AU2007202083B2

AU2007202083B2 - Anti-Cancer Combinations

Info

Publication number: AU2007202083B2
Application number: AU2007202083A
Authority: AU
Inventors: Bronwyn Gae Siim; William Robert Wilson
Original assignee: Cancer Research Technology Ltd
Current assignee: Cancer Research Technology Ltd
Priority date: 2001-09-03
Filing date: 2007-05-09
Publication date: 2009-08-20
Anticipated expiration: 2022-09-03
Also published as: AU2007202083A1; AU2009202760A1

Description

P/00/01 1 28/5/91 Regulation 3.2 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Cancer Research Technology Limited Actual Inventor Bronwyn Gae Siim William Robert Wilson Address for service is: WRAY & ASSOCIATES Level 4, The Quadrant 1 William Street Perth, WA 6000 Attorney code: WR Invention Title: Anti-Cancer Combinations The following statement is a full description of this invention, including the best method of performing it known to me: 1 ANTI-CANCER COMBINATIONS The present invention relates to synergistic combinations of the compound 5,6 dimethylxanthenone-4-acetic acid (DMXAA) and a compound selected from platinum 5 compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors, which have anti-tumour activity. Preferably, the present invention relates to synergistic combinations of the compound 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and a compound selected from carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophosphamide, etoposide, 10 vincristine, doxorubicin and irinotecan. More particularly, the invention is concerned with the use of such combinations in the treatment of cancer and pharmaceutical compositions containing such combinations. 5,6-dirnethylxanthenone-4-acetic acid (DMXAA) is represented by the following 15 formula: 0

H

3 C 0

CH

3 OH 0 Phase I clinical trials of DMXAA have recently been completed, with dynamic MRI 20 (Magnetic Resonance Imaging) showing that it induces a significant reduction in tumour blood flow at well-tolerated doses. DMXAA is thus one of the first antivascular agents for which activity (irreversible inhibition of tumour blood flow) has been documented in human tumours. These findings are in agreement with preclinical studies using tumours or human tumour xenografts which showed that its antivascular activity produced 25 prolonged inhibition of tumour blood flow leading to extensive regions of haemorrhagic necrosis. However, in such studies tumours rapidly regrow from surviving cells in the well-perfused periphery. The transient tumour growth inhibition seen in most preclinical models is consistent with the lack of tumour regressions seen in the phase I clinical studies, and suggests that DMXAA is unlikely to have clinical utility as a single agent. 30 Carboplatin (Paraplatin*) is a platinum coordination cancer chemotherapeutic agent. The chemical name for carboplatin is platinum, diammine [1,1 cyclobutanedicarboxylato(2-)-0, 0']-,(SP-4-2). 5 Cisplatin (Platinol*) is a platinum antineoplastic agent used to treat a variety of tumour types. Gemcitabine (Gemzar*) (HCI) is a nucleotide analogue antimetabolite that exhibits antitumour activity. Gemcitabine HC1 is 2'-deoxy-2',2'-difluorocytidine 10 monohydrochloride (b-isomer). 5-fluorouracil (Adrucil*) is an injectable antineoplastic antimetabolite. Its chemical name is 5-fluoro-2,4(1H,3H)-pyrimidinedione. 15 Cyclophosphamide (Cytoxan) is available as a lyophilised cake for injection or as tablets for oral use. Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. The chemical name for cyclophosphamide is 2-[bis(2 chloroethyl)anino]tetrahydro-2H-13,2-oxazaphosphorine-2-oxide monohydrate. 20 Doxorubicin HCl (Adrianycin*) is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. It has the chemical name (8S,10S)-10-[(3-amino 2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8, 9 ,10-tetrahydro-6,8,11 trihydroxy-l-methoxy-5,12-naphthacenedione hydrochloride. 25 Vincristine (Oncovin*, Vincasar PFS", Vincrex*) is a vinca alkaloid antineoplastic. Etoposide (VePesid@), (also commonly known as VP-16) is a topoisomerase II inhibitor. It is a semisynthetic derivative of podophyllotoxin. It is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-(beta)-D-glucopyranoside]. Etoposide is available for oral or intravenous administration. Irinotecan (Campto@, Camptosar@) is a topoisomerase I inhibitor. It is a semi-synthetic derivative of camptothecin. The chemical name is (S)-4,1 1-diethyl-3,4,12,14-tetrahydro 4-hydroxy-3,14-dioxo-IH-pyrano[3',4':6,7]-indolizinol[1,2-b]quinolin-9-yl-[1,4' bipiperidine]-l'-carboxylate, monohydrocloride, trihydrate. It has now surprisingly been found that by combining, either concomitantly or sequentially, DMXAA with a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors, preferably with a compound selected from carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophospharnide, etoposide, vincristine, doxorubicin and irinotecan, potentiation of antitumour activity is achieved. 5 Thus, in a first aspect, the present invention provides a method for treating cancer, which comprises administering to a mammal, including a human, in need of such treatment an effective amount of DMXAA or a pharmaceutically acceptable salt or ester thereof and concomitantly or sequentially administering an effective amount of a compound selected 10 from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors. In another aspect, the present invention provides the use of DMXAA or a pharmaceutically acceptable salt or ester thereof for the manufacture of a medicament, 15 for administration either concomitantly or sequentially with a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors, for the treatment of cancer. In a further aspect, the present invention provides the use of a compound selected from 20 platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase I inhibitors for the manufacture of a medicament, for administration either concomitantly or sequentially with DMXAA or a pharmaceutically acceptable salt or ester thereof, for the treatment of cancer. 25 In a still further aspect, the present invention provides a combination of DMXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase I inhibitors. 30 According to a still further aspect of the present invention, there is provided a kit comprising in association for separate administration DMXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors. 35 Examples of suitable platinum compounds are cisplatin and carboplatin. An example of a suitable vinca alkaloid is vincristine.

