TREATMENT OF NEUROBLASTOMA WITH MULTI-ARM POLYMERIC CONJUGATES OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN

• US 20100098654A1
• Filed: 10/15/2009
• Published: 04/22/2010
• Est. Priority Date: 10/21/2008
• Status: Abandoned Application

• Current Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Ponzoni, Mirco, Pastorino, Fabio
• Application Number:
  US12/579,614
• Publication Number:
  US 20100098654A1
• Time in Patent Office: Days
• US Class Current: 424/78.17
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to methods of treatment of neuroblastoma. The present invention includes administering polymeric prodrugs of 7-ethyl-10-hydroxycamptothecin to patients in need thereof.

Claims

1. A method of treating neuroblastoma in a mammal, comprising:

administering an effective amount of a compound of Formula (I);

wherein

R₁, R₂, R₃ and R₄ are independently OH or

wherein

L is a bifunctional linker;

(m) is 0 or a positive integer, wherein each L is the same or different when (m) is equal to or greater than 2; and

(n) is a positive integer;

provided that R₁, R₂, R₃ and R₄ are not all OH;

or a pharmaceutically acceptable salt thereof to said mammal.

2. The method of claim 1, wherein (m) is about 1.

3. The method of claim 1, wherein (n) is from about 28 to about 341 so that the total molecular weight of the polymeric portion of the compound ranges from about 5,000 to about 60,000 daltons.

4. The method of claim 1, wherein (n) is from about 114 to about 239 so that the total molecular weight of the polymeric portion of the compound ranges from about 20,000 to about 42,000 daltons.

5. The method of claim 1, wherein (n) is about 227 so that the total molecular weight of the polymeric portion of the compound is about 40,000 daltons.

6. The method of claim 1, wherein the compound of Formula (I) is part of a pharmaceutical composition, and R₁, R₂, R₃ and R₄ are all:

7. The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of

8. The method of claim 1, wherein the compound of Formula (I) is

9. The method of claim 1, wherein the compound of Formula (I) is administered in amounts of from about 0.5 mg/m² body surface/dose to about 50 mg/m² body surface/dose, and wherein the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I).

10. The method of claim 1, wherein the compound of Formula (I) is administered in amounts of from about 1 mg/m² body surface/dose to about 18 mg/m² body surface/dose, and the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I).

11. The method of claim 1, wherein the compound of Formula (I) is administered according to a protocol of from about 1.25 mg/m² body surface/dose to about 16.5 mg/m² body surface/dose given weekly for three weeks, followed by 1 week without treatment, and the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I).

12. The method of claim 11, wherein the amount administered weekly is about 5 mg/m² body surface/dose, and the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I).

13. The method of claim 1, wherein the cancer is metastatic.

14. The method of claim 1, wherein the cancer is a solid tumor.

15. The method of claim 1, wherein the compound of Formula (I) is administered in combination with a second chemotherapeutic agent simultaneously or sequentially.

16. The method of claim 15, wherein the compound of Formula (I) is administered, followed by 13-cis-retinoic acid.

17. The method of claim 1, wherein the compound of Formula (I) is administered in combination with radiotherapy simultaneously or sequentially.

18. The method of claim 1, wherein the cancer is resistant or refractory to an anti-cancer therapy that does not include a compound of Formula (I).

19. The method of claim 18, wherein the cancer is resistant to an anti-cancer agent that is chosen from camptothecin, CPT-11, an epidermal growth factor receptor antagonist, and combinations thereof.

20. The method of claim 19, wherein the epidermal growth factor receptor antagonist is cetuximab.

24. The method of claim 1, wherein L is an amino acid or amino acid derivative, wherein the amino acid derivative is selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, beta-aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-aminobutyric acid, desmosine, 2,2-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, sarcosine, N-methyl-isoleucine, 6-N-methyl-lysine, N-methylvaline, norvaline, norleucine, and ornithine.

25. The method of claim 1, wherein L is glycine, alanine, methionine or sarcosine.

26. The method of claim 1, wherein L is selected from the group consisting of

—

[C(═

O)]_v(CR₂₂R₂₃)_t—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_t—

O—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_t—

NR₂₆—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_t—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_tO—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_tNR₂₆—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_t—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_tO—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_tNR₂₆13 ,

—

[C(═

O)]_v(CR₂₂R₂₃O)_t—

,

—

[C(═

O)]_vO(CR₂₂R₂₃O)_t—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃O)_t—

,

—

[C(═

O)]_v(CR₂₂R₂₃O)_t(CR₂₄R₂₅)_y—

,

—

[C(═

O)]_vO(CR₂₂R₂₃O)_t(CR₂₄R₂₅)_y—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃O)_t(CR₂₄R₂₅)_y—

