the term “ et - 743 ” is also intended here to cover any pharmaceutically acceptable salt , ester , solvate , hydrate or any other compound which , upon administration to the recipient is capable of providing ( directly or indirectly ) the compound as described herein . however , it will be appreciated that non - pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts . the preparation of salts and prodrugs and derivatives can be carried out by methods known in the art . et - 743 is supplied and stored as a sterile lyophilized product , consisting of et 743 and excipient in a formulation adequate for therapeutic use . the combinations of the present invention comprise et - 743 and an antineoplastic platinum compound , preferably a coordination complex . preferred complexes include cisplatin , carboplatin , tetraplatin , ormiplatin , iproplatin , oxaliplatin and the like . preferably , the platinum coordination complex is cisplatin or carboplatin , more preferably cisplatin . the two drugs can be given simultaneously or one after the other in either sequence , preferably in a sequence . as it has been said , the invention provides a method for treatment a human cancer patient . preferably the patients are relapsing or refractory to previous chemotherapy . most preferably the patients are ovarian cancer , head and neck cancer , nscl carcinoma or melanoma patients . in a particularly preferred embodiment the patients are ovarian cancer patients and the previous therapy comprises treatment with platinum compounds . additionally , the present invention provides a method of treating cancer in humans , comprising a step of intravenously infusing a composition comprising et - 743 into a human having cancer at continuous dosage over a period up to 4 hours , followed or preceded by intravenously infusing a composition comprising a platinum antineoplastic compound into a human having cancer at a continuous dosage wherein the step of infusing is repeated weekly on a cyclic basis . the infusing step is typically repeated on a cyclic basis . the cyclic basis comprises two phases , the phase of weekly infusing and a phase of not infusing , referred to as a rest phase . in the rest phase the patients are allowed to recover . usually the cycle is worked out in weeks , and thus the cycle comprises one or more weeks of an infusion phase , and one or more weeks of a rest phase . the rest period can be longer or shorter than the infusion phase . the preferred duration of each cycle is of 2 to 4 weeks ; multiple cycles can be given as needed . cycles of 3 or 4 weeks with 1 or 2 weeks infusion is most preferred . when et - 743 is administered in combination with cisplatin , the dosage amount of et - 743 is preferably below 700 μg / m 2 / day on a day 1 & amp ; 8 every 3 or 4 weeks schedule , preferably from about 400 to about 650 μg / m 2 / day , more preferably from about 500 to about 650 μg / m 2 / day , even more preferably from about 550 to about 650 μg / m 2 / day . in this case the schedule most preferred is the administration of both compounds on a day 1 & amp ; 8 every 4 weeks . on the other hand , when et - 743 is administered in combination with carboplatin , the dosage of et - 743 is preferably below 1200 μg / m 2 / day on a day 1 every 3 weeks schedule , preferably between 650 and 1200 μg / m 2 / day , more preferably between 800 and 1000 μg / m 2 / day , even more preferably between 800 and 900 μg / m 2 / day . the dosage amount of cisplatin is the full dosage range used according to the type of schedule given . preferably it is about 30 - 60 mg / m 2 / day , more preferably about 40 - 50 mg / m 2 / day , even more preferably about 40 mg / m 2 / day . the dosage amount of carboplatin is the full dosage range used according to the type of schedule given . preferably it is about 200 - 400 mg / m 2 / day , more preferably about 250 - 300 mg / m 2 / day . in a particular embodiment , the infusion time of et - 743 is between 1 and 3 hours , preferably between 2 and 3 hours . especially preferred is a time of about 3 hours . the above schedules and dosages allow for an effective combination cancer therapy in humans , while avoiding toxicities . we have found that et - 743 in combination with cisplatin or carboplatin is effective in the treatment of several cancer types , including advanced or metastatic . preferably , the combination et - 743 with a platinum compound is used according to the above schedules and dosages for the treatment of sarcoma , osteosarcoma , ovarian cancer , breast cancer , melanoma , head and neck cancer , colorectal cancer , mesothelioma , renal cancer , endometrial cancer and lung cancer . depending on the type of tumour and the developmental stage of the disease , the treaments of the invention are useful in preventing the risk of developing tumours , in promoting tumour regression , in stopping tumour growth and / or in preventing metastasis . although guidance for the dosage is given above , the correct dosage of the compound will vary according to the particular formulation , the mode of application , and the particular situs , host and tumour being treated . other factors like age , body weight , sex , diet , time of administration , rate of excretion , condition of the host , drug combinations , reaction sensitivities and severity of the disease shall be taken into account . administration can be carried out continuously or periodically within the maximum tolerated dose . in order to evaluate the effects of the combination of et - 743 and cisplatin ( ddp ) in vivo we selected some xenografts relatively resistant to a single dose of ddp and moderately sensitive to a single dose of et - 743 . for the administration of the drugs appropriate vehicles were injected , using the same schedule and route of injection as the drug therapies . et - 743 and ddp were given 1 h apart in sequence or simultaneously . in xenografts transplanted s . c . tumor growth was monitored and tumor weight ( tw ) was determined by measuring the tumor diameters with a vernier caliper every 2 - 4 days and using the formula tw = d 2 × d / 2 ( where d and d represent the shortest and the longest diameter respectively ). the maximal single i . v . dose of ddp and et - 743 that caused no toxic death were respectively 12 mg / kg and 0 . 2 mg / kg . the same dose of each drug could be given when the two drugs were administered in combination with a tolerable toxicity , with a maximal weight loss ranging from 10 to 26 % in different experiments ( n = 14 ) with a median value of 15 %. surprisingly , the treatment with the combination caused only a slightly higher weight loss than the treatment with each drug alone . the toxicity did not appear different when the two drugs were given simultaneously or one given after the other with an interval of 1 h in either of the two sequences . the antitumor activity of the combination was greater than that of each drug alone in all models . in te - 671 rhabdomyosarcoma and sk - n - dz neuroblastoma all three combinations ( i . e . et - 743 given 1 h before ddp or at the same time or 1 h after ddp ) were compared and no significant differences in the antitumor activity were observed . also in h & amp ; n fadu , in nsclc lx - 1 , in melanoma h - 187 and in the ovarian skov where the two sequences were compared no consistent differences related to the sequence was found . collectively all the data indicate that the antitumor activity of the combination was greater than that of each drug alone and the sequence does not influence the treatment efficacy and toxicity in a consistent fashion . the observation that the toxicity of the combination appeared very modest prompted us to test the effect of the combination of et - 743 and ddp splitting the dose of both drugs in three administrations with an interval of 4 days . 1a9 ovarian carcinoma xenografts were relatively resistant to the two drugs used as monotherapy . in contrast ddp at 4 mg / kg ( q4 × 3 ) for a total dose of 12 mg / kg given simultaneously to et - 743 at 0 . 1 mg / kg ( q4 × 3 ) for a total dose of 0 . 3 mg / kg induced a significant twi of 73 %. again we observed no toxic deaths or severe toxicity with the combination ( mean body weight loss 16 %) compared to the single drugs ( 14 % and 12 % with et - 743 and ddp respectively ). thus the combination therapy allows high dosages and even in tumors in which the two drugs produced no significant activity given alone there was evidence of activity of the combination of each of the drugs . the combination is particularly successful in overcoming resistance in ovarian carcinoma xenograft . in ovarian carcinoma patients the tumor spreads into the peritoneal cavity . therefore to mimic clinical disease we have selected a human ovarian xenograft , hoc 8 , which was transplanted intraperitoneally from ascites and disseminated in the peritoneal cavity . this tumor is partially sensitive to ddp ( ils = 139 %) and insensitive to et - 743 ( ils = 21 % and 23 % with 0 . 