WO1992008460A1

WO1992008460A1 - Bis-dioxopiperazines for treating liver tumours

Info

Publication number: WO1992008460A1
Application number: PCT/GB1991/002018
Authority: WO
Inventors: Kurt Hellmann
Original assignee: Windleshaw Enterprises Limited
Priority date: 1990-11-15
Filing date: 1991-11-15
Publication date: 1992-05-29
Also published as: GB9024861D0

Abstract

A compound for use in a treatment for liver tumours, preferably in combination with radiation therapy, characterised by comprising a bis(3,5-dioxopiperazine-1-yl)alkane of general formula (I); where R1 is not the same as R2 and R1 and R2 are hydrogen, or alkyl with 1-4 carbon atoms.

Description

BIS-DIOXOPIPERAZINES FOR TREATING LIVER TUMOURS

DESCRIPTION

The present invention relates to bis-dioxopiperazines for treating liver tumours, particularly liver metastases. In particular, the invention relates to pharmaceutical compositions, for the treatment of liver tumours in combination with radiation, which comprise a bis-dioxopiperazine as an active component; methods of treating such tumours comprising

administering a bisdioxopiperazine in combination with radiation and; methods of inhibiting tumour growth, both in vivo and in vitro, comprising administering a bis-dioxopiperazine in combination with radiation.

The bisdioxopiperazine compounds, to which the present invention relates, are bis(3,5-dioxopiperazine-1-yl)alkanes having a structure as shown in general formula I:-

Where R¹ is not the same as R² and, R¹ and R² are hydrogen, or alkyl with 1-4 carbon atoms. The compounds may be in the (-) levo, (+) dextro or (+/-) racemic form.

Compounds of formula I and other similar compounds are described in British Patent Nos. 1234935 and 1374979. In these documents, it is suggested that these

compounds have an activity in relation to certain forms of cancer. However, no mention of

radiosensitization is made in these documents.

Large numbers of cancer patients die of liver

metastases but treatment of these secondary tumours is very far from satisfactory. Most measures, whether radiotherapy, chemotherapy or immunotherapy elicit no response at all. Radiotherapy for this condition made some progress, but like chemotherapy is hampered by the tolerance of normal liver tissue to the amount of radiation that can be given. Doses of 5 × 400 rads for pain due to liver metastases have frequently been used over many years with good subjective benefit, though objective benefits have been very few and far between and then only confined to liver secondaries due to carcinoma of the breast. Considerable interest has focussed on the possibility of radiotherapeutic gains by means of

radiosensitizers. 5-Fluorouracil in particular has been widely studied in this connection, though the benefit if any is not easy to demonstrate.

Hisonidazole, a hypoxic cell radiosensitizer, has given results which if anything are worse than with

radiotherapy alone.

The racemic compound (+/-) 1,2-bis,(3,5-dioxoρiperazine-1-yl)propane(ICRF 159), razoxane, has been used with radiotherapy with some success in the treatment of soft tissue sarcomas but all tumours are different and none more so than sarcomas and carcinomas. Previous clinical studies with razoxane as a

radiosensitizer have given mixed results. Although in soft tissue sarcomas the drug clearly potentiates radiotherapy, in sguamous carcinomas of the head and neck it did not. It also appeared to be ineffective as a radiosensitizer in carcinoma of the ovary. In all of these studies the drug was given simultaneously with the radiation. This frequently led to a

considerable degree of myelosuppression resulting in the necessity to interrupt treatment and split the dosing.

According to the present invention there is provided a compound for use in a treatment for liver tumours, characterised by comprising a bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I. Preferably, said compound is for use in combination with radiation treatment. The preferred bis(3,5-dioxopiperazine-1-yl)alkane is 1,2-bis(3,5-dioxopiperazine-1-yl)propane, as a racemate or in its levo or dextro form.

An advantage of the present invention is that it provides an effective treatment for carcinoma of the liver, especially for liver metastases. When

administered together with radiotherapy, compounds of the present invention provide a highly significant tumour inhibiting effect. This is roost surprising because radiotherapy is rarely of use in the treatment of carcinomas located in the liver, since this organ cannot stand the usual doses of radiation required to effect a tumour.

In a second aspect, the present invention provides a pharmaceutical composition, for use in a treatment for liver tumours, preferably in combination with

radiation, wherein said composition includes a

bis(3,5-dioxopiperazine- 1-yl)alkane of the general formula I, in admixture with a suitable pharmaceutical carrier. Preferably, the composition includes

1,2-bis(3,5-dioxopiperazine-1-yl)propane, as a racemate, or in its levo or dextro form. The advantages of this aspect of the invention are similar to those of the first aspect.

