HK1058623B - A combination comprising camptothecin and a stilbene derivative for the treatment of cancer - Google Patents

Description

Compositions comprising camptothecin and 1, 2-stilbene derivatives for the treatment of cancer

This application claims priority from the following applications: united states provisional patent application No. 60/243,341, filed on day 27, month 10, 2000; united states provisional patent application No. 60/245,582, filed 11/6/2000; united states provisional patent application No. 60/250,138, filed on 12/1/2000.

Technical Field

The present invention relates to therapeutic combinations for the treatment of cancer comprising an effective amount of camptothecin (CPT-11) and an effective amount of a 1, 2-stilbene derivative (e.g. combretastatin).

The present invention relates to the treatment of cancer, in particular solid tumors, and more particularly to the treatment of non-small cell liver cancer and colorectal cancer, using camptothecin derivatives in combination with other anti-cancer drugs. The invention also relates to the use of the combination in an enhanced treatment.

More particularly, the present invention relates to anticancer therapy using irinotecan (CPT-11; Campto ) in combination with 1, 2-stilbene derivatives (e.g., combretastatin).

Background

Colorectal Cancer is a major factor in morbidity and mortality, with approximately 300,000 new cases per year in the european and american countries and resulting in 200,000 deaths (see p. boyle, "some recent advances in Colorectal Cancer epidemiology", "Management of ColorectalCancer" pages 19-34, Bleiberg h., Rougier p., Wilke h.j., eds. (Martin dunnitz, london 1998); and Midgley r.s., Kerr d.j., "systemic adjuvant chemotherapy for Colorectal Cancer", "Management of colorectalcer" pages 126-27, bleberig h., rougigiger p., wilh.j., eds. (Martin dunnitz, 1998).

While about 50% of patients are cured by surgery alone, the other half eventually die due to disease metastasis, including about 25% of patients who have evidence of disease metastasis at the time of diagnosis.

European patent EP 137,145 (incorporated herein by reference) describes camptothecin derivatives of the formula:

wherein, specifically, R₁Is hydrogen, halogen or alkyl, X is chlorine or NR₂R₃Wherein R is₂And R₃May be the same or different and may be a hydrogen atom, an optionally substituted alkyl group, a carbocyclic ring or an optionally substituted heterocyclic ring; or R₂And R₃Is alkyl (optionally substituted) which, together with the nitrogen atom to which it is attached, forms a heterocyclic ring optionally containing O, S and/or NR₄Another hetero atom of (A), R₄Is a hydrogen atom or an alkyl group; the group X-CO-O-is located at the 9, 10 or 11 position of the A ring.

These camptothecin derivatives are anticancer agents inhibiting type I topoisomerase, and irinotecan or CPT-11, a compound in which X-CO-O-is [4- (1-piperidino) -1-piperidino ] carbonyloxy, is an active ingredient, is particularly effective for the treatment of solid tumors, particularly colorectal cancer.

European patent application EP 74,256 also describes other camptothecin derivatives useful as anticancer agents, in particular structural analogues of the above structure, wherein X-CO-O-is replaced by a group-X 'R', said X 'being O or S, and R' being a hydrogen atom or an alkyl or acyl group.

Other camptothecin derivatives have also been disclosed, for example in the following patent applications: EP 56,692, EP 88,642, EP 296,612, EP 321,122, EP 325,247, EP540,099, EP 737,686, WO 90/03169, WO 96/37496, WO 96/38146, WO 96/38449, WO 97/00876, US 7,104,894, JP 57116,015, JP 57116,074, JP 59005,188, JP 60019,790, JP 01249,777, JP 01246,287 and JP 9112070; or in Canc.Res., 38(1997) Abstract 1526 or 95 (SanDiego-April 12-16 days); res, 55 (3): 603-609(1995) or AFMC int.Med.chem.Symp. (1997) abstract PB-55 (Hancheng-7, 27 to 8, 1).

Camptothecin derivatives are usually administered by injection, more specifically intravenously in the form of a sterile solution or emulsion. However, camptothecin derivatives can also be administered orally in the form of solid or liquid compositions.

Camptothecin is a cytotoxic alkaloid, and has strong antitumor activity. However, camptothecin derivatives are considered to be the most effective substances among those having antitumor activity against colorectal cancer, and the use of these compounds can be enhanced in clinical treatment with other antitumor agents.