An example of a suitable alkylating agent is cyclophosphamide. An example of a suitable anthracycline is doxorubicin. 5 An example of a suitable topoisomerase II inhibitor is etoposide. Examples of suitable antimetabolites are gemcitabine and 5-fluorouracil. 10 An example of a suitable topoisomerase I inhibitor is irinotecan. Thus, in the present invention, the compound selected from platinum compounds, vinca alkaloids, alkylating agents; anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors may, for example, be a compound selected from 15 carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophospharnide, etoposide, vincristine, doxorubicin and irinotecan. In one embodiment of the present invention, the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I 20 inhibitors, antimetabolites and topoisomerase II inhibitors is a compound selected from carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophosphamide, etoposide, vincristine and doxorubicin. In another embodiment of the present invention the compound selected from platinum 25 compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is a compound selected from carboplatin, gemcitabine, cisplatin, cyclophosphamide, etoposide, vincristine and irinotecan. 30 In another embodiment of the present invention the compound selected fi-om platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is a compound selected from carboplatin, gemcitabine, cisplatin, cyclophosphamide, etoposide and vincristine. 35 In another embodiment of the present invention the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is a compound selected from gemcitabine, cisplatin, 5-fluorouracil,doxorubicin and irinotecan.

In another embodiment of the present invention the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is a compound selected from 5 gemcitabine, cisplatin and irinotecan. In another embodiment of the present invention the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is a compound selected from 10 gemcitabine, cisplatin, 5-fluorouracil and doxorubicin. In another embodiment of the present invention the DMXAA is used or is present, or the DMXAA and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and 15 topoisomerase II inhibitors are used or are present, in the absence of an antibody. In another embodiment of the present invention, when the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase U inhibitors is 5-fluorouracil or 20 doxorubicin, the DMXAA is used or is present, or the DMXAA and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors are used or are present, in the absence of an antibody. 25 Brief Description of the Drawings Fig. 1. Illustrates growth delay of MDAH-Mca-4 tumours after treatment of mice with chemotherapeutic drug alone (i.p.) (0) or co-administration of drug with DMXAA (80 stmol/kg) (e). Values are mean i sem for groups of 6-8 mice, ignoring deaths (d) or 30 cures (c), the numbers of which are shown in parentheses. * and ** indicate p<0.05 and <0.01 respectively for significance of growth delay relative to corresponding control (±DMXAA). Fig. 2. Left hand panel: Plasma concentrations of free platinum following administration of carboplatin alone (316 smol/kg) (e), or co-administered with DMXAA (80 pmol/kg) 35 (0). Right hand panel: Tumour concentrations of total platinum following administrationof carboplatin alone (316 pimol/kg) (0), or co-administeredwith DMXAA (80 pLmol/kg) (0).