05 % and 0 . 15 mg / kg , q4 × 3 ). when the two drugs were combined the effect was much greater than that of each drug given as single agent with a dramatic increase in survival . both the low ( ils = 258 % versus vehicle ) and the high ( ils = 322 % versus vehicle ) dose of et - 743 combined with ddp increased the survival time of mice bearing hoc8 , that was significantly improved compared to ddp as monotherapy ( ils = 49 % and 76 % versus ddp with low and high dose of et - 743 respectively ). three animals were still alive after 12 months , two of them belonging to the group receiving the high et - 743 dose . they were sacrificed and a detailed macroscopic and microscopic pathological evaluation was performed . the mouse belonging to the group receiving the low et - 743 dose was apparently cured as the microscopic analysis of liver , splen , pancreas , bone marrow , diagram , ovary uterus omentum and several lymphnodes were negative . instead both the other long term surviving mice showed a residual tumor at the level of omentum and in one of them a single metastasis in the uterus was found , while in the other organs no metastases were detected . this example shows the potential of the combination in ovarian cancer , even if there is metastasis . we designed a multicenter dose finding trial , on a day 1 & amp ; 8 every 3 weeks schedule , with escalating doses of et given as a 3 - hr infusion with steroids and antiemetic prophylaxis , followed 30 minutes later by 1 hr infusion cisplatin at a fixed dose of 40 mg / m 2 , with 2 l ns hydration . 36 patients were entered ( 15 with ovarian cancer , 6 with uterus cancer , 14 with soft tissue sarcoma , 1 with other tumor type ). prior treatments of the patients were the following : prior treatments no of pts with prior chemo for 35 advanced disease n ° of prior chemo regimens median 1 for advanced disease range 0 - 2 n ° of pts w / prior platinum 22 ( 61 %) responders 9 resistant 13 n ° of pts w / prior carboplatin 16 responders 6 resistant 10 et - 743 doses levels were 300 , 400 , 500 , 600 and 700 μg / m 2 / day ; 3 - 6 were treated per dose level according to toxicity . et - 743 escalation was uneventful until 500 μg / m 2 ; at 600 μg / m 2 patients were accrued in 2 separate risk cohort according to prior chemotherapy extent : low risk 1 regimen ( lr ); high risk ≧ 2 regimens ( hr ). hematological toxicity et - 743 d 1 & amp ; 8 enrolled treated pts with toxicity at cy 1 μg / m 2 pts pts g3 g4 300 3 3 none none 400 3 4 * # none none 500 8 7 ° 2 anc none 600 15 15 ° 8 anc none 700 7 7 2 anc 1 hb 2 anc 1 plt * 7 days duration of g4 neutropenia → dlt ° 1 pt at 500 and 1 pt at 600 failed to recover from neutropenia by & gt ; d35 → dlt # 1 pt enrolled at 500 received 400 at cycle 1 non - hematological toxicity by dose & amp ; schedule et - 743 n ° dose of d 1 & amp ; 8 treated asthenia n & amp ; v ast / alt μg / m 2 pts g1 g2 g1 g2 g3 ≦ g2 g3 300 3 1 1 — — — 1 — 400 4 1 1 — 1 — 2 1 500 7 5 1 4 1 — 6 — 600 15 6 — 12 1 — 8 4 700 7 4 1 2 3 1 5 2 other non - hematological toxicity by dose & amp ; schedule et - 743 dose d 1 & amp ; 8 μg / m 2 treated pts g1 g2 300 3 400 4 * 1 anorexia 1 phlebitis 500 7 * 600 15 3 snp 1 abdo cramps 1 abdo pain 700 7 1 anorexia 500 : 1 / 7 treated pts failed to recover at day 35 600 : 3 / 15 treated pts 1 failure to recover hematological toxicity at day 35 1 alt grade 3 not recovered to b / l 1 failure to retreat on day 8 bilirubin grade 1 , alt grade 3 700 : 2 / 7 treated pts anc grade 4 lasting & gt ; 7 days ( 1 pt also had concomitant gr 4 thrombocytopenia and failure to recover hematological toxicity at day 35 ) et - 743 dose d 1 & amp ; 8 sites of ttp tumor prior tx μg / m 2 disease best resp mos ovary carboplatin + taxol ne 600 pelvis , liver pr 6 + paclitaxel pd sts gyn adriamycin / ifosfamide ad 700 lung pr 3 + ovary carboplatin + taxol nc 400 lung pr 6 topotecan pd ovary carboplatin + taxol pr 600 liver abdomen unc pr too early sts - epirubicin + ad 500 abdomen radiological 5 + gyn ifosfamide pr non gemcitabine pd measurable lesions uterus carboplatin ne 400 bone , pelvis radiological 1 colon taxol + epirubicin + cr lung pr non cisplatin measurable lesions ( pr : partial response ; pd : progressive disease ; cr : complete response ; nc : no change ; ad : adjuvant ; ne : non - evaluable ; ttp : time to progression ) in this population the mtd is 700 μg / m 2 in previously treated patients day 1 & amp ; 8 every 4 weeks recommended dose ( rd ) in