 0.1 mg/mL to about 0.9 mg/mL. A preferred surfactant is polyethoxylated castor oil and a preferred diluent is Lactated Ringer's Injection.
Inventor(s): Bandyopadhyay; Rebanta (Portage, MI), Malloy; Timothy M. (Yardley, PA), Panaggio; Andrea (West Windsor, NJ), Raghavan; Krishnaswamy Srinivas (Cranbury, NJ), Varia; Sailesh Amilal (Princeton Junction, NJ)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:10/055,653
Patent Claims: 1. A process for formulating, for parenteral administration, an epothilone analog represented by formula I: ##STR7##

wherein: Q is selected from the group consisting of: ##STR8##

and M is selected from the group consisting of oxygen, sulfur, NR.sup.8, and CR.sup.9 R.sup.10 ; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1, and R.sup.2, are alkyl, they can be joined to form cycloalkyl; R.sup.6, is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.14, C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof, comprising the following steps carried out under protection from light: a) dissolving said epothilone analog in a mixture of at least about 50% by volume tertiary-butanol in water to form a solution; b) performing primary drying of said solution at a temperature of from about -10.degree. C. to about -40.degree. C. under high vacuum of from about 50 millitorr to about 300 millitorr for from about 24 hours to about 96 hours to form a dried product; c) performing secondary drying of the resultant dried product at a temperature of from about 10.degree. C. to about 30.degree. C. under high vacuum of from about 50 millitorr to about 300 millitorr for from 24 hours to about 96 hours to provide a lyophilized product; and d) packaging said lyophilized product in a first vial in combination with a second vial containing a sufficient quantity of an equal mixture by volume of a suitable nonionic surfactant and anhydrous ethanol to effect solution thereof.

2. The process of claim 1 wherein said epothilone analog is represented by formula II: ##STR9##

3. The process of claim 1 wherein in step a) said analog is first wetted with a mixture of at least about 60% tertiary-butanol in water, and then sufficient water, or a mixture of tertiary-butanol and water, is added thereto so that the resulting solution contains from about 2 mg/mL to about 30 mg/mL of said analog in a mixture of from about 50% to about 80% by volume tertiary-butanol in water.

4. The process of claim 2 wherein in step a) said analog is first wetted with a mixture of at least about 60% tertiary-butanol in water, and then sufficient water, or a mixture of tertiary-butanol and water, is added thereto so that the resulting solution contains from about 2 mg/mL to about 30 mg/mL of said analog in a mixture of from about 50% to about 80% by volume tertiary-butanol in water.

5. The process of claim 3 wherein in step a) said analog is initially wetted with a mixture of from about 60% to about 95% by volume tertiary-butanol in water.

6. The process of claim 4 wherein in step a) said analog is initially wetted with a mixture of from about 60% to about 95% by volume tertiary-butanol in water.

7. The process of claim 1 wherein said primary drying in step b) is carried out at a temperature of about -25.degree. C. and a pressure of about 200 millitorr for about 48 hours.

8. The process of claim 2 wherein said primary drying in step b) is carried out at a temperature of about -25.degree. C. and a pressure of about 200 millitorr for about 48 hours.

9. The process of claim 1 wherein said secondary drying in step c) is carried out at a temperature of about 25.degree. C. and a pressure of about 150 millitorr for about 48 hours.

10. The process of claim 2 wherein said secondary drying in step c) is carried out at a temperature of about 25.degree. C. and a pressure of about 150 millitorr for about 48 hours.

11. The process of claim 1 wherein said surfactant is polyethoxylated castor oil.

12. The process of claim 2 wherein said surfactant is polyethoxylated castor oil.

13. The process of claim 11 wherein said second vial contains an amount of said mixture sufficient to form a solution of from about 2 mg/mL to about 4 mg/mL of said analog therein.

14. The process of claim 12 wherein said second vial contains an amount of said mixture sufficient to form a solution of from about 2 mg/mL to about 4 mg/mL of said analog therein.

15. A pharmaceutical preparation comprising, a first vial containing a lyophilized epothilone analog and a second vial containing a quantity of a solvent for the lyophilized epothilone said solvent comprising a mixture of about equal parts by volume of dehydrated ethanol and a suitable nonionic surfactant, said analog being represented by formula I: ##STR10##

wherein: Q is selected from the group consisting of ##STR11## M is selected from the group consisting of oxygen, sulfur, NR.sup.8, and CR.sup.9 R.sup.10; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1 and R.sup.2 are alkyl, they can be joined to form cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof.