In the inventionContainer

It has been found that: the combined administration of camptothecin derivatives and 1, 2-stilbene derivatives is particularly effective for the treatment of many solid tumors, such as colorectal cancer. Among the most effective 1, 2-stilbene derivatives are combretastatin A-4 and one derivative of this compound which is simply called combretastatin. Both compounds show strong mitotic inhibitory activity, cytotoxicity and inhibition of tubulin polymerization.

The structure of the combretastatin A-4 is as follows:

the novel alkali of windmill of the invention has the following structure:

these combretastatin bases are soluble in water and can be used in the form of salts, such as hydrochloride, acetate, phosphate, and mesylate salts, and the like.

US patent No. 5,525,632 discloses a process for the preparation of 1, 2-stilbene derivatives, including the preparation of combretastatin a-4, pharmaceutically acceptable salts, hydrates and solvates thereof, and a process for the preparation of pharmaceutical compositions in oral and/or parenteral dosage forms comprising the above compounds, inert pharmaceutically acceptable carriers and/or diluents. This patent and US5,674,906 disclose the following: 1, 2-stilbene derivatives (including combretastatin) have low toxicity and carcinostatic activity in vivo when used alone.

It has recently been found that: for mammals with tumors, the combined administration of camptothecin and combretastatin significantly reduces the development of tumor volume compared to the administration of each compound alone. In fact, for the treatment of cancer, particularly colon adenocarcinoma, the combined administration of the camptothecin derivative CPT-11 and the 1, 2-stilbene derivative combretastatin in a sequential order is more effective at lower doses than the maximum non-toxic dose of each of the active agents used alone. See in particular table IV below.

The effect of the combination can be demonstrated by measurement of therapeutic synergy. A combination shows therapeutic synergy if the therapeutic effect of the combination is superior to the effect of the individual components when taken individually at the optimal dose (t.h. corbett et al, cancer treatment Reports, 66, 1187 (1982)).

The effect of the combination can also be determined by: the maximum tolerated dose of the combination was compared to the maximum tolerated dose of each individual component in the study. This effect can be expressed in quantitative form, e.g. in log₁₀The cell killing number is expressed by the following calculation formula:

log₁₀the number of cell kills ═ T-C (days)/3.32 × Td,

where T-C represents the time required for cell growth, which is the average number of days required for a treated (T) tumor to reach a predetermined volume (e.g., 1g) and the number of days required for a control (C) tumor to reach the same volume, and Td represents the number of days required for the control tumor to double in volume (T.H. Corbett et al, Cancer, 40, 2660.2680 (1977); F.M. Schabel et al, Cancer Drug Development, division B, Methods in Cancer Research, 17, 3-51, New York, Academic Press Inc. (1979)). If log of product₁₀The product is considered effective if the cell killing number is greater than or equal to 0.7; if its Log₁₀The product is considered to be very effective if the cell kill number is greater than 2.8.

In the present invention, 1, 2-stilbene derivatives (e.g., combretastatin) can be used in combination with camptothecin derivatives (e.g., CPT-11) in amounts sufficient to inhibit tumor proliferation for administration to a mammal in need of treatment, reduction, or prevention of a tumor, particularly for administration to a patient having tumor cell proliferation to inhibit growth of tumor cells.

Inhibiting tumor cell proliferation means inhibiting tumor cells that are susceptible to treatment comprising administering to a patient suffering from tumor cell proliferation an effective amount of combretastatin and an effective amount of CPT-11. Where acceptable, such administration inhibits proliferation of tumor cells, or reduces the measurable volume of the tumor. In the best case, the tumor regresses completely.

As described above, there is no particular limitation on the method of administering the antitumor agent of the present invention to the mammal to be treated. They may be administered orally or parenterally, for example by the intravenous, subcutaneous or intramuscular route. For increased efficiency, it is preferred to administer combretastatin parenterally, for example by intravenous and subcutaneous routes of administration as an infusion. In the method of administration of the pharmaceutical formulation of the invention, combretastatin may be administered simultaneously with CPT-11, or the two may be administered sequentially in any order. In practical applications, the method and sequence of administration may vary depending on the following circumstances: specific formulations of combretastatin, specific formulations of CPT-11, specific tumor cells to be treated, and specific hosts to be treated. The optimal method and order of administration of combretastatin and CPT-11 can be selected by those skilled in the art according to routine techniques and as described herein.

Graptophanine and camptothecin in amounts effective to inhibit tumor proliferation represent therapeutic units that inhibit tumor cell proliferation and are susceptible to administration to patients suffering from tumor cell proliferation. The actual unit of treatment required may vary, depending on factors such as: specific dosage forms of combretastatin, of CPT-11, of the specific tumor cells to be treated and of the specific host to be treated. The optimal therapeutic unit for a given condition can be appropriately selected by those skilled in the art according to the therapeutic test unit and the contents described in the present application.

