Treatment Of Gastrointestinal Stromal Tumors With Imatinib And Midostaurin

Abstract

The present invention relates to the use of a combination comprising (a) imatinib or a pharmaceutically acceptable salt thereof and midostaurin or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of gastrointestinal stromal tumors, e.g. imatinib-resistant gastro-intestinal stromal tumors.

Description

PHARMACEUTICAL COMPOSITIONS

Capsules containing 119.5 mg of the imatinib mesylate corresponding to 100 mg of imatinib (free base) as active substance are prepared in the following composition:

Composition 1
Imatinib mesylate  119.5 mg
Cellulose MK GR    92 mg
Crospovidone XL    15 mg
Aerosil 200        2 mg
Magnesium stearate 1.5 mg
                   230 mg

The capsules are prepared by mixing the components and filling the mixture into hard gelatin capsules, size 1.

Midostaurin Pharmaceutical Preparations

Composition A:

Gelucire 44/14 (82 parts) is melted by heating to 60° C. Powdered MIDOSTAURIN (18 parts) is added to the molten material. The resulting mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25 mg dosage and others a 75 mg dosage of the MIDOSTAURIN. The resulting capsules are suitable for oral administration.

Composition B:

Gelucire 44/14 (86 parts) is melted by heating to 60° C. Powdered MIDOSTAURIN (14 parts) is added to the molten material. The mixture is homogenised and the dispersion obtained is introduced into hard gelatin capsules of different size, so that some contain a 25 mg dosage and others a 75 mg dosage of the MIDOSTAURIN. The resulting capsules are suitable for oral administration.

Gelucire 44/14 available commercially from Gattefossé; is a mixture of esters of C8-C18 saturated fatty acids with glycerol and a polyethylene glycol having a molecular weight of about 1500, the specifications for the composition of the fatty acid component being, by weight, 4-10% caprylic acid, 3-9% capric acid, 40-50% lauric acid, 14-24% myristic acid, 4-14% palmitic acid and 5-15% stearic acid.

A preferred example of Gelucire formulation consists of:

Gelucire (44/14): 47 g

MIDOSTAURIN: 3.0 g filled into a 60 mL Twist off flask

An example of soft gel will contain the following Microemulsion:

	Cornoil glycerides	85.0	mg
	Polyethylenglykol 400	128.25	mg
	Cremophor RH 40	213.75	mg
	MIDOSTAURIN	25.0	mg
	DL alpha Tocopherol	0.5	mg
	Ethanol absolute	33.9	mg
	Total	486.4	mg

Treatment Example

Adult patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) which are refractory to therapy with imatinib are treated with imatinib mesylate as a single daily dose of 600 mg imatinib base and midostaurin at a dose of 100 mg twice daily (4 capsules b.i.d.). The morning dose of imatinib should be taken about half an hour before midostaurin. Both drugs are taken with food and with a large glass of water to minimize the risk of GI irritation. In the event that serious side effects occur, the dose of midostaurin is reduced to 100 mg/day (50 mg b.i.d.).

2 out of the 6 patients have stable disease over treatment.

Claims

1. Use of a combination comprising imatinib or a pharmaceutically acceptable salt thereof and midostaurin or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of gastrointestinal stromal tumors.

2. The use according to claim 1 wherein imatinib is administered in a dose of from 100 to 1000 mg.

3. The use according to claim 2 wherein the dose of imatinib administered is 200 to 800 mg daily.

4. The use according to claim 3 wherein the dose of imatinib administered daily is 400, 600 or 800 mg.

5. The use according to claim 1 wherein the midostaurin is administered in a dose of 100 to 300 mg daily.

6. The use according to claim 5 wherein the dose is 150 to 250 mg daily.

7. The use according to claim 6 wherein the dose is 200 mg daily.

8. The use according to any one of the preceding claims wherein imatinib and midostaurin are each administered orally.

9. The use according to any one of the preceding claims wherein imatinib is administered as its monomethanesulfonic acid salt.

10. The use according to any one of the preceding claims wherein imatinib and midostaurin are dosed independently.

11. The use according to any one of the preceding claims wherein the gastrointestinal stromal tumor is an imatinib-resistant gastrointestinal stromal tumor.

12. Use of the COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of gastrointestinal stromal tumors.

13. The use of claim 12 gastrointestinal stromal tumors are refractory to therapy with imatinib.

14. A commercial package comprising package imatinib or package midostaurin together with instructions to use both imatinib and midostaurin, or salts thereof, together for the treatment of gastrointestinal stromal tumors.

15. A method of treating a patient suffering from gastrointestinal stromal tumors, which comprises administering an effective combination of imatinib, or a pharmaceutically acceptable salt thereof, and midostaurin, or a pharmaceutically acceptable salt thereof, to the patient.