In a third aspect, the invention provides a method for treating liver tumours in a human or animal subject, comprising administering a pharmaceutically effective amount of a bis(3,5- dioxopiperazine-1-yl)alkane, of general formula I, to said subject. Preferably the bis(3,5-dioxopiperazine-1-yl)alkane is administered in combination with radiation.

Preferably, the tumour is a liver metastasis, which is preferably of gastrointestinal origin.

In a preferred regime, a compound of general formula I is administered prior to irradiation of a tumour.

Administration of the compound may continue during and after irradiation.

The advantages of the third aspect of the invention are similar to those of the first aspect, set out above. In further aspects, the present invention provides the use of a bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I, in the manufacture of a medicament for use in a treatment for liver tumours and a method of inhibitig the growth of a liver tumour, comprising administering a bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I, to a liver tumour. Preferably, the medicament is for use with radiation and the method is carried out in conjunction with the administration of radiation to the tumour.

In embodiments of all aspects of the invention, the preferred compound used or administered is

1,2-bis(3,5-dioxopiperazine-1-yl)propane; either as a racemate, or in its levo, or dextro form.

A significant advantage of the present invention is that reductions in tumour size and activity can be achieved, using minimal doses of radiation. Thus, in an embodiment, razoxane can be given by means of pretreatment with maximal doses, followed by radiation with minimal doses as outlined in Table 1. Using this regime and giving the radiation to the whole liver the responses seen are given in Table 2 and the acute toxicity encountered in Table 3. The number and degree of responses is surprising and could not have been anticipated.

The responses have been analysed precisely by

volumetric analysis of the CT scans of the liver. Example 1

Patients with unresectable liver metastases due to histologically proven gastrointestinal, chiefly

colorectal cancer, underwent the regime outlined in

Table 1. The patient's ages ranged from 40 to 77 and there were 5 men and 6 women. Host of them had not received any chemotherapy or radiotherapy previously. All patients had a complete physical examination which include chest x-ray, full blood count and liver function tests. In addition serum bilirubin and carcino-embryonic antigen (CEA) tests were done. These procedures were followed by a computerized tomography scan of the liver and the total metastatic involvement in this organ was calculated by digitalized CT

volumetric analysis.

Patients were then given razoxane 125mgs 3 times per day for 3 consecutive days followed on the 4th and subsequent 4 days by whole liver irradiation of 400cGy. They also received 125mgs razoxane once per day on each radiotherapy day. At the end of the 5th day or radiation treatment all biochemical, blood and CEA examinations were repeated. Antiemetics were given as required. Patients then received 125mgs razoxane daily for 4 weeks (Razoxane is available from ICI

Pharmaceuticals Ltd., Macclesfield, UK.) after the end of radiotherapy when CEA, liver function tests and haematological values were reexamined. A liver CT scan was also repeated at this time and tumour and liver volumes were again calculated.

Toxicity

Although all patients received antiemetics, nausea and vomiting was only experienced on the first day of radiation treatment and none of the patients were nauseated or vomited after the first day. Some

complained of tiredness and appetite improved gradually but none gained weight. There were no other acute side effects attributable to the treatment. No evidence of hepatitis or nephritis was observed. Results

Of 11 patients who were entered one was lost to follow-up and two did not respond. Both non-responding patients had not received the full dose of razoxane following the end of radiotherapy treatment.

Of the 7 patients who are evaluable all had reductions in their tumour volumes ranging between 20 and 85% (Table 2a and b). A 100% response rate in successive patients with liver metastases has not previously been reported in any series.

Patient 5 had had a recurrence of a carcinoma of the stomach 3 years after a partial gastrectomy as well as liver metastases. These tumours both responded by reductions of over 80%. They have since responded even further so that only approximately 5% of the original tumours are visible on CT scan.

Patient 3 is also noteworthy since although the reduction of his tumour load appears to be smallest at 20% this nevertheless represents a volume diminution of 427ml. Three months after his initial treatment the volume of his tumour load has remained static but his CEA as an indicator of active tumour continues to decline.

These results could not have been obtained with the same or higher doses of radiation alone as higher doses than those used (i.e. 2000 cGy) and given to the same area, have shown no response in the past. The results could not be due to razoxane alone because patients who responded well to the combined treatment (in the area radiation treated), did not enjoy any tumour reduction or response, if the tumour was outside the irradiated area.