,

—

[C(═

O)]_v(CR₂₂R₂₃O)_t(CR₂₄R₂₅)_yO—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_t(CR₂₄R₂₅O)_y—

,

—

[C(═

O)]_vO(CR₂₂R₂₃O)_t(CR₂₄R₂₅)_yO—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_t(CR₂₄R₂₅O)_y—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃O)_t(CR₂₄R₂₅)_yO—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_t(CR₂₄R₂₅O)_y—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_tO—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_tNR₂₆—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_tS—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_tO—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_tNR₂₆—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_tS—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_tO—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_tNR₂₆—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_tS—

(CR₂₈R₂₉)_t′

—

,

—

[C(═

O)]_v(CR₂₂R₂₃CR₂₈R₂₉O)_tNR₂₆—

,

—

[C(═

O)]_v(CR₂₂R₂₃CR₂₈R₂₉O)_t—

,

—

[C(═

O)]_vO(CR₂₂R₂₃CR₂₈R₂₉O)_tNR₂₆—

,

—

[C(═

O)]_vO(CR₂₂R₂₃CR₂₈R₂₉O)_t—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃CR₂₈R₂₉O)_tNR₂₆—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃CR₂₈R₂₉O)_t—

,

—

[C(═

O)]_v(CR₂₂R₂₃CR₂₈R₂₉O)_t(CR₂₄R₂₅)_y—

,

—

[C(═

O)]_vO(CR₂₂R₂₃CR₂₈R₂₉O)_t(CR₂₄R₂₅)_y—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃CR₂₈R₂₉O)_t(CR₂₄R₂₅)_y—

,

—

[C(═

O)]_v(CR₂₂R₂₃CR₂₈R₂₉O)_t(CR₂₄R₂₅)_yO—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_t(CR₂₄R₂₅CR₂₈R₂₉O)_y—

,

—

[C(═

O)]_v(CR₂₂R₂₃)_t(CR₂₄R₂₅CR₂₈R₂₉O)_yNR₂₆—

,

—

[C(═

O)]_vO(CR₂₂R₂₃CR₂₈R₂₉O)_t(CR₂₄R₂₅)_yO—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_t(CR₂₄R₂₅CR₂₈R₂₉O)_y—

,

—

[C(═

O)]_vO(CR₂₂R₂₃)_t(CR₂₄CR₂₅CR₂₈R₂₉O)_yNR₂₆—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃CR₂₈R₂₉O)_t(CR₂₄R₂₅)_yO—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_t(CR₂₄R₂₅CR₂₈R₂₉O)_y—

,

—

[C(═

O)]_vNR₂₁(CR₂₂R₂₃)_t(CR₂₄R₂₅CR₂₈R₂₉O)_yNR₂₆—

,

wherein;

R₂₁-R₂₉ are independently selected from the group consisting of hydrogen, amino, substituted amino, azido, carboxy, cyano, halo, hydroxyl, nitro, silyl ether, sulfonyl, mercapto, C_1-6 alkylmercapto, arylmercapto, substituted arylmercapto, substituted C_1-6 alkylthio, C_1-6 alkyls, C_2-6 alkenyl, C_2-6 alkynyl, C_3-19 branched alkyl, C_3-8 cycloalkyl, C_1-6 substituted alkyl, C_2-6 substituted alkenyl, C_2-6 substituted alkynyl, C_3-8 substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C_1-6 heteroalkyl, substituted C_1-6 heteroalkyl, C_1-6 alkoxy, aryloxy, C_1-6 heteroalkoxy, heteroaryloxy, C_2-6 alkanoyl, arylcarbonyl, C_2-6 alkoxycarbonyl, aryloxycarbonyl, C_2-6 alkanoyloxy, arylcarbonyloxy, C_2-6 substituted alkanoyl, substituted arylcarbonyl, C_2-6 substituted alkanoyloxy, substituted aryloxycarbonyl, C_2-6 substituted alkanoyloxy, substituted and arylcarbonyloxy;

(t), (t′

) and (y) are independently selected from zero or a positive integer; and

(v) is 0 or 1.

27. The method of claim 1, wherein (m) is from about 1 to about 10.

21. A method of treating neuroblastoma in a mammal, comprising:

administering an effective amount of a compound of

or a pharmaceutically acceptable salt thereof to said mammal

wherein the compound is administered in amounts of from about 1 mg/m² body surface/dose to about 18 mg/m² body surface/dose and the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I); and

(n) is about 227.

22. The method of claim 21, wherein the compound is administered according to a protocol of from about 1.25 mg/m² body surface/dose to about 16.5 mg/m² body surface/dose given weekly for three weeks, followed by 1 week without treatment;

and the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I).

23. The method of claim 22, wherein the amount administered weekly is about 5 mg/m² body surface/dose, and the amount is the weight of 7-ethyl-10-hydroxycamptothecin included in the compound of Formula (I).