16. The pharmaceutical preparation of claim 15 wherein said epothilone analog is represented by formula II: ##STR12##

17. The pharmaceutical preparation of claim 15 wherein said nonionic surfactant is polyethoxylated castor oil.

18. A process for forming a pharmaceutical composition for parenteral administration comprising mixing the contents of the vials of the pharmaceutical preparation of claim 15 to effect solution of said lyophilized epothilone analog and diluting the resultant solution with a quantity of a suitable parenteral diluent such that the concentration of said analog therein will be from about 0.1 mg/mL to about 0.9 mg/mL.

19. A process for forming a pharmaceutical composition for parenteral administration comprising mixing the contents of the vials of the pharmaceutical preparation of claim 16 to effect solution of said lyophilized epothilone analog and diluting the resultant solution with a quantity of a suitable parenteral diluent such that the concentration of said analog therein will be from about 0.1 mg/mL to about 0.9 mg/mL.

20. A process for forming a pharmaceutical composition for parenteral administration comprising mixing the contents of the vials of the pharmaceutical preparation of claim 17 to effect solution of said lyophilized epothilone analog and diluting the resultant solution with a quantity of a suitable parenteral diluent such that the concentration of said analog therein will be from about 0.1 mg/mL to about 0.9 mg/mL.

21. The process of claim 18 wherein said diluent is Lactated Ringer's Injection.

22. The process of claim 19 wherein said diluent is Lactated Ringer's Injection.

23. The process of claim 20 wherein said diluent is Lactated Ringer's Injection.

24. A method for treating a patient in need of treatment with an epothilone analog represented formula I: ##STR13##

wherein: Q is selected from the group consisting of M, ##STR14## M is selected from the group consisting of oxygen, sulfur, NR.sup.8, and CR.sup.9 R.sup.10 ; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1 and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2, and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof, comprising administering to said patient, by intravenous injection or infusion, an effective amount of a pharmaceutical composition of claim 18.

25. A method for treating a patient in need of treatment with an epothilone analog represented formula I: ##STR15##

wherein: Q is selected from the group consisting of ##STR16## M is selected from the group consisting of oxygen, sulfur, NR.sup.8 and CR.sup.9 R.sup.10; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.13, R.sup.14, and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R' and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; and R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11, C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof, comprising administering to said patient, by intravenous injection or infusion, an effective amount of a pharmaceutical composition of claim 19.

26. A method for treating a patient in need of treatment with an epothilone analog represented formula I: ##STR17##

wherein: Q is selected from the group consisting of ##STR18## M is selected from the group consisting of oxygen, sulfur, NR.sup.8 and CR.sup.9 R.sup.10 ; each R', R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1 and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R .sup.14C--O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof, comprising administering to said patient, by intravenous injection or infusion, an effective amount of a pharmaceutical composition of claim 20.

27. The method of claim 24 wherein said diluent is Lactated Ringer's Injection.

28. The method of claim 25 wherein said diluent is Lactated Ringer's Injection.

29. The method of claim 26 wherein said diluent is Lactated Ringer's Injection.

30. A pharmaceutical composition suitable for parenteral administration comprising in lyophilized form a compound represented by formula I: ##STR19##

wherein: Q is selected from the group consisting of ##STR20## M is selected from the group consisting of oxygen, sulfur, NR.sup.8, and CR.sup.9 R.sup.10 ; each R', R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R' and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.2 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof; dehydrated alcohol; and a non-ionic surfactant.

31. The composition of claim 30,wherein the surfactant is polyethoxylated castor oil.

32. The composition of claim 30, wherein the surfactant is Cremophor EL.RTM..

33. The composition of claim 30, wherein the concentration of the compound of formula I is from about 2 mg/mL to 4 mg/mL.

34. A pharmaceutical composition suitable for parenteral administration comprising a compound represented by formula II: ##STR21## and any salts, solvates, or hydrates thereof: dehydrated alcohol; and a non-ionic surfactant.

35. A method of treating cancer in a patient comprising intravenously administering to said patient a therapeutically effective amount of the pharmaceutical formulation of claim 30 diluted in a parenteral diluent.

36. The method of claim 35, wherein the parenteral diluent is 5% dextrose, lactated ringer's and dextrose injection, or sterile water for injection.

37. The method of claim 35, wherein the concentration of the compound of formula I in the parenteral diluent is about 0.1 mg/mL to 0.9 mg/mL.

38. The method of claim 35, wherein the compound of formula I is administered in a dose of about 1 mg/m.sup.2 to 65 mg/m.sup.2.

39. The method of claim 35, wherein the compound of formula I is administered at a dose of about 25 mg/m.sup.2.

40. The method of claim 35, wherein the pharmaceutical composition is administered weekly as an IV infusion.

41. The method of claim 35, wherein the IV infusion is administered over a period of about 45 minutes to 90 minutes.

42. The method of claim 35, wherein the IV infusion is administered over a period of about 1 hour.

43. The method of claim 35, further comprising administering to said patient one or more additional agents to prevent nausea, vomiting, hypersensitivity, or gastric irritation.