The DMIXAA or pharmaceutically acceptable salt or ester thereof and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors may be administered concomitantly or sequentially. Preferably the DMXAA or 5 pharmaceutically acceptable salt or ester thereof and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors are administered concomitantly. 10 Preferably the DMXAA or pharmaceutically acceptable salt or ester thereof and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase Il inhibitors are present in a potentiating ratio. 15 The term 'potentiating ratio' is used herein to indicate that the DMXAA or pharmaceutically acceptable salt or ester thereof and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors are present in a ratio such that the antitumour activity of the combination is greater than that of DMXAA alone or the 20 compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors alone or of the additive activity that would be predicted for the combinations based on the activities of the individual components. Thus the individual components act synergistically in combination provided they are present in a potentiating ratio. 25 A potentiating ratio, for DMXAA and antirnetabolites, for example gemcitabine and 5 fluorouracil, which may be successfully used to treat cancer, is in the range 1:100 to 1:2 of DMXAA:antimetabolite. Suitably,the potentiatingratio is in the range 1:75 to 1:5. A further potentiating ratio is in the range 1:50 to 1:10. A preferred potentiating ratio is in 30 the range 1:30 to 1:15, more preferably in the range 1:25 to 1:20 of DMIXAA:antimetabolite. A potentiating ratio, for DMXAA and platinum compound, for example carboplatin or cisplatin, which may be successfully used to treat cancer, is in the range 20:1 to 1:20. 35 For example, in the case of carboplatin, a potentiating ratio which may be successfully used to treat cancer, is in the range 1:20 to 1:1 of DMXAA:carboplatin. Suitably, in the case of carboplatin the potentiating ratio is in the range 1:16 to 1:2. A further potentiating ratio in the case of carboplatin is in the range 1:10 to 1:2. A preferred potentiating ratio in the case of carboplatin is in the range 1:8 to 1:3, more preferably in the range 1:6 to 1:4 of DMXAA:carboplatin. Similarly, in the case of cisplatin, a potentiating ratio, which may be successfully used to treat cancer, is in the range 20:1 to 1:1 of DMXAA:cisplatin. Suitably, in the case of cisplatin the potentiating ratio is in the 5 range 10:1 to 1:1. A further potentiating ratio in the case of cisplatin is in the range 8:1 to 1:1. A preferred potentiating ratio in the case of cisplatin is in the range 6:1 to 2:1, more preferably in the range 4:1 to 2:1 of DMXAA:cisplatin. A potentiating ratio, for DMIXAA and alkylating agents, for example cyclophosphamide, 10 which may be successfully used to treat cancer, is in the range 1:100 to 1:2 of DMXAA:alkylating agent. Suitably, the potentiating ratio is in the range 1:50 to 1:5. A further potentiating ratio is in the range 1:30 to 1:5. A preferred potentiating ratio is in the range 1:20 to 1:8, more preferably in the range 1:16 to 1:12 of DMXAA:alkylating agent. 15 A potentiating ratio, for DMXAA and topoisomerase II inhibitors, for example etoposide, which may be successfully used to treat cancer, is in the range 10:1 to 1:10 of DMXAA: topoisomerase II inhibitor. Suitably, the potentiating ratio is in the range 5:1 to 1:5. A further potentiating ratio is in the range 5:1 to 1:3. A preferred potentiating 20 ratio is in the range 3:1 to 1:2, more preferably in the range 2:1 to 1:2 of DMXAA: topoisomerase II inhibitor. A potentiating ratio, for DMXAA and vinca alkaloids, for example vincristine, which may be successfully used to treat cancer, is in the range 200:1 to 5:1 of DMXAA: vinca 25 alkaloid. Suitably, the potentiating ratio is in the range 150:1 to 10:1. A further potentiating ratio is in the range 100:1 to 40:1. A preferred potentiating ratio is in the range 100:1 to 60:1, more preferably in the range 90:1 to 70:1 of DMXAA:vinca alkaloid. 30 A potentiating ratio, for DMIXAA and anthracyclines, for example doxorubicin, which may be successfully used to treat cancer, is in the range 50:1 to 1:1 of DMIXAA: anthracycline, Suitably, the potentiating ratio is in the range 25:1 to 1:1. A further potentiating ratio is in the range 16:1 to 2:1. A preferred potentiating ratio is in the range 8:1 to 2:1, more preferably in the range 6:1 to 4:1 of DMXAA: anthracycline. 35 Preferably the pharmaceutically acceptable salt of DMXAA is the sodium salt.

In one embodiment the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomeraselI inhibitors is carboplatin. 5 In one embodiment the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomeraselI inhibitors is gemcitabine. In one embodiment the compound selected from platinum compounds, vinca alkaloids, 10 alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase I inhibitors is cisplatin. In one embodiment the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and 15 topoisomerase II inhibitors is 5-fluorouracil. In one embodiment the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is cyclophosphamide. 20 In one embodiment the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is etoposide. 25 In one embodiment the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors is vincristine. In one embodiment the compound selected from platinum compounds, vinca alkaloids, 30 alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomeraseIl inhibitors is doxorubicin. In one embodiment the compound selected fi-om platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and 35 topoisomerase II inhibitors is irinotecan. The amount of a combination of DMXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors required to be effective as an anticancer agent will, of course, vary and is ultimately at the discretion of the medical practitioner. The factors to be considered include the route of administration and nature of the formulation, the mammal's 5 bodyweight, age and general condition and the nature and severity of the disease to be treated. A suitable effective dose of DMIXAA, or a pharmaceutically acceptable salt thereof, for administration, either concomitantly or sequentially, with a compound selected from 10 platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors to man for the treatment of cancer is, for example, in the range of 500 to 4900 mg/m 2 . For example, from 600 to 4900 mg/m 2 , suitably from 600-3100mg/m 2 , more suitably from 1000-2500 mg/m 2 and particularly from 1100-1500 mg/m 2 . Alternatively, the amount of DMXAA, or a 15 pharmaceutically acceptable salt thereof, may, for example, be from 2500 to 4000 mg/m 2 , suitably from 1200 to 3500 mg/m 2 , more suitably from 2000 to 3000 mg/m 2 , still more suitably from 1200 to 2500 mg/m 2 , particularly from 2500 to 3500 mg/m 2 , and more particularly from 2250 to 2750 mg/m 2 . Preferably the DMXAA, or pharmaceutically acceptable salt thereof, is administered by IV once every week or every 3 weeks. 20 A suitable effective dose of platinum compound, for example carboplatin or cisplatin, for administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 10 to 500 mg/m 2 . 25 In the case of carboplatin a suitable effective dose for administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 100 to 500 mg/m 2 . For example, from 100 to 300 mg/m2, suitably from 250 to 400 mg/rn 2, more suitably 30 from 150 to 350 mg/m 2 , particularly from 150 to 250 mg/m 2 , and more particularly from 175 to 225 mg/m2. Similarly, in the case of cisplatin, a suitable effective dose for administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt 35 thereof, to man for the treatment of cancer is, for example, in the range 10 to 200 mg/m 2 . For example, from 20 to 150 mg/m 2 , suitably from 30 to 120 mg/m 2 , more suitably from 40 to 100 mg/m 2 , particularly from 40 to 80 mg/m 2 , more particularly from 60 to 100 mg/m 2 , and preferably from 75 to 100 m/m 2

.

