Combination treatment

Abstract

The present invention relates to the use of combinations comprising 8-[(1R)-1-(3,5-difluorophenylamino)ethyl]-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide or a pharmaceutically acceptable salt thereof and a taxane in the treatment or prophylaxis of cancer; pharmaceutical compositions comprising Compound [I] (or a pharmaceutically acceptable salt thereof) and a taxane; kits comprising Compound [I] or a pharmaceutically acceptable salt thereof and a taxane, optionally with instructions for use; and methods of treatment comprising the simultaneous, sequential or separate administration of Compound [I] or a pharmaceutically acceptable salt thereof and a taxane to warm-blooded animal, such as man.

Claims

1. A method of treating cancer in a warm-blooded animal comprising administering to said animal an effective amount of Compound [I], or a pharmaceutically acceptable salt thereof: ##STR00002## in combination with an effective amount of a taxane, wherein Compound [I], or a pharmaceutically acceptable salt thereof, is dosed intermittently.

2. The method of claim 1, wherein the taxane is docetaxel.

3. The method of claim 1, wherein Compound [I], or a pharmaceutically acceptable salt thereof, and the taxane are administered in a dosage cycle of 8-29 days in length.

4. The method of claim 3, wherein the taxane is administered only once in a given dosage cycle.

5. The method of claim 4, wherein the taxane is administered within the 24 hours prior to the first administration of Compound [I], or a pharmaceutically acceptable salt thereof, in a given dosage cycle.

6. The method of claim 3, wherein the dosage cycle is 15-29 days long and comprises administration of the taxane within 24 hours prior to the first administration of Compound [I], or a pharmaceutically acceptable salt thereof, followed by intermittent dosing of Compound [I], or a pharmaceutically acceptable salt thereof, in 7 day periods consisting of 5 days wherein Compound [I], or a pharmaceutically acceptable salt thereof, is dosed followed by 2 days wherein no Compound [I], or a pharmaceutically acceptable salt thereof, is dosed.

7. The method of claim 3, wherein the dosage cycle is 15-29 days long and comprises administration of the taxane within 24 hours prior to the first administration of Compound [I], or a pharmaceutically acceptable salt thereof, followed by intermittent dosing of Compound [I], or a pharmaceutically acceptable salt thereof in 7 day periods consisting of 4 days wherein Compound [I], or a pharmaceutically acceptable salt thereof, is dosed followed by 3 days wherein no Compound [I], or a pharmaceutically acceptable salt thereof, is dosed.

8. The method of claim 1, wherein the taxane is dosed at 50-140 mg/m.sup.2 of patient surface area on the day(s) when it is dosed and Compound [I], or a pharmaceutically acceptable salt thereof, is dosed at 0.1-200 mg/kg twice daily on the days when it is dosed.

9. The method of claim 1, wherein the cancer is selected from castrate-resistant prostate cancer, squamous non-small cell lung cancer, colorectal cancer, pancreatic cancer and triple negative breast cancer.

10. The method of claim 3, wherein Compound [I] or a pharmaceutically acceptable salt thereof is not administered for 1, 2, 3, 4, 5, 6 or 7 days within a given dosage cycle.

11. The method of claim 3, wherein the dosage cycle is 8 days long and comprises administering Compound [I] or a pharmaceutically acceptable salt thereof for 5 consecutive days followed by 2 consecutive days in which Compound [I] or a pharmaceutically acceptable salt thereof is not administered.

12. The method of claim 3, wherein the dosage cycle is 8 days long and comprises administering Compound [I] or a pharmaceutically acceptable salt thereof for 4 consecutive days followed by 3 consecutive days in which Compound [I] or a pharmaceutically acceptable salt thereof is not administered.

13. The method of claim 3, wherein the dosage cycle is 8 days long and comprises administering Compound [I] or a pharmaceutically acceptable salt thereof for 3 consecutive days followed by 4 consecutive days in which Compound [I] or a pharmaceutically acceptable salt thereof is not administered.

Description

EXPERIMENTAL DETAILS

(1) Compound [I] may be prepared according to the procedures described in WO2011/051704, relevant details of which are incorporated herein by reference.

(2) Female Swiss athymic nu/nu mice were implanted subcutaneously in the left flank with 0.1 ml PC3 cells (1×10.sup.6 cells in Iscove's serum free medium mixed 50:50 with matrigel) or HCC70 cells (1×10.sup.6 cells in RPMI serum free medium mixed 50:50 with matrigel). Once tumours reached ˜200-500 mm.sup.3 in size animals were randomised into control and treatment groups.