44. The method of claim 43, wherein the one or more additional agents is an H1 or H2 antihistamine.

45. The method of claim 35, wherein the patient has not previously been treated for cancer.

46. The method of claim 35, wherein the patient has been previously treated for cancer.

47. The method of claim 35, wherein the cancer is refractory to radiation therapy.

48. The method of claim 35, wherein the cancer is refractory to anti-cancer chemotherapy.

49. A method of treating cancer in a patient previously experiencing neurotoxicity comprising intravenously administering to said patient a therapeutically effective amount of the pharmaceutical formulation of claim 30 diluted in a parenteral diluent as a weekly infusion, wherein the total dose of the compound of formula I is less than about 200 mg/m.sup.2.

50. The method of claim 35, wherein the cancer is a solid tumor.

51. The method of claim 29, wherein the cancer is a solid tumor.

52. A method of treating cancer while reducing or avoiding neurotoxicity which comprises intravenously administering a therapeutically effective amount of compound represented by formula I: ##STR22##

wherein: Q is selected from the group consisting of ##STR23## M is selected from the group consisting of oxygen, sulfur, NR.sup.8 and CR.sup.9, R.sup.10, each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14 and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R' and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.12 SO.sub.2 and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof; over a period of one (1) hour to a patient in need thereof.

53. The method of claim 52, wherein the infusion is made on a weekly basis.

54. The method of claim 52, wherein the therapeutically effective amount is from about 1 mg/m.sup.2 to about 65 mg/m.sup.2.

55. The method of claim 54, wherein the amount is 25 mg/m.sup.2.

56. A method of treating cancer while reducing or avoiding neurotoxicity which comprises intravenously infusing a therapeutically effective amount of compound represented by formula I: ##STR24##

over a period of one (1) hour to a patient in need thereof.

57. The method of claim 56 which further comprises orally administering said compound 1 week before or after an intravenous administration.

58. A method of treating cancer in a human patient in need thereof with a synthetic or semi-synthetic epothilone analogue that is active against cancer which comprises a four (4) week dosing cycle wherein said cycle comprises three weeks of weekly intravenous administration and one week of oral administration of said epothilone analogue.

59. The method of claim 58 wherein the compound is administered daily for 3 days with a period of 1 week to 3 weeks between cycles where there is no administration of the compound.

60. The method of claim 58 wherein the compound is administered daily for 3 days with a period of 1 week to 3 weeks between cycles where there is no administration of the compound.

61. The method of claim 58 wherein the compound is administered daily for 5 days with a period of 1 week to 3 weeks between cycles where there is no administration of the compound.

62. The method of claim 58 wherein the compound is administered daily for 5 days with a period of 1 week to 3 weeks between cycles where there is no administration of the compound.

63. A method of treating cancer in a patient comprising orally administering to said patient daily for 3 days, daily for 5 days, or weekly a therapeutically effective amount of a compound represented by formula I: ##STR25##

wherein: Q is selected from the group consisting of ##STR26## M is selected from the group consisting of oxygen, sulfur, NR.sup.8 and CR.sup.9 R.sup.10 ; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7 R.sup.11 R.sup.12 R.sup.13 R.sup.14 and R.sup.15 is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1 and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof.

64. The method of claim 63, wherein the compound of formula I is administered in a dose of about 0.05 mg/kg to 200 mg/kg.

65. The method of claim 64, wherein the compound of formula I is administered at a dose of about 1 mg/m.sup.2 to 65 mg/m.sup.2.

66. The method of claim 64, wherein the compound is administered every 3 weeks.

67. The method of claim 63 wherein the compound is administered daily for 3 days with a period of 1 week to 3 weeks between cycles where there is no administration of the compound.

68. The method of clam 66 wherein the compound is administered daily for 5 days with a period of 1 week to 3 weeks between cycles where there is no administration of the compound.

69. The method of claim 66 wherein the compound is administered daily for 3 days with a period of 4 days between cycles where there is no treatment.

70. The method of claim 66 wherein the compound is administered daily for 5 days with a period of 2 days between cycles where there is no treatment.

71. The pharmaceutical preparation of claim 1, wherein the lyophilized epothilone analog is free of excipients.

72. The pharmaceutical preparation of claim 15, wherein the lyophilized epothilone analog is free of excipients.

73. The pharmaceutical preparation of claim 16, wherein the lyophilized epothilone analog is free of excipients.

74. A process for forming a pharmaceutical composition for parenteral administration comprising mixing the contents of the vials of the pharmaceutical preparation of claim 72 to effect solution of said lyophilized epothilone analog and diluting the resultant solution with a quantity of a suitable parenteral diluent such that the concentration of said analog therein will be from about 0.1 mg/mL to about 0.9 mg/mL.

