Therapeutic compositions containing at least one pyrrolobenzodiazepine derivative and fludarabine
View Patent ↗The invention concerns the use of a therapeutic composition comprising at least one pyrrolobenzodiazepine derivative combined with fludarabine for treating cancer and more particularly hematological diseases.
1. A method of treating a patient who has chronic lymphoid leukemia comprising administering a combination of a compound of formula (I):
in which the dotted lines represent an optional second bond, and
R is absent and X represents hydrogen when the second bond is present between the carbon to which X is attached and the nitrogen atom to which R is attached, or R represents hydrogen and X represents—OH when there is no second bond between the carbon to which X is attached and the nitrogen atom to which R is attached; and
R 1 is absent and X 1 represents hydrogen when the second bond is present between the carbon to which X 1 is attached and the nitrogen atom to which R 1 is attached, or R 1 represents hydrogen and X 1 represents—OH when there is no second bond between the carbon to which X 1 is attached and the nitrogen atom to which R 1 is attached,
or an addition salt thereof, with fludarabine to a patient in need thereof, in a therapeutically synergistic amount exhibiting a combination index of less than one, wherein the combination index is calculated from dose-response curves for the compound of formula (I) and fludarabine on chronic lymphoid leukemia cells.
2. The method of claim 1 , comprising administering the compound of formula (I) at a concentration in the range of 1×10 −11 M and 1×10 −7 M.
3. The method of claim 1 , comprising administering the fludarabine at a concentration between 1×10 −7 M and 1×10 −5 M.
4. The method of claim 1 , wherein the molar ratio of fludarabine to the compound of formula (I) is approximately 100 to 1.
5. The method of claim 1 , wherein the molar ratio of fludarabine to the compound of formula (I) is 100 to 1.
6. The method of claim 1 , comprising administering the compound of formula (I) and fludarabine simultaneously.
7. The method of claim 1 , comprising administering the compound of formula (I) and fludarabine separately.
8. The method of claim 1 , comprising administering the compound of formula (I) and fludarabine spread over time.
9. The method of claim 5 , wherein the compound of formula (I) is administered at a concentration between 1×10 −11 M and 1×10 −7 M, and the fludarabine is administered at a concentration between 1×10 −7 M and 1×10 −5 M.
10. The method of claim 1 , comprising administering the compound of formula (I) at a concentration between 1×10 −11 M and 1×10 −7 M, and the fludarabine at a concentration between 1×10 −7 M and 1×10 −5 M.
11. The method of claim 1 , wherein the compound of formula (I) is administered as an amorphous form of the compound.
12. The method of claim 1 , wherein the compound of formula (I) is administered as a crystalline form of the compound.
13. The method of claim 1 , wherein the compound of formula (I) is administered as a racemic form of the compound.
14. The method of claim 1 , wherein the compound of formula (I) is administered as an enantiomeric form of the compound.
15. The method of claim 1 , comprising administering the compound of formula (I) where R represents hydrogen and X represents—OH.
16. The method of claim 1 , wherein the molar ratio of fludarabine to compound of formula (I) ranges from 250 to 1 to 100 to 1.
17. The method of claim 1 , wherein the compound of formula (I) is administered at a dose between 1 and 150 μg/m 2 .
18. The method of claim 1 , wherein the compound of formula (I) is administered at a dose between 10 and 100 μg/m 2 .
19. The method of claim 1 , wherein the therapeutically synergistic amount exhibits a combination index of less than 0.93.
20. The method of claim 15 , comprising administering the compound of formula (I) where R 1 represents hydrogen and X 1 represents—OH.