Preferably the platinum compound, for example, carboplatin or cisplatin is administered by IV once every 4 weeks. 5 A suitable effective dose of antimetabolite, for example gemcitabine or 5-fluorouracil, for administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 400 to 2000 mg/m 2 . For example, from 500 to 1500 mg/m 2 suitably from 600 to 1200 mg/m 2 , more suitably from 600 to 1000 mg/m 2 , particularly 10 from 800 to 1200 mg/m 2 , more particularly from 800 to 1000 mg/m 2 , preferably from 750 to 980 mg/m 2 , more preferably from 750 to 965 mg/m2. A suitable effective dose of antimetabolite, for example gemcitabine or 5-fluorouracil, for administration, either concomitantly or sequentially, with DMXAA, or a 15 pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 2 to 20 mg/kg. For example, from 2 to 15 mg/kg, suitably from 2 to 8 mg/kg, more suitably from 6 to 12 mg/kg, particularly from 4 to 10 mg/kg, and preferably from 4 to 6 mg/kg. 20 Preferably the gemcitabine is administered by IV once every week and preferably the 5 fluorouracil is administered on alternate days for a period of about 2 weeks. A suitable effective dose of alkylating agent, for example cyclophospharnide, for administration, either concomitantly or sequentially, with DMXAA, or a 25 pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 100 to 1000 mg/m 2 . For example, from 200 to 800 mg/m 2 , suitably from 200 to 500 mg/m 2 , more suitably from 350 to 700 mg/m 2 , particularly from 450 to 650 mg/m 2 , more particularly from 500 to 600 mg/m 2 , and preferably from 550 to 650 mg/m 2 . 30 Preferably the alkylating agent, for example cyclophosphamide, is administered by IV once every 4 weeks. A suitable effective dose of topoisomerase 11 inhibitor, for example etoposide, for 35 administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 5 to 150 mg/m 2 . For example, from 5 to 120 mg/m2, suitably from 10 to 100 mg/m 2 , more suitably from 15 to 50 mg/m 2 , particularly from 60 to 120 mg/m 2 , more particularly from 35 to 75 mg/m 2 , and preferably from 30 to 60 mg/m 2 . Preferably the topoisomerase II inhibitor, for example etoposide, is administered by IV 5 daily for 4 to 7 days. A suitable effective dose of vinca alkaloid, for example vincristine, for administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 0.1 to 2.0 mg/m 2 . 10 For example, from 0.125 to 1.75 mg/m 2 , suitably from 0.15 to 1.5 mg/m 2 , more suitably from 0.2 to 1.4 mg/m 2 , particularly from 0.6 to 1.4 mg/m 2 , more particularly from 0.8 to 1.4 mg/m 2 , and preferably from 0.5 to 1.0 mg/m 2 . Preferably the vinca alkaloid, for example vincristine, is administered by IV once every 15 week. A suitable effective dose of anthracycline, for example doxorubicin, for administration, either concomitantly or sequentially, with DMXAA, or a pharmaceutically acceptable salt thereof, to man for the treatment of cancer is, for example, in the range 5 to 100 Mg/M 2 . 20 For example, from 10 to 80 mg/m 2 , suitably from 20 to 60 mg/m 2 , more suitably from 40 22 to 75 mg/m2, particularly from 20 to 50 mg/m 2 , more particularly from 15 to 35 mg/m 2 and preferably from 40 to 60 mg/m 2 . Preferably the anthracycline, for example doxorubicin, is administered by IV once every 25 3-4 weeks. The DMXAA or pharmaceutically acceptable salt or ester thereof and the compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors may be 30 administered in any suitable form. However, for use according to the present invention the combination of DMXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected fi-om platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomeraselI inhibitors is preferably presented as a pharmaceutical formulation. 35 Pharmaceutical formulations comprise the active ingredients (that is, the combination of DMIXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors) together with one or more pharmaceutically acceptable carriers therefor and optionally other therapeutic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formula and not deleterious to 5 the recipient thereof. Accordingly, the present invention provides a pharmaceutical formulation comprising a combination of DMXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, 10 anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors in association with one or more pharmaceutically acceptable carriers therefor. The present invention further provides a process for the preparation of a pharmaceutical formulation which process comprises bringing into association a combination of 15 DMXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors with one or more pharmaceutically acceptable carriers therefor. 20 Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal and parenteral (including subcutaneous, intradermal, intramuscular and intravenous) administration as well as administration by naso-gastric tube. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of 25 pharmacy. All methods include the step of bringing into association the active ingredients with the pharmaceutically acceptable carrier(s), for example liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. 30 Preferably the pharmaceutical formulations are adapted for parenteral administration, most preferably intravenous administration. For example the compounds may be administered intravenously using formulations for each compound already known in the art. 35 Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of the active ingredients. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compounds in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an inert liquid diluent. 5 Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling the active ingredients, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein the active ingredients together with any accessory ingredient(s) are sealed in a rice paper envelope. The combination of 10 DMIXAA or a pharmaceutically acceptable salt or ester thereof and a compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged e.g. in a sachet. 15 Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion. Formulations for oral administration include controlled release dosage forms e.g. tablets 20 wherein the active ingredients are formulated in an appropriate release - controlling matrix, or are coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use. The active ingredients may also be formulated as a solution or suspension suitable for 25 administration via a naso-gastric tube. Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be 30 conveniently formed by admixture of the active combination with the softened or melted carrier(s) followed by chilling and shaping in moulds. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of the active combination in aqueous or oleaginous vehicles. 35 Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, the active ingredients may be in powder form which are constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use. The pharmaceutical formulations may, for example, be in the form of liposomal 5 formulations. The combination of DMXAA or a pharmaceutically acceptable salt or ester thereof and compound selected from platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II 10 inhibitors may also be formulated as a long-acting depot preparation, which may be administered by intramuscular injection or by implantation e.g. subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use. 15 It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations for the various routes of administration described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, 20 preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient. DMXAA may be prepared according to the methods described in Journal of Medicinal Chemistry 34(1): 217-22, January 1991 the contents of which are incorporated herein by 25 reference. Platinum compounds, vinca alkaloids, alkylating agents, anthracyclines, topoisomerase I inhibitors, antimetabolites and topoisomerase II inhibitors, for example, carboplatin, gemcitabine, cisplatin, 5-fluorouracil, cyclophosphamide, etoposide, vincristine, 30 doxorubicin and irinotecan, are well known compounds and may be prepared by methods known to those skilled in the art. It is to be understood that the present invention covers all combinations of suitable and preferred groups described hereinabove. 3S Cancers that may be treated in accordance with the present invention include, but are not limited to, solid tumors, for example, non-small cell lung cancers, small cell lung cancers, breast cancer, cancer of the pancreas, ovarian cancer, colorectal cancer, prostate cancer, and gastric cancer. The present invention will now be illustrated, but is not intended to be limited, by means 5 of the following examples. EXAMPLES Example 1: 10 Materials And Methods Compounds: A stock solution of DMXAA, synthesised in the Auckland Cancer Society Research Centre, was prepared in phosphate-buffered saline, protected from light and 15 stored frozen. Cisplatin (Sigma Chemical Co., St Louis, MO) was dissolved in 0.9% saline. Stock solutions of carboplatin and 5-fluorouracil (Bristol Myers Squibb, Sermonita, Italy) and cyclophosphamide (Mead Johnson Oncology Products, Princeton, NJ) were diluted with sterile water. Doxorubicin (Farmitalia Carlo Erba Pty Ltd, Clayton North, Australia), etoposide, and vincristine (Bristol-Myers Squibb, Serrnonita, 20 Italy) were diluted using 0.9% saline. All compounds were administered to mice by i.p. injection at 0.01 ml/g body weight. Animals and Turnours: Murine mammary carcinoma MDAH-Mca-4 tumours were grown from stocks stored in liquid nitrogen at the sixth transplant generation. Tumours 25 (eighth transplant generation when used) were grown from 20 pl of cell suspension (7 mg packed cells), inoculated i.m. (intra-muscular) in the right gastrocnemius muscle of female C 3 H/HeN mice (22-25 g at the time of treatment). Mice were randomised to treatment which commenced when the tumour+ leg diameterreached 10-11 mm (0.5 0.7 g tumour). 