75. A process for forming a pharmaceutical composition for parenteral administration comprising mixing the contents of the vials of the pharmaceutical preparation of claim 73 to effect solution of said lyophilized epothilone analog and diluting the resultant solution with a quantity of a suitable parenteral diluent such that the concentration of said analog therein will be from about 0.1 mg/mL to about 0.9 mg/mL.

76. A method of treating cancer in a patient comprising intravenously and orally administering to said patient a therapeutically effective amount of a compound represented by formula II: ##STR27##

77. A method of treating cancer in a patient comprising intravenously administering to said patient a therapeutically effective amount of the compound of claim 76 diluted in a parenteral diluent.

78. The pharmaceutical preparation of claim 15, wherein the quantity of solvent is an amount such that when the solvent is combined with the lyophilized epothilone the resulting solution contains from about 2 mg/mL to about 4 mg/mL of said analog.

79. A method of treating cancer in a patient comprising intravenously administering to said patient daily for 3 days or daily for 5 days a therapeutically effective amount of a compound represented by formula I: ##STR28##

wherein: Q is selected from the group consisting of ##STR29## M is selected from the group consisting of oxygen, sulfur, NR, and CR.sup.9 R.sup.10; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15, is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1 and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof.

80. The method of claim 79, wherein the compound of formula I is administered daily for 3 days.

81. The method of claim 79, wherein the compound of formula I is administered daily for 5 days.

82. The method of claim 81, wherein the compound of formula I is administered in a dose of about 0.05 mg/kg to 200 mg/kg.

83. The method of claim 79, wherein the compound of formula I is administered at a dose of about 1 mg/m.sup.2 to 65 mg/m.sup.2.

84. The method of claim 83, wherein the compound of formula I is administered at a dose of about 25 mg/m.sup.2.

85. The method of claim 79, wherein the IV infusion is administered over a period of about 45 minutes to 90 minutes.

86. The method of claim 79, wherein the IV infusion is administered over a perioe of about 1 hour.

87. The method of claim 79, further comprising administering to said patient one or more additional therapeutic agents to prevent nausea, vomiting, hypersensitivity, or gastric irritation.

88. The method of claim 86, wherein the one or more additional therapeutic agents is an H.sup.1, or H.sup.2, antihistamine.

89. The method of claim 79, wherein the patient has not previously been treated for cancer.

90. The method of claim 86, wherein the patient has been previously treated for cancer.

91. The method of claim 79, wherein the cancer is refractory to radiation therapy.

92. The method of 79, wherein the cancer is refractory to anti-cancer chemotherapy.

93. A method of treating cancer in a patient comprising intravenously administering to said patient every week or every 3 weeks a therapeutically effective amount of a compound represented by formula I: ##STR30##

wherein: Q is selected from the group consisting of ##STR31## M is selected from the group consisting of oxygen, sulfur, NR, and CR.sup.9 R.sup.10 ; each R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15, is, independently, selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl and heterocyclo, and wherein R.sup.1 and R.sup.2 are alkyl, they can be joined to form a cycloalkyl; R.sup.6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo and substituted heterocyclo; R.sup.8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, R.sup.11 C.dbd.O, R.sup.12 OC.dbd.O and R.sup.13 SO.sub.2 ; and each R.sup.9 and R.sup.10 is, independently, selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, aryl, heterocyclo, hydroxy, R.sup.14 C.dbd.O, and R.sup.15 OC.dbd.O; and any salts, solvates, or hydrates thereof.

94. The method of 93, wherein the compound of formula I is administered every week.

95. The method of 93, wherein the compound of formula I is administered every 3 weeks.

96. The method of claim 95, further comprising orally administering the compound of formula I before the 3 week cycle.

97. The method of claim 95, further comprising orally administering the compound of formula I after the 3 week cycle.

98. The method of claim 97, wherein the compound of formula I is administered as one or more 28 day cycles, wherein the compound of formula I is administered as an IV infusion on days 1, 7, and 14 and orally on day 21.

99. The method of claim 93, wherein the IV infusion is administered over a period of about 1 hour.

100. The method of claim 93, further comprising administering to said patient one or more additional therapeutic agents to prevent nausea, vomiting, hypersensitivity, or gastric irritation.

101. The method of claim 100, wherein the one or more additional therapeutic agents is an H.sup.1, or H.sup.2, antihistamine.

102. The method of claim 93, wherein the patient has not previously been treated for cancer.

103. The method of claim 93, wherein the patient has been previously treated for cancer.

104. The method of claim 93, wherein the cancer is refractory to radiation therapy.

105. The method of claim 93, wherein the cancer is refractory to anti-cancer chemotherapy.
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