The antitumor agent of the present invention is a pharmaceutical preparation containing at least the above combretastatin and camptothecin compounds, so that these two active ingredients can be contained in a pharmaceutical preparation mixture. However, the two active ingredients of the present invention may also be contained separately in different pharmaceutical preparations, in combination in a sequential order. It should be noted that: as for the pharmaceutical preparations containing other agents such as other antitumor agents (third and fourth medicinal ingredients, etc.), they are naturally also included in the scope of the present invention as long as the pharmaceutical preparations contain the active ingredients used in the present invention. Furthermore, the antitumor agent of the present invention may contain a pharmaceutically acceptable carrier, diluent and other substances suitable for any of the pharmaceutical preparations of the present invention (the two components of the present invention are contained in separate pharmaceutical preparations, and each of the separate pharmaceutical preparations contains one of the two components to be administered in combination)

The antitumor agent of the present invention can be suitably used with suitable pharmaceutically acceptable carriers and diluents, which are well known to those skilled in the art of pharmaceutical preparations. As mentioned above, the antineoplastic agents of the present invention may suitably be administered parenterally. In such cases, the pharmaceutically acceptable carrier is formulated with the antineoplastic agent for intravenous infusion or injection using a variety of methods well known to those skilled in the art. Preferably, the pharmaceutical agent is prepared according to conventional techniques, e.g., as a unit dosage form of the two active ingredients, or as a lyophilized mixture of the two active ingredients, and then reconstituted in water for infusion or other suitable liquid.

20-116.5mg, preferably 36-60mg, of combretastatin and 144-400mg, preferably 240-400mg, of CPT-11 may be combined in various doses of the pharmaceutical formulation of the invention. The physiological drug value of a pharmaceutical composition used as an injection or infusion liquid can be adjusted by the content of a buffer as is well known in the art.

Detailed Description

The invention will now be explained in more detail with reference to preferred embodiments. It should be noted that these are only examples and should not be construed as limiting the present invention.

Antitumor efficacy and safety testTest (experiment)

The effect of the combination of CPT-11 and combretastatin was evaluated in mice with colon adenocarcinoma C51. CPT-11 was administered orally on days 2-5, four times daily, at different doses. Graptopethine was administered intravenously twice daily on days 1-5. In a combination regimen, three different doses of CPT-11 were administered orally on days 2-5, twice daily; three different doses of combretastatin were administered intravenously daily on days 1-5, twice daily.

Administration of CPT-11 and combretastatin in a single active agent and concurrent administration of CPT-11/wind

The results of the study of the carbapenem base are shown in Table I below.

TABLE I

Combretastatin (intravenous injection) and CPT-11 (oral administration) combined administration

New alkali CPT-11s Log of windmill10Cell killing number colon 51PR1
	Single active agent
- 400 1.1 -
	116.5 - 1.3 5/5
Simultaneous combined administration
	51.5 180 1.1 3/5

Tumor size 400-500 mg; td 2.4 days

The scheme is as follows: CPT-11 is administered 4 times a day for 2-5 days; the obtained new alkaloids are administered 2 times per day for 1-5 days¹Partial response-number of mice in which tumor volume was reduced by at least 50% in the test mice; that is, of the 5 mice tested, 5 mice responded at least partially.

Table 1 shows the effect of combretastatin and CPT-11 as single agents administered at the maximum non-toxic dose (HNTD). Table 1 also shows that: when these anti-tumor compounds are administered simultaneously, cure rates increase at lower doses (45% of the maximum non-toxic dose of the individual active agents). Thus, effective treatment can be achieved with reduced toxicity.

Table II shows the effect of sequential administration of CPT-11 after administration of combretastatin

TABLE II

Combretastatin (intravenous injection) and CPT-11 (oral administration) were administered sequentially in combination,

wherein Graptopetalum paraguayense is first administered

New alkali of windmill	CPT-11	Log10Number of cells killed	Colon 51PR
				60	400	Toxicity	-
	240	1.7	5/5
					144	1.5	5/5
36	400	Toxicity	-
					240	1.4	5/5
21.6	400	1.4	5/5
					240	1.4	4/5

combretastatin-HNTD-116.5 mg/kg/injection-HNTD dose mg/kg/%; 60 (51%); 36 (31%); 21.6 (18%). These doses alone did not cause regression.