Although results were obtained by means of a precise volumetric analysis, in at least 3 fo the 7 assessable patients the response could also be easily seen by means of standard CT scans. This rate of response is as high as any which ahs been claimed, but has been obtained at a greatly improved cost to the patient in terms of toxicity and quality of life.

TABLE 2

Entered 11

Lost to follow-up 1

Too early to assess 1

Protocol violations - no

razoxane after radiation 1

Razoxane for 6/28 days 1

Assessable

Responses 7 (with 5/7 of more than 50% volume reduction)

TABLE 2B

LIVER 2° RESPONSE - CT SCAN

(Volume) ml

Pt Treatment

Init. Pre Post Vol(ml) % on 2D Comments

1 mth change

↓

HMcD 2306 2442 0 0 1. No Rz

postt'ment

2.Widespread pulmonary & peritoneal deposits

JS 155 58 97 63

WC 49 49 Rz only for

6/30 days

GW 187 4 × 400cGy no Rz post- RTX WA-A 301 65 236 79 PH 1559 TABLE 3

RTX + Rz for Liver 2° - TOXICITY

No. of Pts

Evaluable 10

N & V 2

Diarrhoea 0

Neutropenia (<3000/mm³) 3

Alopecia 0

Interruption of RTX 1

Quality of Life good

Cost minimal

Example 2

Twenty-five patients (15 men and 10 women) with unresectable liver metastases due to histologically proven carcinomas (22 colorectal, 2 gastric and 1 bronchus) were treated with radiotherapy and razoxane. Patients' ages ranged from 40 to 77 years. Two had quite small diffuse tumours and three had enormous masses.

All patients had their history taken followed by a physical examination. A CT scan of the liver was done to calculate the total tumour volume and the volume of the liver. Patients had a full blood count and liver function tests, i.e. serum alkaline phosphatase, AST, ALT and bilirubin done before, immediately after radiotherapy and again 4 weeks later. Their CEA was determined at the same time on each occasion.

CT liver scans were done before and 4 weeks after the end of radiotherapy treatment. The total metastatic involvement of the liver was measured on each occasion. Hetastases volumes were measured using the ELSCINT 3D soft tissue imaging programme available with the EXEL 2400 computerised tomography (CT) scanner. Ten millimeter contiguous unenhanced axial slices were taken through the liver. Tumour metastases were identified as focal areas of low soft tissue density and regions of interest were drawn around each

metatasis using a ball driven cursor. Data summation by the imaging programme produced 3D reconstructed images and accurate volume measurements. Careful calibration showed a consistant underestimate of less than 10% on all readings.

Treatment consisted of razoxane 125mgs 8 hourly for 3 consecutive days followed on the 4th-8th day inclusive by 400cGy daily to the whole liver (except for patient 25 who received 10 fractions of 250cGy). Patients also

received 125mgs razoxane on each radiotherapy day. At the end of the 5th day of radiation treatment all biochemical, blood and CEA examinations were repeated. Ondansetron 8mg 1-2 hours before radiotherapy was given as standard. After their radiation treatment patients took 125mgs razoxane daily continuously for 1 month. 4 weeks after the end of radiotherapy reinvestigation, as outlined above, was carried out. Results

Results are shown in Table 4. It is noteworthy that 2 of 4 (Nos. 4 & &) patients who previously had 5-FU and leucovorin have had significant reductions of their tumour volumes. Horeover another patient (No. 14) with a recurrent carcinoma of the stomach who had previously had adriamycin, VP16 and cisplatin, had an excellent response of his tumour load which dimnished by nearly 70%. This is in contrast to most secondary treatments which are usually ineffective. Of the 25 patients 12

(48%) have had hepatic tumour load reductions of more than 50% while 4 have had lesser reductions and are clased as 'minor' responses. Radiotherapy is rarely given to the liver because the maximum radiation dose tolerated by this organ is insufficient to influence tumour growth. It is surprising, therefore, that using a radiation dosage of only 1139 rets - 2000 cGy/5/5d gave a response rate of 48% (or 64% if all responses are considered). These results could not have been obtained by radiation or by razoxane alone. The quality of life of most patients has been excellent and only in two has there been concern as a result of the treatment. They may have had radiation hepatitis which is unpredictable and not related to fractionation or total dose of radiation and both patients responded well to small doses of