30 Host Toxicity and Antitumour Activity: Mice were treated with chemotherapeutic drugs at a range of doses, at 1.33-fold increments, up to the expected MTD (maximum tolerated dose, as estimated in pilot experiments or from the literature). Toxicity was assessed as lethality, and body weight loss measured four days after treatment. Any 35 animals becoming moribund were terminated and treated as drug-related deaths in the analysis. The diameter of the tumour-bearing leg was measured 3 times per week after treatment. Antitumour activity was assessed from the tumour growth delay, defined as the difference in time to reach the endpoint of 13 mm (1.5 g tumour) for treated and control groups. Responses were classed as cures if animals were free of evident tumour 120 days after treatment. The statistical significance of tumour growth inhibition was tested by ANOVA using SAS for Windows, with Dunnett's test to evaluate p-values for differences between treatment groups. In experiments with substantial numbers of cures (free of tumour for > 120 days after treatment), statistical significance was tested by Kruskal-Wallis non-parametric analysis of variance using SAS for Windows, and the difference between treatment and control groups by Dunn's test using Sigmastat v2.0. The gradient and standard error of dose-response curves was determined by linear regression using Sigmastat, and the DMF (Dose Modifying Factor) calculated as the gradient with DMXAA/gradient without DMXAA. 10 Tumour blood flow inhibition: Tumour blood flow was assessed using the fluorescent perfusion marker Hoechst 33342 (8mg/ml in saline), which was administered i.v. at various times after drug treatment. Mice were scarified 2 min later, and frozen sections (14 sm) prepared from the distal, central and proximal regions of each tumour. Sections 15 were examined with a Nikon epifluorescence microscope at lOx magnification using a UV-lA filter block (excitation 365 nm, barrier filter 400 nm, and dichroic mirror 400 nm). A grid with 81 squares (100 x 100 pm), was used for point scoring of staining. The whole area of each section was scored to avoid bias between peripheral and central regions (which were less well perfused). Normal tissue was excluded but necrotic areas 20 were included. Differences between groups were treated for significance using the Student's t-test (Sigma Stat, version-2.0, Jandel Scientific Limited). Pharmacokinetics: Female C 3 H/HeN mice bearing MDAH-Mca-4 tumours (0.5-0.7 g) were injected i.p. with carboplatin (316 ymol/kg), DMXAA (80 smol/kg), or 25 simultaneously received carboplatin and DMXAA, at the same doses. At various times blood was collected from the retro-orbital sinus of anaesthetised mice into heparinised tubes, and the plasma separated by centrifugation. Tumours were rapidly dissected and frozen at -80*C. Groups of 2-5 mice were used for each time point. 30 ICP-MS (Inductively coupled plasma-mass spectroscopy) analysis of platinum: Concentrations of platinum in plasma and tumours were determined using the following previously published ICP-MS method. Tumours were weighted, placed in 15 ml screw cap tubes containing Iml of 70% nitric acid (Riedel-de-Haen, Seelze, Germany), and left to stand overnight at room temperature. The following day, tumours were digested for 35 2 h at 90*C in a sand-filled electric frying pan positioned with a fume hood. After cooling, the solubilized tumour tissues were made to volume in 10-ml volumetric flasks using Milli-Q water and then introduced into the ICP-MS. Plasma was prepared for analysis by methanol precipitation of plasma protein. Plasma was added to an equal volume of ice-cold methanol, mixed and left to stand at -20*C for 18 h. The sample was centrifuged and an aliquot of supernatant was diluted (1:40) in 0.1% nitric acid before being introduced into the ICP-MS. 5 The ICP-MS system comprised a Hewlett Packard HP 4500 ICP-MS with a nickel sampling cone, Babington (v-groove) nebulizer and a Scott double-pass spray chamber maintained at 2*C. Platinum was read at 195 amu with a dwell time of 100 ms and a replicate time of 6000 ins. Calibration curves were linear (r 2 >0.98) over a wide range (0.5 to 5000 ng/ml). Intra-assay and inter-assay variability and recovery were within 10 acceptable limits. The limits of quantitation were 12.5 pg of platinum per ml of plasma and 10 ng of platinum per g of tumour tissue. HPLC analysis of DMXAA: Concentrations of DMXAA in plasma were determined as follows. Aliquots of plasma (50 pl) were treated with 1 ml of ice-cold 15 acetonitrile:methanol (3:1 v/v), centrifuged, and the resulting supernatants evaporated using a Speed-Vac solvent concentrator (Savant Instruments, NY). The residues were dissolved in 200 jl of 10 mM ammonium acetate buffer (pH 5) and 25 L was analysed by HPLC using a HPI 100 system with diode array detector (278 nm) and fluorescence detector. The column used was a 3.2 mm x 150 mm C 8 5 pm column (AlItima 20 Associates Inc., Deerfield, IL) and a flow rate of 0.7 ml/min, with a mobile phase of 16% acetonitrile (v/v) in 10 mM ammonium acetate buffer (pH 5). The retention time for DMXAA was 7.3 min. Spiking of control plasma showed assay linearity from 0.1-100 pM (r 2 = 0.999). The intra- and inter- assay precision and accuracy gave coefficients of variation <7%, and an average recovery of 70%. The lower sensitivity limit of detection 25 by fluorescence (signalnoise ratio of 3) was 0.1 AM. Pharmacokinetic Modelling: Modelling of pharmacokinetic data was done using ModelMaker version 4.0 (Cherwell Scientific Limited, The Magdalen Centre, Oxford Science Park, Oxford OX4 4GA, United Kingdom). The following phannacokinetic 30 parameters were used: Kab,, the first-order rate constant for absorption into the central compartment; Cl, total body clearance; Clew intercompartmental clearance; Vd, apparent volume of distribution of the central compartment; Vd2, apparent volume of distribution of the second compartment; Km,, Michaelis-Menten constant; Vmx, theoretical maximum rate; AUC, area under the concentration-time curve. For all 35 compounds it was assumed that all of the administered dose would reach the central compartment (i.e. 100% bioavailability). Differences between treatment groups were tested using a F-test comparing the entire curves and if this difference was significant (i.e. ps0.05) the estimates of each individual model parameter for both groups were tested using a 2-tailed t-test. The concentrations of free platinum and total platinum in plasma and tumour were flitted with a 1-compartment open model assuming linear pharmacokinetics. Plasma concentrations of DMXAA were fitted using a 1 compartment open model with saturable (Michaelis-Menten) elimination kinetics. 5 Results Activity of DMXAA + chemotherapy drugs against MDAH-Mca-4 tumour. The antitumour activity and host toxicity of DMXAA/cytotoxic drug combinations was 10 assessed by varying the dose of chemotherapeutic drug up to the toxicity limit, with co administration of a fixed DMXAA dose (80pimol/kg, ca. 80% of MTD), and evaluating subsequent tumour growth delay, as illustrated in Fig 1. Of the seven drugs investigated, four (doxorubicin, 5-fluorouracil, cyclophosphamide and cisplatin) showed appreciable activity against this tumour as indicated by dose-response relationships providing 15 significant slopes by linear regression, and highly significant growth delays of ca 10 days at their MTDs (which are recorded in Table 1). The other three compounds (carboplatin, etoposide and vincristine) were essentially inactive, with no individual treatment groups showing significant activity (although carboplatin gave weakly positive dose responses by linear regression). 20 DMXAA alone showed appreciable activity as a single agent at 80 pumollkg, providing transient regressions and mean tumour growth delays in the range 3.5 - 8.3 days (overall mean 6.6 * 0.6 days). Co-administration of DMXAA at this dose increased the host toxicity of doxorubicin and the MTD for the chemotherapy drug was lowered by one 25 dose level (1:33-fold) in the combination (Table 1). For the other compounds, co administration of DMXAA did not alter the formal MTD although some additional toxicity was evident as indicated by the greater body weight loss in the combination. In contrast to this small effect on host toxicity, co-administration of DMXAA produced a 30 large enhancement of tumour growth delay (Table 1). The contribution of DMXAA was assessed by determining the slope of each dose-response curve by linear regression, and the DMF for DMXAA was calculated as the ratio of slopes with and without DMXAA. By this criterion the magnitude of the synergy decreased in the order vincristine > (carboplatin, cisplatin, cyclophosphamide, etoposide, doxorubicin)> 5-fluorouracil. For 35 each of these compounds, except the later, the DMF was significantly greater than unity. As an alternative criterion, the maximum tumour growth delay achievable at the MTD of the combination again indicated synergy for all the compounds with growth delays in the range 15-30 davs.