When combretastatin is administered first, the most effective sequential combination is: 60mg/km combretastatin (51% of HNTD) was administered first, followed by 240mg/kg CPT-11 (60% of HNTD). Such combined administration results in log₁₀The number of cell kills was 1.7, and all showed partial regression of colon 51 tumors in 5 tested mice. The therapeutic effect of such combined administration is therefore superior to the effect of the individual agents when applied in optimal doses.

Such administration is toxic to test animals when CPT-11(400mg /) is administered at the maximum non-toxic dose after administration of combretastatin at the highest non-toxic doses of 51% and 31%. Log only when combretastatin was combined at 18% and CPT-11 at the highest non-toxic dose₁₀The number of cell kills was 1.4, with partial response in all 5 mice tested. The log cell kill of this combination was higher than the log cell kill of each agent, indicating the therapeutic efficacy of the combination.

Surprisingly, when 18% combretastatin was administered followed by administration of CPT-11 at 60% of the highest non-toxic dose, the log cell kill remained unchanged (1.4) and showed significant efficacy.

Table III below shows the log of CPT-11 administered first at the maximum non-toxic dose (400mg/kg) and then 36mg/kg of combretastatin (31% of the maximum non-toxic dose)₁₀The cell kill number was 1.9. Similarly, log of CPT-11 and combretastatin when administered as single active agents at the maximum non-toxic dose₁₀The cell kill numbers were 1.1 and 1.3, respectively, indicating that co-administration of combretastatin after administration of CPT-11 can produce a synergistic therapeutic effect.

TABLE III

Combretastatin (intravenous) and CPT-11 (oral) are administered in combination sequentially

Administration of CPT-11 first

New alkali of windmill	CPT-11	Log10Number of cells killed	Colon 51PR2
				60	400	Toxicity
36		1.9	5/5
				60	240	Toxicity	-
36		1.4	5/5

²Partial response-number of test mice with at least 50% reduction in tumor volume

The results of intravenous administration of combretastatin and oral administration of CPT-11 were tested in several different protocols as shown in Table IV below. When administered as a single active agent, combretastatin is administered twice daily for 5 consecutive days. CPT-11 was administered once daily for 4 consecutive days.

When administered sequentially, two regimens are applied. When combretastatin was first administered, CPT-11 was administered on day 1, followed by administration at a frequency of 1 time per day on days 2-5. When CPT-11 was administered first, it was administered at a frequency of 1 time per day on days 1-4, and then combretastatin was administered on day 5.

TABLE IV

Combretastatin (intravenous administration) and CPT-11 (oral administration) are co-administered in maximal non-toxic doses

Medicine

New alkali CPT-11 Log of windmill10Cell killing number colon 51PR2
	Single active agent
- 400 1.1 -
	116.5 - 1.3 5/5
Simultaneous combined administration
	51.5 180 1.1 3/5

Sequential combined administration, first administering combretastatin

60.0 240 1.7 5/5

Sequential co-administration of CPT-11 first

36.0 400 1.9 5/5

²Partial response-tumor volume of test mice was reduced by an amount of at least 50%.

Table IV above shows: when combretastatin and CPT-11 are administered in combination in sequence, the combination is more effective than the individual agents administered alone or in combination in any order. It can be seen that: the sequential administration of CPT-11/combretastatin has a synergistic effect against colon adenocarcinoma. In addition, the effect of the combination of CPT-11/combretastatin is better than the effect of CPT-11 or combretastatin alone at the maximum non-toxic dose.

These tests show that: combretastatin and CPT-11 can be administered in different ways to achieve the optimal effect of the combination of these compounds. Thus, the present invention is not limited to compositions obtained by physical combination of these drugs, but also encompasses combination modes allowing independent administration either simultaneously or sequentially.

Claims (5)

1. A product containing therapeutically effective amounts of combretastatin and camptothecin as a combined preparation for simultaneous, separate or sequential use in the treatment of a solid tumor, wherein said combretastatin is a compound selected from the group consisting of:

the camptothecin is irinotecan.

2. The product according to claim 1, wherein the solid tumor is a colon adenoma.

3. A product according to claim 1 or 2 in the form of a composition.

4. Use of a therapeutically effective amount of combretastatin in combination with camptothecin for the preparation of a pharmaceutical formulation for simultaneous, separate or sequential use in the treatment of a solid tumor, wherein the combretastatin is a compound selected from the group consisting of:

the camptothecin is irinotecan.

5. Use according to claim 4, wherein the solid tumour is a colon adenoma.