(3) Compound [I] in the free base form was dosed either in the presence or absence of ABT (aminobenzotriazole). For groups where ABT was administered, Compound [I] was formulated once weekly either alone in 10% DMSO/60% TEG/30% WFI or in the presence of ABT at 10 mg/ml. For twice daily dosing Compound [I] was co-dosed with ABT at hour 0, and then administered alone as the single formulation at hour 6-8. For groups where ABT was not administered, Compound [I] was formulated once weekly as a suspension in HPMC/Tween and dosed once or twice daily (0 and 6-8 hours)

(4) Docetaxel (Taxotere™) was formulated fresh in physiological saline at 1.5 mg/ml and dosed as a single i.v. bolus at a rate of 0.1 ml/10 g on Day 0, 24 hours prior to the administration of Compound [I].

(5) Tumour volume was calculated twice weekly from bilateral calliper measurements using the formula (length×width×width)×π/6. Growth inhibition from the start of treatment was assessed by comparison of the geometric mean change in tumour volume for the control and treated groups. Statistical significance was evaluated using a one-tailed “t”-test.

LIST OF FIGURES

(6) FIG. 1—Long Term Continuous Dosing of Compound [I] formulated with ABT in Combination With Docetaxel in a mouse PC3 Xenograft Model.

(7) This figure shows the change in tumour volume in a mouse PC3 (a prostate cancer cell line) xenograft model over a 42-day period when treated with: i. Compound [I] alone at a dose of 10 mg/Kg bid; ii. Compound [I] alone at a dose of 30 mg/Kg bid; iii. A taxane (docetaxel) alone; iv. A combination of Compound [I] at a dose of 10 mg/Kg bid and a taxane (docetaxel) together; and v. A combination of Compound [I] at a dose of 30 mg/Kg bid and a taxane (docetaxel) together.

(8) FIG. 1 shows that use of the combination of Compound [I] and docetaxel appears to achieve additional tumour shrinkage when compared to the use of either Compound [I] or docetaxel alone.

(9) FIG. 2—Anti-tumour Activity of Compound [I] formulated in the Absence of ABT When Dosed Continually in Combination With Docetaxel in a mouse HCC70 Xenograft Model.

(10) This figure shows the change in tumour volume in a mouse HCC70 (a breast cancer cell line) xenograft model over a 21-day period when treated with: i. Compound [I] alone at a dose of 25 mg/Kg bid; ii. Compound [I] alone at a dose of 50 mg/Kg bid; iii. A taxane (docetaxel) alone; iv. A combination of Compound [I] at a dose of 25 mg/Kg bid and a taxane (docetaxel) together; and v. A combination of Compound [I] at a dose of 50 mg/Kg bid and a taxane (docetaxel) together.

(11) FIG. 2 again shows that use of the combination treatment appears to achieve additional tumour shrinkage over the use of either Compound [I] or docetaxel alone.

(12) FIG. 3—Anti-tumour Activity of Intermittent High Dose Compound [I] formulated in the absence of ABT when dosed in combination with Docetaxel in an HCC70 Xenograft Model.

(13) FIG. 3 shows the change in tumour volume in a mouse HCC70 (a breast cancer cell line) xenograft model over a 23-day period when treated with: i. A taxane (docetaxel) alone; ii. Compound [I] alone at a dose of 100 mg/Kg bid, wherein the Compound [I] was administered on 5 consecutive days of a 7 day period only, with no agent administered on the remaining 2 days; and iii. A combination of Compound [I] at a dose of 100 mg/Kg bid and docetaxel together, wherein the Compound [I] was administered on 5 consecutive days of a 7 day period only, with no agent administered on the remaining 2 days.

(14) FIG. 3 shows that even intermittent dosage of Compound [I] in combination with a single dose of docetaxel can result in sustained additional anti-tumour activity over either docetaxel or Compound [I] alone.

(15) FIG. 4—Anti-tumour Activity of Intermittent Low Dose Compound [I] formulated in the absence of ABT when dosed in combination with Docetaxel in an HCC70 Xenograft Model.

(16) This figure shows the change in tumour volume in a mouse HCC70 (a breast cancer cell line) xenograft model over a 21-day period when treated with: i. A taxane (docetaxel) alone; ii. A combination of Compound [I] at a dose of 25 mg/Kg bid and a taxane (docetaxel) together, continuously dosed; iii. A combination of Compound [I] at a dose of 25 mg/Kg bid and docetaxel together, wherein the Compound [I] was administered on 5 consecutive days of a 7 day period only, with no agent administered on the remaining 2 days. iv. A combination of Compound [I] at a dose of 25 mg/Kg bid and docetaxel together, wherein the Compound [I] was administered on 2 consecutive days of a 7 day period only, with no agent administered on the remaining 5 days.

(17) FIG. 4 shows that even intermittent dosage of Compound [I] at a relatively low dose in combination with a single dose of docetaxel can result in sustained additional anti-tumour activity when compared to either docetaxel or Compound [I] alone.