Pharrnacokinetics of DMXAA and carboplatin: Studies were conducted to deduce whether a pharmacokinetic interaction underlies the synergistic therapeutic interaction between DMXAA and carboplatin. The study was conducted in C 3 H mice bearing 5 MDAH-Mca-4 tumours of the same size as in the therapeutic studies. Following administration of carboplatin (316 pmol/Kg, i.p.) clearance of Pt from plasma (measured, after deproteinization, by ICP-MS) was biphasic, and was unaffected by co administration of DMXAA (Fig 2). Total Pt in the tumour also showed biphasic kinetics which were unaffected by co-administration of DMXAA. The lack of effect of DMXAA 10 was confirmed by modelling the plasma with tumour pharmacokinetics as a 2 compartment open model with linear pharrnacokinetics, which provided the model parameters of Table 2 and indicated that there is no significant effect of DMIXAA. This study tests the hypothesis that antivascular agents such as DMXAA have the 15 potential to combine synergistically with conventional cytotoxic agents in the treatment of solid tumours. The early passage mammary tumour MDAH-Mca-4, used for this comparative study, was moderately refractory to most of the cytotoxic drugs tested (using single drug doses) but showed significant responses to doxorubicin, '5 fluorouracil, cyclophosphamide and cisplatin. DMXAA alone showed consistent activity 20 as a single agent, of similar magnitude to these four agents, but neither the chemotherapy drugs nor DMXAA provided prolonged regressions or cures. However, co-administration of DMXAA with the cytotoxic drugs caused a marked increase in response (Fig. 1). This interaction can be classified as synergistic (super 25 additive) on the basis of the increased slope of the cytotoxic drug dose response curve on addition of DMXAA. The interaction, quantified as the DMF (ratio of the linear regression slopes with and without DMIXAA), was significantly greater than unity for all drugs except 5-fluorouracil. It is noteworthy that the interaction with DMXAA resulted in substantial activity with several compounds which did not show any single agent 30 activity.