corticosteroids. LTVER METASTASES RESPONSE TO RADIOTHERAPY ft RAZOΪAWR

Pt.No. Sex Total tumour load Tumour Response Survival

(mis) load (πths) before after reduct(4 wks) ion

%

1 X 967 237 76 PR 4

2 F 1495 1000 33 MR 8

3 X 2164 1737 20 XR 6

4 F 357 146 59 PR 3

(stom) 5 F 112 17 85 PR 13+

6 X 155 58 63 PR 3

7 F 301 65 79 PR 4

8 X 1559 1310 16 0 2

9 F 10 6 0 4

10 F 3 6 0 8+

11 X 583 205 65 PR 7+ at 2 mths

12 F 330 292 12 0 7

13 K 578 445 23 KR 7+

(stom)14 X 133 41 69 PR 7+

15 X 387 346 11 0 6+

16 X 431 511 +19 Prog 5+

17 F 33 14 PR 3+

18 X 316 120 61 PR 3+

19 X 119 150 +26 Prog 3+

20 X 34 17 50 PR 3+

21 X 93 43 54 PR 2+

22 F 242 116 52 PR 3+

23 X 28 28 0 O 2+

(lung) 24 X too diffuse to measure 0 2

25 F 2436 1502 38 XR 2+ PR = partial response; XR = minimal response; Prog = progressionO = no response; stom. = stomach

Claims

1. A compound for use in a treatment for liver tumours, characterised by comprising a

bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I:-

, where R₁ is not the same as R₂, and R₁ and R₂ are hydrogen, or alkyl with 1-4 carbon atoms.

2. A compound as claimed in claim 1, for use in combination with radiation, in a treatment for liver tumours.

3. A compound as claimed in claim 1 or claim 2, characterised by comprising 1,2-bis(3,5-dioxopiperazine-1-yl)propane, as a racemate, or in its levo or dextro form.

4. A pharmaceutical composition, for use in a

treatment for liver tumours, characterised by

comprising a bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I, as defined in claim 1, in admixture with a suitable pharmaceutical carrier.

5. A pharmaceutical composition, as claimed in claim 4, for use in combination with radiation in a treatment for liver tumours.

6. A composition as claimed in claim 4 or claim 5, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is 1,2-bis(3,5-dioxopiperazine-1-yl)propane, as a

racemate, or in its levo or dextro form.

7. Use of a bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I, as defined in claim 1, in the manufacture of a medicament for use in a treatment for liver tumours.

8. The use claimed in claim 7, wherein the

medicament is for use in combination with radiation.

9. A use as claimed in claim 7 or claim 8, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is 1,2-bis(3,5- dioxopiperazine-1-yl)propane.

10. A use of a bis(3,5-dioxopiperazine-1-yl)alkane, as claimed in any of claims 7-9, wherein said compound is in admixture with a suitable pharmaceutical carrier.

11. A method of inhibiting the growth of a liver tumour, comprising administering a

bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I, as defined in claim 1, to a liver tumour.

12. A method as claimed in claim 11, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is administered in combination with radiation.

13. A method for treating liver tumours in a human or animal subject, comprising administering to said subject a pharmaceutically effective amount of a bis(3,5-dioxoρiperazine-1-yl)alkane, as defined in claim 1.

14. A method as claimed in claim 13, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is administered in combination with radiation.

15. A method of potentiating the effect of radiation on a liver tumour, comprising administering a bis(3,5-dioxopiperazine-1-yl)alkane of the general formula I, as defined in claim 1, in addition to irradiating said tumour.

16. A method as claimed in any of claims 11-15, wherein the liver tumour comprises a liver metastasis.

17. A method as claimed in claim 16, wherein the liver metastasis is of gastrointestinal origin.

18. A method as claimed in any of claims 12-17, wherein the bis(3,5-dioxopiρerazine-1-yl)alkane is administered prior to irradiation of the tumour.

19. A method as claimed in claim 18, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is administered during a period in which the tumour undergoes irradiation and, preferably, administration continues after irradiation has completed.

20. A method as claimed in claim 19, wherein the 1,2-bis(3,5-dioxopiperazine-1-yl)propane is

administered for a period of about 3 days prior to irradiation of the tumour, for a period of about 5 days in which the tumour undergoes radiation treatment and for about 4 weeks after radiation treatment has ceased.

21. A method as claimed in claim 20, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is administered in a dose of about 375mg per day, prior to irradiation, and in a dose of about 125mg per day during radiation treatment and subsequent to irradiation.

22. A method as claimed in any of claims 11-21, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is 1,2-bis(3,5-dioxopiperazine-1-yl)propane, in its racemic, dextro or levo form.

23. A method as claimed in any of claims 11-22, wherein the bis(3,5-dioxopiperazine-1-yl)alkane is administered in the form of a pharmaceutical composition with a suitable pharmaceutical carrier.