previously treated patients is 500 μg / m 2 day 1 & amp ; 8 every 4 weeks the dlt is myleosuppression , particulatly neutropenia at doses ≧ 600 μg / m 2 day 1 & amp ; 8 every 3 weeks delayed recovery from neutropenia was observed in the majority of patients . main non - hematological toxicities are dose - dependent nausea and vomits ( n & amp ; v ), asthenia and liver toxicity ( always reversible and mild up to 600 μg / m 2 / day ). main non - hematological toxicities were dose - dependent n & amp ; v and asthenia optimum interval of re - treatment is day 28 we designed a multicenter dose finding trial , on a day 1 every 3 weeks schedule , with carboplatin given at a fixed dose of 300 mg / m 2 as a 1 hour infusion followed by escalating doses of et given as a 3 hours infusion with steroids and antiemetic prophylaxis . 11 patients were entered ( 6 with ovarian cancer , 1 with lung cancer , 4 with soft tissue sarcoma ). prior treatments of the patients were the following : n of patients 11 type of tumor non small cell lung cancer ( nsclc ) 1 epithelial ovarian carcinoma 6 soft tissue sarcoma 4 previous treatment one line chemotherapy 6 two or more lines 5 previous treatment with carboplatin 6 ( all ovarian carcinoma ) et - 743 doses levels were 500 , 650 and 800 μg / m 2 / day ; 3 - 6 pts were treated per dose level according to toxicity . the maximum tolerated dose ( mtd ) was defined as the highest dose level tested of the combination at which at least 2 patients experience a dlt in cycle 1 . if one patient encountered drug - induced dlt during either cycle 1 or 2 , up to a maximum of 6 patients could be treated at that level . if dlt was not observed in the additional patients , new patients could be treated at the next higher dose level . the cycle 1 haematological toxicities for platelets and absolute neutrophil count ( anc ) are reported in the following table : no of neutropenia thrombopenia level patients g0 g1 g2 g3 g0 g1 g2 g3 500 3 2 0 1 0 0 2 1 0 650 3 0 1 2 0 0 3 0 0 800 5 2 1 1 1 1 1 1 2 two patients developed dlt during the first course with grade 3 thrombocytopenia in dose level 3 . both patients had ovarian carcinoma pretreated with carboplatin . the following table shows haematological toxicities for platelets and anc for all the courses administered , as well as the number of cycles without haematological recovery by day 21 and 28 . no of courses no of courses without without haematological haematological et - 743 dose no of recovery recovery at administration courses at day + 21 day + 28 400 * 4 1 / 4 0 / 3 500 13 ( 1 ) 6 / 13 5 / 13 650 4 ( 2 ) 4 / 4 0 / 3 800 9 3 / 6 0 / 5 * all after dose reduction ; ( 1 ) 8 after dose reduction ; ( 2 ) 1 after dose reduction and the number of patients with dose delayed ( and reduced ) at cycle 2 with the reason for this delay is reported in the following table for each dose level : no of patients receiving dose delayed ( and level cy 2 reduced ) at cycle 2 reason 500 3 / 3 1 pt anc g2 650 3 / 3 3 pts thrombopenia g1 anc g2 anc g2 800 4 / 5 * 2 pts anc g3 anc g3 * one patient too early as can be inferred from the cycle 1 data from 11 patients treated : in this population the mtd is 800 μg / m 2 of et - 743 with carboplatin at a fixed target ( 300 mg / m 2 ) dlts consist of thrombocytopenia grade 3 in this population at the second dose level , 100 % of patients had a dose delay with dose reduction at the second cycle because of haematological toxicity at the third dose level , 50 % of patients had a dose delay with dose reduction at the second cycle because of haematological toxicity given this haematological safety profile , with long lasting , though moderate neutropenia that prevent from achieving an adequate dose intensity of et - 743 , and the 2 dlts consisting of thrombopenia grade 3 in two patients with ovarian carcinoma previously pretreated with carboplatin , it can be inferred the following schedule : in patients previously treated with carboplatin : administration of carboplatin at a fixed target ( 250 mg / m 2 ) over 1 h infusion followed by et - 743 over 3 hours iv infusion on day 1 every 3 weeks . in patients not previously treated with carboplatin : administration of carboplatin at a fixed target ( 300 mg / m 2 ) over 1 h infusion followed by et - 743 over 3 hours iv infusion on day 1 every 3 weeks .
et - 743 can be used to mitigate resistance to and potentiate the cytotoxic effects of a platinum coordination complex anti - neoplastic agent in a human cancer patient .