Table I Effect of DMXAA on host toxicity and antitumour activity of chemotherapeutic drugs against MDAH-Mca-4 tumours. Drugs were co-administered with DMIXAA by i.p. injection Chemotherapy DMXAA MTD % body weight Slope of DMF drug (Amol/kg) (pmol/kg) change at 4 days dose/response (days/ ymollkg) 5-fluorouracil - 1780 -8.5±0.8 0.0051±0.0001a 0.5±0.2 80 1780 -14.1±1.5 0.0027±0.001 Carboplatin - 316 -5.6±1.5 0.0094±0.0035 3.4±2.3 80 316 -8.5-t1.4 0.032±0.010 Cisplatin - 42.1 -9.5±1.4 0.19±0.06 1.8±1.2 80 42.1 -14.4±2.3 0.35±0.12 Cyclo- - 2.335 -0.8±1.3 0.0062±0.0001 2.7±0.3 phosphamide 80 1335 -9.2±1.4 0.0167k0.0013 Etoposide - ;25 -2.051.7 0.030-10.010 4.7±2,9 80 75(ld) -6.513.3 0.14±0.04 Vincristine - 1.0 -7.0±1.2 -0.0±1.3 >7c 80 1.0 -10.051.4 14.1*5.4 Doxorubicin - 23.7 -3.9t0.6 0.42±0.10 2.5±1.1 80 17.8 -5.5±1.2 1.04±0.23 "Standard error of the slope *Estimated using upper error estimate of the slope for the chemotherapy drug only. ? 1 Table 2. Pharmacokinetic parameters for Carboplatin (316 ymol/kg), and DMXAA (80 pmol/kg) in plasma and tumour of female C 3 H/HeN mice bearing MDAH-Mca-4 tumours (ca 0.7g). Numbers in parentheses are % CV. Parameter Plasma Tumour Carboplatin DMXAA Carboplatin Kas, (hf) 12.6 (266) 9.3 (39) 14.0 (286) Km - 220 (9.2) Vm (.M hr') - 63(6.1) Cl (1 hr-' kg') 1.9 (41) - 0.28 (31) Cl 1 er (1 hr- kg-') 0.41(99) - 2.3 (24) Va.1 kg- . 1.0(49) 0.17(1.2) 2.7(19) Vd (1 kg-1 (coadmin.) Vd2 (1 kg') 7.4(227) - 11.3 (1163) AUC (gM.hr)a 1125 3628' 4 16 b AUC (yM.hr)' 1181'C 3136* 4756 (coadmin.) 'AUC was calculated using the linear trapezoidal rule b0-24 hours e Coadministration with DMXAA d 0_8 hours * 0-3 0 hours Example 2 Materials and Methods Human tumour xenografts (PSN1) were established by subcutaneous injection of 5x 106 cells in the right flank of female MF1 nude mice. PSN1 is a pancreatic carcinoma. Tumours were allowed to grow to a diameter of 6-8 mm before treatment (a volume of approximately 0.15 cm 3 ). Treatment groups were randomised in such a way that the mean volume in each group on the day of treatment was not statistically different. Stock solutions of DMXAA and gemcitabine (Eli Lilly & Company, Indiana) were diluted in saline and injected intravenously into tumour bearing nude mice via a lateral tail vein. For combination therapy, the two drugs were given by sequential injections into the two lateral tail veins. Control mice were untreated.

Tumours were measured in three orthogonal dimensions two to three times per week and the volume expressed as the tumour volume relative to the volume on the day of treatment. Tumours were measured until they had at least tripled in volume. The end point was the tumour volume tripling time. Results The Tables below show, in the column headed "Median", the median tumour volume' tripling times for PSNI pancreatic tumour xenografts treated with gemcitabine with or without DMXAA. The column headed "Treated - Control" shows the treated minus control tripling time, i.e. the advantage of the drug or drug combination over untreated tumours. The gemcitabine data have been analysed as volume doubling times and tripling times. In both cases the combination of the two drugs is synergistic, the treated minus control for the combination being greater than the sum of each drug given alone.

PSN1 volume tripling times (days) Gemcitabine plus DMXAA Treatment Median Treated-Control Control 4.9 20 mg/kg DMXAA 6.0 1.1 240 mg/kg gemcitabine 13.9 9.0 240 mg/kg gemcitabine+ >17 >12 20 mg/kg DMXAA PSNI volume doubling times (days) Genzcitabine plus DMXAA Treatment Median Treated-Control Control 3.2 20 mg/kg DMXAA 3.6 0.4 240 mg/kg gemcitabine 9.7 7.5 240 mg/kg gemcitabine+ 15.4 12.2 20 mg/kg DMXAA I

Claims

1. A method for treating cancer, which comprises administering to a mammal, including a human, in need of such treatment an effective amount of DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and concomitantly or sequentially administering an effective amount of a compound selected from carboplatin and etoposide.

2. A method according to claim 1 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are administered in a potentiating ratio.

3. A method according to claim 1 or claim 2 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are administered concomitantly.

4. A method according to claim 1 or claim 2 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are administered sequentially.

5. Use of DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 for the manufacture of a medicament, for administration either concomitantly or sequentially with a compound selected from carboplatin and etoposide for the treatment of cancer.

6. Use of a compound selected from carboplatin and etoposide for the manufacture of a medicament, for administration either concomitantly or sequentially with DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 , for the treatment of cancer. 25

7. Use according to claim 5 or 6 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are present in a potentiating ratio.

8. Use according to any of claims 5 to 7 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are administered concomitantly.

9. Use according to any of claims 5 to 7 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are administered sequentially.

10.A combination of DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and a compound selected from carboplatin and etoposide, wherein the combination is adapted for administration to a patient to treat cancer.

11.A combination according to claim 10 wherein the DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are present in a potentiating ratio.

12.A pharmaceutical formulation comprising a combination of DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and a compound selected from carboplatin and etoposide in association with one or more pharmaceutically acceptable carriers therefor, wherein the combination is adapted for administration to a patient to treat cancer.

13.A pharmaceutical formulation according to claim 12 wherein the formulation is adapted for intravenous administration.

14.A pharmaceutical formulation according to claim 12 or 13 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of 26 from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are present in a potentiating ratio.

15.A process for the preparation of a pharmaceutical formulation which process comprises bringing into association a combination of DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and a compound selected from carboplatin and etoposide with one or more pharmaceutically acceptable carriers therefor.

16.A process according to claim 15 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are present in a potentiating ratio.

17.A kit comprising in association for separate administration the components DMXAA or a pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and a compound selected from carboplatin and etoposide, wherein the kit is adapted for administration to a patient to treat cancer.

18.A kit according to claim 17 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof in a dose of from about 1100 to 4900 mg/m 2 and the compound selected from carboplatin and etoposide are present in a potentiating ratio.

19.A method, use, combination, pharmaceutical formulation, process or kit according to any one of claims 1 to 18 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof is in a dose of from about 1200 to 4900 mg/m 2 .

20.A method, use, combination, pharmaceutical formulation, process or kit according to any one of claims 1 to 18 wherein the DMXAA or pharmaceutically acceptable salt or ester thereof is in a dose of from about 1200 to 3500 mg/m 2 .

21.A method, use, combination, pharmaceutical formulation, process or kit according to any one of the preceding claims wherein the mammal is a human. 27